Purpose of This PDQ Summary
Introduction

General Information Family History as a Risk Factor for Breast Cancer Family History as a Risk Factor for Ovarian Cancer Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition Difficulties in Identifying a Family History of Breast and Ovarian Cancer Risk Other Risk Factors for Breast Cancer         Age         Reproductive and menstrual history         Oral contraceptives         Radiation exposure         Alcohol intake         Benign breast disease and mammographic density         Other factors Other Risk Factors for Ovarian Cancer         Age         Reproductive history         Surgical history         Oral contraceptives Models for Prediction of Breast Cancer Risk

Major Genes

Introduction BRCA1 BRCA2 BRCA1 and BRCA2 Function Mutations in BRCA1 and BRCA2         Variants of uncertain significance Prevalence and Founder Effects Penetrance of Mutations Population Estimates of the Likelihood of Having a BRCA1 or BRCA2 Mutation Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation Role of BRCA1 and BRCA2 in Sporadic Cancer Genotype-Phenotype Correlations Pathology/Prognosis of Breast Cancer         BRCA1         BRCA2 Pathology/Prognosis of Ovarian Cancer         Pathology         Prognosis Other Rare Breast and Ovarian Cancer Associated Syndromes         Li-Fraumeni syndrome         Cowden syndrome         Peutz-Jeghers syndrome

Low Penetrance Predisposition to Breast and Ovarian Cancer

Background Confirmed Candidate Breast Cancer Susceptibility Genes         CHEK2         ATM         BRIP1         PALB2         CASP8 and TGFB1 Genome-Wide Searches

Interventions

Breast Cancer         Screening         Risk modification         Breast conservation therapy for BRCA1/2 mutation carriers         Role of BRCA1 and BRCA2 in response to chemotherapy Ovarian Cancer         Screening         Risk Modification

Psychosocial Issues in Inherited Breast Cancer Syndromes

Introduction Interest in and Uptake of Genetic Testing What People Bring to Genetic Testing: Impact of Risk Perception, Health Beliefs, and Personality Characteristics Genetic Counseling for Hereditary Predisposition to Breast Cancer Emotional Outcomes of Individuals Family Effects         Family communication about genetic testing and hereditary risk         Family functioning         Partners of high-risk women         At-risk males         Children         Reproductive issues Cultural/Community Effects Ethical Concerns Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Ovarian Cancer         Decision aids for persons considering risk management options for hereditary breast and ovarian cancer         Uptake of cancer risk management options         Cancer screening and risk-reducing behaviors Psychosocial Outcome Studies         Risk-reducing mastectomy         Risk-reducing salpingo-oophorectomy Interventions: Psychological Behavioral Outcomes

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Changes to This Summary (12/23/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of breast and ovarian cancer. This summary is reviewed regularly and updated as necessary by the Cancer Genetics Editorial Board ¹.

The following information is included in this summary:

• Family history and other risk factors for breast and ovarian cancer.
• Models for predicting breast cancer risk.
• Major genes associated with breast and ovarian cancer risk.
• Screening and risk modification for hereditary breast and ovarian cancer.
• Psychosocial issues associated with hereditary breast and ovarian cancer and genetic testing.

The summary also contains level-of-evidence designations. These designations are intended to help readers assess the strength of the evidence in relation to specific studies or strategies. A description of how level-of-evidence designations are made is described in detail in the PDQ summary Cancer Genetics Overview ².

This summary is intended to provide clinicians a framework for discussing genetic testing, screening, and risk modification options with individuals at risk for hereditary breast and ovarian cancer, as well as for making referrals to cancer risk counseling services. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

Introduction

General Information

 [Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms ³. When a linked term is clicked, the definition will appear in a separate window.]

Among women, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and is the second leading cause of cancer deaths after lung cancer. In 2008, an estimated 182,460 new cases will be diagnosed, and 40,480 deaths from breast cancer will occur.[1] The incidence of breast cancer, particularly for estrogen receptor-positive cancers occurring after age 50 years, has declined at a faster rate since 2003; this may be temporally related to a decrease in hormone replacement therapy following early reports from the Women’s Health Initiative.[2] Ovarian cancer is the eighth most common cancer, with an estimated 21,650 new cases in 2008, but is the fifth most deadly, with an estimated 15,520 deaths in 2008.[1] (Refer to the PDQ summary on Breast Cancer Treatment ⁴ and Ovarian Epithelial Cancer Treatment ⁵ for more information on breast cancer and ovarian cancer rates, diagnosis, and management.)

A possible genetic contribution to both breast and ovarian cancer risk is indicated by the increased incidence of these cancers among women with a family history (see the Family History as a Risk Factor for Breast Cancer ⁶ and the Family History as a Risk Factor for Ovarian Cancer ⁷ sections below), and by the observation of rare families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with autosomal dominant inheritance of cancer susceptibility. Formal studies of families (linkage analysis) have subsequently proven the existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the identification of several highly penetrant genes as the cause of inherited cancer risk in many cancer-prone families. (Refer to the PDQ summary Cancer Genetics Overview ² for more information on linkage analysis.) Mutations in these genes are rare in the general population and are estimated to account for no more than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other genetic factors contribute to the etiology of some of these cancers.

In cross-sectional studies of adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first-degree relative or a second-degree relative with breast cancer.[3-6] The risk conferred by a family history of breast cancer has been assessed in both case-control and cohort studies, using volunteer and population-based samples, with generally consistent results.[7] In a pooled analysis of 38 studies, the relative risk (RR) of breast cancer conferred by a first-degree relative with breast cancer was 2.1 (95% confidence interval [CI], 2.0-2.2).[7] Risk increases with the number of affected relatives and age at diagnosis.[4,5,7] Refer to the Penetrance of Mutations ⁸ section for a discussion of familial risk for women from families with BRCA1/2 mutations who themselves test negative for the family mutation.

Although reproductive, demographic, and lifestyle factors affect risk of ovarian cancer, the single greatest ovarian cancer risk factor is a family history of the disease. A large meta-analysis of 15 published studies estimated an odds ratio (OR) of 3.1 for the risk of ovarian cancer associated with at least one first-degree relative with ovarian cancer.[8]

Autosomal dominant inheritance of breast/ovarian cancer is characterized by transmission of cancer predisposition from generation to generation, through either the mother’s or the father’s side of the family, with the following characteristics:

• Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression.



• Both males and females can inherit and transmit an autosomal dominant cancer predisposition. A male who inherits a cancer predisposition and shows no evidence of it can still pass the altered gene on to his sons and daughters.

Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are BRCA1 or BRCA2 mutation syndromes. Breast cancer is also a common feature of Li-Fraumeni syndrome ⁹ due to TP53 mutations; of Cowden syndrome ¹⁰ due to PTEN mutations; and with mutations in CHEK2 ¹¹ .[9] Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia (AT) gene ¹² and Peutz-Jeghers syndrome ¹³. Ovarian cancer has also been associated with Lynch syndrome ¹⁴, basal cell nevus (Gorlin) syndrome (OMIM ¹⁵), and multiple endocrine neoplasia type 1 (MEN1) (OMIM ¹⁶).[9] Mutations in each of these genes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.

The family characteristics that suggest hereditary breast and ovarian cancer predisposition include the following:

• Cancers typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk).



• Two or more primary cancers in a single individual. These could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancer of different types (e.g., breast and ovarian cancer in the same individual).



• Cases of male breast cancer.



• Possible increased risk of other selected cancers and benign features for males and females. (Refer to the Major Genes ¹⁷ section of this summary for more information.)

There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers with those occurring in noncarriers. Breast cancers occurring in BRCA1 mutation carriers are more likely to be estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2/neu receptor-negative and have a basal phenotype. BRCA1-associated ovarian cancers are unlikely to be of mucinous or borderline histopathology. [Refer to the Pathology/Prognosis of Breast Cancer ¹⁸ and Pathology/Prognosis of Ovarian Cancer ¹⁹ sections for more information.]

When using family history to assess risk, the accuracy and completeness of family history data must be taken into account. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than on the maternal side and thus may be more difficult to obtain. When comparing self-reported information with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.[10,11]

Other risk factors for breast cancer include age, reproductive and menstrual history, hormone therapy, radiation exposure, mammographic breast density, alcohol intake, physical activity, anthropometric variables, and a history of benign breast disease. (Refer to the PDQ summary on Prevention of Breast Cancer ²⁰ for more information.) These factors are considered in more detail in numerous reviews,[12,13] including among BRCA1/BRCA2 mutation carriers.[14] Brief summaries are given below, highlighting, where possible, the effect of these risk factors in women who are genetically susceptible to breast cancer. (More information about their effects in BRCA1/BRCA2 mutation carriers can be found in the section on Interventions ²¹ later in this document.)

Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years.[15] In women with a genetic susceptibility, breast cancer, and to a lesser degree, ovarian cancer, tends to occur at an earlier age than in sporadic cases.

Breast cancer risk increases with early menarche and late menopause, and is reduced by early first full-term pregnancy. Although results have been complex and may be gene dependent, several studies have suggested that the influence of these factors on risk in BRCA1/BRCA2 mutation carriers appear to be similar to noncarriers.[14,16]

Oral contraceptives may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with oral contraceptive use did not vary according to a family history of breast cancer.[17]

Oral contraceptives are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers, but studies of their effect on breast cancer risk have been inconsistent.[18-20]

Data exist from both observational and randomized clinical trials regarding the association between postmenopausal hormone replacement therapy (HRT) and breast cancer. A meta-analysis of data from 51 observational studies indicated a RR of breast cancer of 1.35 (95% CI, 1.21–1.49) for women who had used HRT for 5 or more years after menopause.[21] The Women's Health Initiative ²² (WHI), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined HRT or placebo, was halted early because health risks exceeded benefits.[22,23] Adverse outcomes prompting closure included significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR = 1.24; 95% CI, 1.02–1.5, P <.001) and increased risks of coronary heart disease, stroke, and pulmonary embolism. Similar findings were seen in the estrogen-progestin arm of the prospective observational Million Women’s Study in the United Kingdom.[24] The risk of breast cancer was not elevated, however, in women randomly assigned to estrogen-only versus placebo in the WHI study (RR = 0.77; 95% CI, 0.59–1.01). Eligibility for the estrogen-only arm of this study required hysterectomy, and 40% of these patients also had undergone oophorectomy, which potentially could have impacted breast cancer risk.[25]

The association between HRT and breast cancer risk among women with a family history of breast cancer has not been consistent; some studies suggest risk is particularly elevated among women with a family history, while others have not found evidence for an interaction between these factors.[26-30,21] The increased risk of breast cancer associated with HRT use in the large meta-analysis did not differ significantly between subjects with and without a family history. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations.[23] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.[21,31] The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 mutations has been studied only in the context of bilateral risk-reducing oophorectomy, in which short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk.[32]

Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure. The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear.

Preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of BRCA1 and BRCA2 mutations,[33-36] and in association with germline ATM and TP53 mutations.[37,38] Since BRCA1/2 mutation carriers are heterozygotes, however, radiation sensitivity might occur only after a somatic mutation has damaged the normal copy of the gene.

The possibility that genetic susceptibility to breast cancer occurs via a mechanism of radiation sensitivity raises questions about radiation exposure. It is possible that diagnostic radiation exposure, including mammography, poses more risk in genetically susceptible women than in women of average risk. Therapeutic radiation could also pose carcinogenic risk. A cohort study of BRCA1 and BRCA2 mutation carriers treated with breast-conserving therapy, however, showed no evidence of increased radiation sensitivity or sequelae in the breast, lung, or bone marrow of mutation carriers.[39] Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Studies examining the impact of mammography and chest x-ray exposure in BRCA1 and BRCA2 mutation carriers have had conflicting results.[40,41] (Refer to text on Radiation ²³ in the Interventions ²¹ section of this summary for more information.)

The risk of breast cancer increases by approximately 10% for each 10g of daily alcohol intake (approximately 1 drink or less) in the general population.[42,43] One study of BRCA1/BRCA2 mutation carriers found no increased risk associated with alcohol consumption.[44]

Weight gain and being overweight are commonly recognized risk factors for breast cancer. In general, overweight women are most commonly observed to be at increased risk of postmenopausal breast cancer and at reduced risk of premenopausal breast cancer. Sedentary lifestyle may also be a risk factor.[45] These factors have not been systematically evaluated in women with a positive family history of breast cancer or in carriers of cancer-predisposing mutations, but one study suggested a reduced risk of cancer associated with exercise among BRCA1 and BRCA2 mutation carriers.[46]

Benign breast disease (BBD) is a risk factor for breast cancer, independent of the effects of other major risk factors for breast cancer (age, age at menarche, age at first live birth, and family history of breast cancer).[47] There may also be an association between benign breast disease and family history of breast cancer.[48]

An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram,[47,49,50] and breast density may have a genetic component in its etiology.[51-53]

Other risk factors, including those that are only weakly associated with breast cancer and those that have been inconsistently associated with the disease in epidemiologic studies (e.g., cigarette smoking), may be important in subgroups of women defined according to genotype. For example, some studies have suggested that certain N-acetyl transferase alleles may influence female smokers’ risk of developing breast cancer.[54] One study [55] found a reduced risk of breast cancer among BRCA1/2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.[56]

Factors that increase risk for ovarian cancer include increasing age and nulliparity, while those that decrease risk include surgical history and oral contraceptives.[57,58] (Refer to the PDQ summary on Prevention of Ovarian Cancer ²⁴ for more information.) Relatively few studies have addressed the effect of these risk factors in women who are genetically susceptible to ovarian cancer. (Refer to the Risk Modification ²⁵ section for more information.)

Ovarian cancer incidence rises in a linear fashion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote; even in hereditary cancer families.[59]

Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2 mutation carriers.[60] Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid.[57,61] Evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-progesterone schedules.[62-65]

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk,[57,66,67] including in BRCA1/BRCA2 mutation carriers.[68] Ovarian cancer risk is reduced more than 90% in women with documented BRCA1 or BRCA2 mutations who chose risk-reducing salpingo-oophorectomy (RRSO). In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer.[69,70] For further information on these studies refer to the Risk-Reducing Salpingo-Oophorectomy ²⁶ section of this summary.

Use of oral contraceptives for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population.[57,58] A majority of, but not all, studies also support oral contraceptives being protective among BRCA1/ BRCA2 mutation carriers.[60,71-74]

Models to predict an individual’s lifetime risk for developing breast cancer are available. In addition, models exist to predict an individual’s likelihood of having a BRCA1 or BRCA2 mutation. For further information on these models refer to the Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation ²⁷ section of this summary. Not all models can be appropriately applied for all patients. Each model is appropriate only when the patient’s characteristics and family history are similar to the study population on which the model was based. The table, Characteristics of the Gail and Claus Models ²⁸, summarizes the salient aspects of the risk assessment models and is designed to aid in choosing the one that best applies to a particular individual.

Two models for predicting breast cancer risk, the Claus model [75,76] and the Gail model,[77] are widely used in research studies and clinical counseling. Both have limitations, and the risk estimates derived from the two models may differ for an individual patient. These models, however, represent the best methods currently available for individual risk assessment.

It is important to note that these models will significantly underestimate breast cancer risk for women in families with hereditary breast cancer susceptibility syndromes. In those cases, Mendelian risks would apply. A 3-generation cancer family history is taken before applying any model. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling ²⁹ for more information on Taking a Family History ³⁰.) Generally, the Claus or Gail models should not be the sole model used for families with one of the following characteristics:

• Three individuals with breast or ovarian cancer (especially when one or more breast cancers are diagnosed before age 50 years).
• A woman who has both breast and ovarian cancer.
• Ashkenazi Jewish ancestry with at least one case of breast or ovarian cancer (as these families are more likely to have a hereditary cancer susceptibility syndrome).

The Gail model has been found to be reasonably accurate at predicting breast cancer risk in large groups of white women who undergo annual screening mammography.[81-85] While the model is reliable in predicting the number of breast cancer cases expected in a group of women from the same age-risk strata, it is less reliable in predicting risk for individual patients. Risk can be overestimated in:

• Nonadherent women (i.e., does not adhere to screening recommendations).[81,82]
• Women in the highest risk strata.[84]

Risk could be underestimated in the lowest risk strata.[84] Earlier studies [81,82] suggested risk was overpredicted in younger women and underpredicted in older women. More recent studies [83,84] using the modified Gail model (which is currently used) found it performed well in all age groups. Further studies are needed to establish the validity of the Gail model in minority populations.[85]

A study of 491 women aged 18 to 74 years with a family history of breast cancer compared the most recent Gail model to the Claus model in predicting breast cancer risk.[86] The two models were positively correlated (r = .55). The Gail model estimates were higher than the Claus model estimates for most participants. Presentation and discussion of both the Gail and Claus models risk estimates may be useful in the counseling setting.

The Gail model is the basis for the Breast Cancer Risk Assessment Tool ³², a computer program that is available from the NCI by calling the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237, or TTY at 1-800-332-8615). This version of the Gail Model estimates only the risk of invasive breast cancer.

The Tyrer-Cuzick model incorporates both genetic and non-genetic factors.[87] A three generation pedigree is used to estimate the likelihood that an individual carries either a BRCA1/BRCA2 mutation or a hypothetical low penetrance gene. In addition, the model incorporates personal risk factors such as parity, body mass index, height, and age at menarche, menopause and first live birth. Both genetic and nongenetic factors are combined to develop a risk estimate. Although powerful, the model at the current time is less accessible to primary care providers than the Gail and Claus models. The BOADICEA model examines family history to estimate breast cancer risk, and also incorporates both BRCA1/2 and non-BRCA1/2 genetic risk factors.[88]

Other models incorporating breast density have been developed, but are not ready for clinical use.[89,90] In the future, models may be developed or refined to include such factors as breast density and other biomarkers.

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41. Andrieu N, Easton DF, Chang-Claude J, et al.: Effect of chest X-rays on the risk of breast cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators' Group. J Clin Oncol 24 (21): 3361-6, 2006.  [PUBMED Abstract]
    
    
42. Smith-Warner SA, Spiegelman D, Yaun SS, et al.: Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 279 (7): 535-40, 1998.  [PUBMED Abstract]
    
    
43. Hamajima N, Hirose K, Tajima K, et al.: Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 87 (11): 1234-45, 2002.  [PUBMED Abstract]
    
    
44. McGuire V, John EM, Felberg A, et al.: No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages <50 years. Cancer Epidemiol Biomarkers Prev 15 (8): 1565-7, 2006.  [PUBMED Abstract]
    
    
45. McTiernan A: Behavioral risk factors in breast cancer: can risk be modified? Oncologist 8 (4): 326-34, 2003.  [PUBMED Abstract]
    
    
46. King MC, Marks JH, Mandell JB, et al.: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302 (5645): 643-6, 2003.  [PUBMED Abstract]
    
    
47. Chen J, Pee D, Ayyagari R, et al.: Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density. J Natl Cancer Inst 98 (17): 1215-26, 2006.  [PUBMED Abstract]
    
    
48. Dupont WD, Page DL, Parl FF, et al.: Long-term risk of breast cancer in women with fibroadenoma. N Engl J Med 331 (1): 10-5, 1994.  [PUBMED Abstract]
    
    
49. Boyd NF, Byng JW, Jong RA, et al.: Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 87 (9): 670-5, 1995.  [PUBMED Abstract]
    
    
50. Byrne C, Schairer C, Wolfe J, et al.: Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst 87 (21): 1622-9, 1995.  [PUBMED Abstract]
    
    
51. Pankow JS, Vachon CM, Kuni CC, et al.: Genetic analysis of mammographic breast density in adult women: evidence of a gene effect. J Natl Cancer Inst 89 (8): 549-56, 1997.  [PUBMED Abstract]
    
    
52. Boyd NF, Lockwood GA, Martin LJ, et al.: Mammographic densities and risk of breast cancer among subjects with a family history of this disease. J Natl Cancer Inst 91 (16): 1404-8, 1999.  [PUBMED Abstract]
    
    
53. Vachon CM, King RA, Atwood LD, et al.: Preliminary sibpair linkage analysis of percent mammographic density. J Natl Cancer Inst 91 (20): 1778-9, 1999.  [PUBMED Abstract]
    
    
54. Ambrosone CB, Freudenheim JL, Graham S, et al.: Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA 276 (18): 1494-501, 1996.  [PUBMED Abstract]
    
    
55. Brunet JS, Ghadirian P, Rebbeck TR, et al.: Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes. J Natl Cancer Inst 90 (10): 761-6, 1998.  [PUBMED Abstract]
    
    
56. Ghadirian P, Lubinski J, Lynch H, et al.: Smoking and the risk of breast cancer among carriers of BRCA mutations. Int J Cancer 110 (3): 413-6, 2004.  [PUBMED Abstract]
    
    
57. Whittemore AS, Harris R, Itnyre J: Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 136 (10): 1184-203, 1992.  [PUBMED Abstract]
    
    
58. John EM, Whittemore AS, Harris R, et al.: Characteristics relating to ovarian cancer risk: collaborative analysis of seven U.S. case-control studies. Epithelial ovarian cancer in black women. Collaborative Ovarian Cancer Group. J Natl Cancer Inst 85 (2): 142-7, 1993.  [PUBMED Abstract]
    
    
59. Amos CI, Struewing JP: Genetic epidemiology of epithelial ovarian cancer. Cancer 71 (2 Suppl): 566-72, 1993.  [PUBMED Abstract]
    
    
60. Modan B, Hartge P, Hirsh-Yechezkel G, et al.: Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 345 (4): 235-40, 2001.  [PUBMED Abstract]
    
    
61. Brinton LA, Lamb EJ, Moghissi KS, et al.: Ovarian cancer risk after the use of ovulation-stimulating drugs. Obstet Gynecol 103 (6): 1194-203, 2004.  [PUBMED Abstract]
    
    
62. Rodriguez C, Patel AV, Calle EE, et al.: Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 285 (11): 1460-5, 2001.  [PUBMED Abstract]
    
    
63. Riman T, Dickman PW, Nilsson S, et al.: Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. J Natl Cancer Inst 94 (7): 497-504, 2002.  [PUBMED Abstract]
    
    
64. Lacey JV Jr, Mink PJ, Lubin JH, et al.: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 288 (3): 334-41, 2002.  [PUBMED Abstract]
    
    
65. Anderson GL, Judd HL, Kaunitz AM, et al.: Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 290 (13): 1739-48, 2003.  [PUBMED Abstract]
    
    
66. Tortolero-Luna G, Mitchell MF: The epidemiology of ovarian cancer. J Cell Biochem Suppl 23: 200-7, 1995.  [PUBMED Abstract]
    
    
67. Hankinson SE, Hunter DJ, Colditz GA, et al.: Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA 270 (23): 2813-8, 1993.  [PUBMED Abstract]
    
    
68. Rutter JL, Wacholder S, Chetrit A, et al.: Gynecologic surgeries and risk of ovarian cancer in women with BRCA1 and BRCA2 Ashkenazi founder mutations: an Israeli population-based case-control study. J Natl Cancer Inst 95 (14): 1072-8, 2003.  [PUBMED Abstract]
    
    
69. Kauff ND, Satagopan JM, Robson ME, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346 (21): 1609-15, 2002.  [PUBMED Abstract]
    
    
70. Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002.  [PUBMED Abstract]
    
    
71. Narod SA, Risch H, Moslehi R, et al.: Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 339 (7): 424-8, 1998.  [PUBMED Abstract]
    
    
72. Narod SA, Sun P, Ghadirian P, et al.: Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet 357 (9267): 1467-70, 2001.  [PUBMED Abstract]
    
    
73. Whittemore AS, Balise RR, Pharoah PD, et al.: Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer 91 (11): 1911-5, 2004.  [PUBMED Abstract]
    
    
74. McGuire V, Felberg A, Mills M, et al.: Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations. Am J Epidemiol 160 (7): 613-8, 2004.  [PUBMED Abstract]
    
    
75. Claus EB, Risch N, Thompson WD: Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73 (3): 643-51, 1994.  [PUBMED Abstract]
    
    
76. Claus EB, Risch N, Thompson WD: The calculation of breast cancer risk for women with a first degree family history of ovarian cancer. Breast Cancer Res Treat 28 (2): 115-20, 1993.  [PUBMED Abstract]
    
    
77. Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81 (24): 1879-86, 1989.  [PUBMED Abstract]
    
    
78. Domchek SM, Eisen A, Calzone K, et al.: Application of breast cancer risk prediction models in clinical practice. J Clin Oncol 21 (4): 593-601, 2003.  [PUBMED Abstract]
    
    
79. Rubinstein WS, O'Neill SM, Peters JA, et al.: Mathematical modeling for breast cancer risk assessment. State of the art and role in medicine. Oncology (Huntingt) 16 (8): 1082-94; discussion 1094, 1097-9, 2002.  [PUBMED Abstract]
    
    
80. Rhodes DJ: Identifying and counseling women at increased risk for breast cancer. Mayo Clin Proc 77 (4): 355-60; quiz 360-1, 2002.  [PUBMED Abstract]
    
    
81. Bondy ML, Lustbader ED, Halabi S, et al.: Validation of a breast cancer risk assessment model in women with a positive family history. J Natl Cancer Inst 86 (8): 620-5, 1994.  [PUBMED Abstract]
    
    
82. Spiegelman D, Colditz GA, Hunter D, et al.: Validation of the Gail et al. model for predicting individual breast cancer risk. J Natl Cancer Inst 86 (8): 600-7, 1994.  [PUBMED Abstract]
    
    
83. Rockhill B, Spiegelman D, Byrne C, et al.: Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J Natl Cancer Inst 93 (5): 358-66, 2001.  [PUBMED Abstract]
    
    
84. Costantino JP, Gail MH, Pee D, et al.: Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst 91 (18): 1541-8, 1999.  [PUBMED Abstract]
    
    
85. Bondy ML, Newman LA: Breast cancer risk assessment models: applicability to African-American women. Cancer 97 (1 Suppl): 230-5, 2003.  [PUBMED Abstract]
    
    
86. McTiernan A, Kuniyuki A, Yasui Y, et al.: Comparisons of two breast cancer risk estimates in women with a family history of breast cancer. Cancer Epidemiol Biomarkers Prev 10 (4): 333-8, 2001.  [PUBMED Abstract]
    
    
87. Tyrer J, Duffy SW, Cuzick J: A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 23 (7): 1111-30, 2004.  [PUBMED Abstract]
    
    
88. Antoniou AC, Pharoah PP, Smith P, et al.: The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer 91 (8): 1580-90, 2004.  [PUBMED Abstract]
    
    
89. Barlow WE, White E, Ballard-Barbash R, et al.: Prospective breast cancer risk prediction model for women undergoing screening mammography. J Natl Cancer Inst 98 (17): 1204-14, 2006.  [PUBMED Abstract]
    
    
90. Tice JA, Cummings SR, Ziv E, et al.: Mammographic breast density and the Gail model for breast cancer risk prediction in a screening population. Breast Cancer Res Treat 94 (2): 115-22, 2005.  [PUBMED Abstract]
    
    

Major Genes

Introduction

Epidemiologic studies have clearly established the role of family history as an important risk factor for both breast and ovarian cancer. After gender and age, a positive family history is the strongest known predictive risk factor for breast cancer. In most cases an extensive family history (more than four relatives in the same biologic line affected) is not present. However, it has long been recognized that in some families, there is hereditary breast cancer which is characterized by an early age of onset, bilaterality, and the presence of breast cancer in multiple generations through either the maternal or paternal lines in an apparent autosomal dominant pattern of transmission and familial association with tumors of other organs, particularly the ovary and prostate gland.[1,2] We now know that some of these “cancer families” can be explained by specific mutations in single cancer susceptibility genes. The isolation of several of these genes, which when mutated are associated with a significantly increased risk of breast/ovarian cancer, makes it possible to identify individuals at risk. Although such cancer susceptibility genes are very important, only 5% to10% of individuals who develop breast cancer are known to carry highly penetrant gene mutations.

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families.[3] The search for genes associated with hereditary susceptibility to breast cancer has been facilitated by the study of large kindreds with multiple affected individuals, and has led to the identification of several susceptibility genes, including BRCA1, BRCA2, TP53, PTEN/MMAC1, and STK11. Other genes, such as the mismatch repair genes MLH1 and MSH2, have been associated with an increased risk of ovarian cancer, but have not been consistently associated with breast cancer.

In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12-21.[4] The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed.[5] The BRCA1 gene (OMIM ³⁴) was subsequently identified by positional cloning methods, and has been found to contain 24 exons that encode a protein of 1,863 amino acids. Mutations in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance section ⁸ for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with mutations in BRCA1;[6-9] however, male breast cancer, pancreatic cancer, and prostate cancer are more strongly associated with mutations in BRCA2.

A second breast cancer susceptibility gene, BRCA2, was localized to the long arm of chromosome 13 through linkage studies of 15 families with multiple cases of breast cancer that were not linked to BRCA1. Mutations in BRCA2 (OMIM ³⁵) are associated with multiple cases of breast cancer in families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, melanoma, and pancreatic cancer.[8-13] (Refer to the Penetrance section ⁸ for more information.) BRCA2 is also a large gene with 27 exons that encode a protein of 3,418 amino acids.[14] While not homologous genes, both BRCA1 and BRCA2 have an unusually large exon 11 and translational start sites in exon 2. Like BRCA1, BRCA2 appears to behave like a tumor suppressor gene. In tumors associated with both BRCA1 and BRCA2 mutations there is often loss of the wild-type (unmutated) allele.

Mutations in BRCA1 and BRCA2 appear to be responsible for disease in 45% of families with multiple cases of breast cancer only, and in up to 90% of families with both breast and ovarian cancer.[15]

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function, although some missense mutations cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on one copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. In most breast and ovarian cancers that have been studied from mutation carriers, however, the normal allele is deleted, resulting in loss of all function. This finding strongly suggests that BRCA1 and BRCA2 are in the class of tumor suppressor genes, i.e., genes whose loss of function can result in neoplastic growth.[16,17]

In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in a myriad of functions within cells including homologous DNA repair, genomic stability, transcriptional regulation and cell cycle control.[18,19]

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.[20] Approximately one in 400 to 800 individuals in the general population may carry a pathogenic mutation in BRCA1 and BRCA2.[21,22] The mutations that have been associated with increased risk of cancer result in missing or nonfunctional proteins, supporting the hypothesis that BRCA1 and BRCA2 are tumor suppressor genes. While a small number of these mutations have been found repeatedly in unrelated families, most have not been reported in more than a few families.

Mutation screening methods vary in their sensitivity. Methods widely used in research laboratories, such as single-stranded conformational polymorphism (SSCP) analysis and conformation-sensitive gel electrophoresis (CSGE), miss nearly a third of the mutations that are detected by DNA sequencing.[23] In addition, large genomic rearrangements are missed by most of the techniques, including direct DNA sequencing. Such rearrangements are believed to be responsible for 10% to 15% of BRCA1 inactivating mutations.[24-26]

Germline deleterious mutations in the BRCA1/BRCA2 genes are associated with an approximately 60% lifetime risk of breast cancer and a 15% to 40% lifetime risk of ovarian cancer. There are no definitive functional tests for BRCA1 or BRCA2; therefore, classifying deleterious nucleotide changes to predict their functional impact relies on imperfect data. The majority of accepted deleterious mutations result in protein truncation and/or loss of important functional domains. However, 10% to 15% of all individuals undergoing genetic testing with full sequencing of BRCA1 and BRCA2 will not have a clearly deleterious mutation detected but will have a variant of uncertain (or unknown) significance (VUS). Variants of uncertain significance may cause substantial problems in counseling, particularly in terms of cancer risk estimates and risk management. Clinical management of such patients needs to be highly individualized and must take into consideration factors such as the patient’s personal and family cancer history, as well as the likelihood that the VUS is significant.

African Americans appear to have a higher rate of VUS.[27] A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratory over a 3-year period.[28] Among subjects who had no clearly deleterious mutation, 13% had VUS defined as “ missense mutations and mutations that occur in analyzed intronic regions whose clinical significance has not yet been determined, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins.” The classification of a sequence variant as a VUS is a moving target. An additional 6.8% of individuals had sequence alterations that were once considered VUS, but were reclassified, usually as a polymorphism though occasionally as a deleterious mutation. As additional information is accumulated, VUS are reclassified and such information may impact the continuing care of affected individuals.

A number of methods for discriminating deleterious from neutral VUS exist and others are in development.[29,30] Interpretation of VUS is greatly aided by efforts to track VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. Variant tracking is accomplished by testing parents and all affected family members (these costs are generally covered by Myriad Genetic Laboratory). The Myriad Genetic Laboratory typically provides additional information when a VUS is reported, including available data on cosegregation and whether the VUS has been seen in conjunction with a known deleterious mutation. In general, a VUS observed in subjects who also have a deleterious mutation, especially when it occurs with different mutations, is not felt to be in itself deleterious, although there are rare exceptions. Models based on sequence conservation and the biochemical properties of amino acid changes exist [29,31-34] and are an adjunct to the clinical information. An attempt at further refining such models has also incorporated information on pathologic characteristics of BRCA1- and BRCA2- related tumors (such as the fact that BRCA1-related breast cancers are usually estrogen receptor negative).[35] Functional studies that measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 have been employed as well.[36,37] When attempting to interpret a VUS, all available information should be examined.

Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1[38,39] and BRCA2[39] mutations in various ethnic groups. The prevalence of mutations by ethnic group was as follows:

BRCA1

• 3.5% Hispanic,
• 1.3% to 1.4% African American,
• 0.5% Asian American,
• 2.2% to 2.9% non-Ashkenazi Caucasian, and
• 8.3 % to 10.2% Ashkenazi Jewish.[38,39]

BRCA2

• 2.6% African American and
• 2.1% Caucasian.[39]

Among cases identified from the Cancer Surveillance System of Western Washington, the frequency of BRCA1 mutations was highest in cases diagnosed before age 30 years (23% carriers, 95% confidence interval [CI], 5.0-53.8), and in those with more than three relatives with breast cancer (20%, 95% CI, 6%-44%). A family history of ovarian cancer in a first-degree relative was also associated with an increased prevalence of BRCA1 mutations (25%, 95% CI, 3.2%-65.1%).[40] In a second study, 263 women with familial breast cancer were analyzed.[41] BRCA1 mutations were found in 7% (95% CI, 0.3%-39%) of families with site-specific breast cancer, 18% of families with bilateral breast cancer, and 40% (95% CI, 1.7%-80.0%) of families with both breast and ovarian cancer. In a population-based series of incident cases of ovarian cancer in Canada, the overall prevalence of BRCA1/2 mutations was 11.7%; among women with a first-degree relative with breast or ovarian cancer, it was 19%. Of note, 6.5% of women with no affected first-degree relative carried a mutation, suggesting a higher overall prevalence of mutations in women with a diagnosis of ovarian cancer than in those with breast cancer.[39,42,43]

In some cases the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a founder effect. This occurs when a contemporary population can be traced back to a small, isolated group of founders. Most notably, two specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews (those tracing their roots to Central and Eastern Europe). Carrier frequencies for these mutations have been determined in the general Jewish population: 0.9% (95% CI, 0.7%-1.1%) for the 185delAG mutation, 0.3% (95% CI, 0.2%-0.4%) for the 5382insC mutation, and 1.3% (95% CI, 1.0%-1.5%) for the BRCA2 6174delT mutation.[44-47] Altogether, the frequency of these three mutations approximates 1 in 40 among Ashkenazi Jews; they account for 25% of early-onset breast cancer, and up to 90% of families with multiple cases of both breast and ovarian cancer in this population.[48,49] Additional founder mutations have been described in multiple non–Ashkenazi Jewish populations including the Netherlands (BRCA1 2804delAA and several large deletion mutations), Iceland (BRCA2, 999del5), Portugal (BRCA2, exon 3 Alu insertion),[50] and Sweden (BRCA1, 3171ins5).[51-54]

The presence of these founder mutations has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without pitfalls. It is estimated that up to 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.[28]

The proportion of individuals carrying a mutation who will manifest the disease is referred to as penetrance. For adult-onset diseases, penetrance is usually dependent upon the individual carrier's age and sex. For example, the penetrance for breast cancer in female BRCA1/2 mutation carriers is often quoted by age 50 years (generally premenopausal) and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual mutation carrier's risk of cancer involves some level of imprecision.

Estimates of penetrance by age 70 years for BRCA1 and BRCA2 mutations show a large range, from 14% to 87% for breast cancer and 10% to 68% for ovarian cancer.[12,15,42,43,46,55-70] Initial penetrance estimates for BRCA1 and BRCA2 mutations were derived from multiple-case families from the Breast Cancer Linkage Consortium (BCLC), families studied to localize and clone the genes.[15,55,56] For breast cancer, the estimates ranged from 50% to 73% by age 50 years and 65% to 87% by age 70 years for BRCA1, and 59% and 82% at ages 50 years and 70 years, respectively, for BRCA2. For ovarian cancer, the estimates were as high as 29% by age 50 years and 63% by age 70 years.[55,56] For many patients currently seeking genetic testing for BRCA1 and BRCA2, the family history will not be as strong as this study by the BCLC (e.g., more than four affected relatives in the same biologic lineage) and therefore, these estimates may not apply.

There are now several lines of evidence indicating that primary fallopian tube cancer should be considered a part of the BRCA1/2 phenotype. Epidemiologic evidence points to an increased risk of early-onset breast and/or ovarian cancer among first-degree relatives of women with fallopian tube cancers.[71] Histopathologic examination of fallopian tubes removed prophylactically from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that are accompanied by changes in cell-cycle and apoptosis-related proteins, suggesting a premalignant phenotype.[72,73] A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%.[74] While the true incidence of fallopian tube tumors in BRCA carriers is not known, there is a growing consensus that risk-reducing oophorectomy should be accompanied by removal of the fallopian tubes.

In addition to the estimates from multiple-case families and patients from high-risk genetics clinics,[12,15,55,56,58,63,69,75] at least 13 studies have estimated penetrance by studying the families of mutation carriers who were not specifically recruited and studied because of a positive family history.[42,43,46,59-68] Often these studies have concentrated on founder populations in which testing of larger, more population-based subjects are possible owing to a reduced number of mutations that require testing,[46,57,59,61,64,65,67] compared with complete sequencing of the two genes required in most populations. The first study of a community-based series was carried out in the Washington, D.C., area. Blood samples and family medical histories were collected from more than 5,000 Ashkenazi Jewish individuals.[46] Study participants were tested for three founder mutations: 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. The prevalence of breast cancer in the relatives of carriers was compared with that reported by mutation-negative individuals. The risk of breast cancer in carriers of these mutations was estimated to be 56% (95% CI, 40%-73%) by age 70 years. Ovarian cancer risk was estimated to be 16% (95% CI, 6%-28%). These values were lower than most prior risk estimates. Men carrying BRCA1 and BRCA2 mutations were at modestly increased risk of prostate cancer, reaching 16% by age 70 years. Subsequent studies have provided additional support for an approximately twofold increased risk of prostate cancer in BRCA2 mutation carriers.[61,76,77].

Many subsequent studies, whether in founder or predominantly outbred populations, have estimated breast cancer risks by age 70 years of approximately 60% or lower and ovarian cancer risks of approximately 40% or lower, though often with large confidence limits because, even in studies of founder populations, the number of identified mutation carriers is relatively small. A meta-analysis of ten studies estimates risks among BRCA1 and BRCA2 mutation carriers of 57% and 49% for breast cancer and 40% and 18% for ovarian cancer.[78] Most studies have done molecular testing on the proband only and have done no,[42,46,57,59,61-65,67,68] or limited,[60,69] testing among relatives. Instead, the mutation status of relatives is modeled on simple Mendelian principles that on average, one-half of first-degree relatives of mutation carriers will themselves be carriers. Such modeling may lead to imprecision in the penetrance estimates; by chance, more than or less than half the relatives of some families will be carriers. In the New York Breast Cancer Study of 104 mutation-positive Ashkenazi Jews with breast cancer, penetrance estimates were based only on relatives whose mutation status was known.[43] These estimates were 69% and 74% for breast cancer by age 70 years for BRCA1 and BRCA2 mutation carriers, respectively, and 46% and 12% for ovarian cancer for BRCA1 and BRCA2, respectively.

The largest study to date to estimate penetrance involved a pooled analysis of 22 studies of over 8,000 breast and ovarian cancer cases unselected for family history.[68] Subjects were from 12 different countries and had a broad spectrum of mutations. Using modified segregation analysis on the families of the nearly 500 cases found to carry a BRCA1/2 mutation, the cumulative risk of breast cancer by age 70 years was 65% (95% CI, 44%-78%) for BRCA1 and 45% (95% CI, 31%-56%) for BRCA2. The penetrances for cancer are somewhat higher for BRCA1 mutation carriers, especially for ovarian cancer and early-onset breast cancer. These estimates are average risks of cancer among mutation carriers, assuming there is at least one family member with breast cancer or ovarian cancer (since all probands had these cancers), the situation likely to be encountered in clinical genetics situations. A case series of 491 women with stage I or stage II breast cancer and a known or suspected deleterious BRCA1/2 mutation was reviewed for incidence of ovarian cancer. The actuarial risk of developing ovarian cancer at 10 years following diagnosis of breast cancer was 12.7% for BRCA1 mutation carriers and 6.8% for BRCA2 mutation carriers. Eight of 83 cancer deaths (9.6%) in this series were because of ovarian cancer. Systemic treatment for the primary breast cancer did not alter these findings.[79] Several studies have suggested that cancer risks in BRCA1/BRCA2 mutation carriers are affected by the type of cancer of the index case. Relatives of breast cancer index cases were more likely to develop breast cancer, and relatives of ovarian cancer index cases were more likely to develop ovarian cancer.[68,80-82] Risk of breast cancer appears increased in more recent birth cohorts.[43,80]

The continuing uncertainty as to the exact penetrance for breast and ovarian cancer among BRCA1/2 mutation carriers may be due to several factors, including differences owing to study design, allelic heterogeneity (differing risks for different mutations within either of the genes), and to modifying genetic and/or environmental factors, such as differing rates of oophorectomy.[43,68,83-87] A large population-based family study found that the risk of breast cancer for relatives of probands with deleterious BRCA1/2 mutations demonstrated significant interfamilial variation, even when controlling for age at diagnosis of the proband and the presence of contralateral breast cancer.[88] While the average breast and ovarian cancer penetrances may not be as high as initially estimated, they are substantial, both in relative and absolute terms, and additional studies will be required to further characterize potential modifying factors in order to arrive at more precise individual risk projections. Precise penetrance estimates for less common cancers, such as pancreatic cancer, are lacking.

The tables titled “ Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Breast Cancer ³⁶ ” and “ Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Ovarian Cancer ³⁷ ” review the incidence of breast and ovarian cancer among BRCA1 and BRCA2 mutation carriers.

There is conflicting evidence as to the residual familial risk among women who themselves test negative for the BRCA1/BRCA2 mutation segregating in their family. Based on prospective evaluation of 353 women who tested negative for the BRCA1 mutation segregating in the family, five incident breast cancers occurred during more than 6,000 person-years of observation, for a lifetime risk of 6.8%.[86] A report that the risk may be as high as fivefold in women who have tested negative for the BRCA1 or BRCA2 mutation in the family[89] was followed by numerous letters suggesting that ascertainment biases account for much of this observed excess risk.[90-93] Two additional analyses have suggested an approximately twofold excess risk.[94,95] All studies have been based on small observed numbers of cases and most have involved retrospective analyses. Additional prospective analyses will be required to determine whether women from BRCA1/BRCA2 families who test negative in families are at the general population risk for breast cancer.[96] No information has been published regarding ovarian cancer risk in this setting.

Statistics regarding the percentage of women found to be BRCA mutation carriers among samples of women and men with a variety of personal cancer histories regardless of family history are provided below. These data can help determine who might best benefit from a referral for cancer genetic counseling and consideration of genetic testing, but cannot replace a personalized risk assessment, which might indicate a higher or lower mutation likelihood based on family history characteristics.

Among non-Ashkenazi Jewish individuals (likelihood of having any BRCA mutation):

• General non-Ashkenazi Jewish population: 1 in 500 (.2%).[97]
• Women with breast cancer (all ages): 1 in 50 (2%).[98]
• Women with breast cancer (younger than 40 years): 1 in 11 (9%).[99]
• Men with breast cancer (regardless of age): 1 in 20 (5%).[100]
• Women with ovarian cancer (all ages): 1 in 10 (10%).[42,101]

Among Ashkenazi Jewish individuals (likelihood of having one of three founder mutations):

• General Ashkenazi Jewish population: 1 in 40 (2.5%).[46]
• Women with breast cancer (all ages): 1 in 10 (10%).[43]
• Women with breast cancer (younger than 40 years): 1 in 3 (30%-35%).[43,102,103]
• Men with breast cancer (regardless of age): 1 in 5 (19%).[104]
• Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%-41%).[64,74,105]

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer. These studies have used populations derived from clinical referral centers.[41,106-111] Personal characteristics associated with an increased likelihood of a BRCA1 or BRCA2 mutation include the following:

• Breast cancer diagnosed at an early age.
• Bilateral breast cancer.
• A history of both breast and ovarian cancer.
• The presence of breast cancer in one or more male family members.[41,106-108,111]

Family history characteristics associated with an increased likelihood of carrying a BRCA1 or BRCA2 mutation include the following:

• Multiple cases of breast cancer in the family.
• Both breast and ovarian cancer in the family.
• One or more family members with two primary cancers.
• Ashkenazi Jewish background.[41,106-108]

Many models have been developed to predict the probability of identifying germline BRCA1/2 mutations in individuals or families. These models include those using logistic regression,[28,41,106,108,111-113], “genetic” models using Bayesian analysis (BRCAPRO and BOADICEA),[111,114] and empiric observations,[39,42,44,45,61,62] including the Myriad prevalence tables ⁴⁰. Two of the earliest models predicted only for BRCA1 mutations and are not clinically useful at this time.[41,106] More recently, using complex segregation analysis, a polygenetic model (BOADICEA) examining both breast cancer risk and the probability of having a BRCA1 or BRCA2 mutation has been published.[114] Prediction models have been shown to increase the discrimination power of even experienced providers in identifying patients in whom BRCA1/2 mutations are likely to be found.[115,116] Many of the models have been compared with each other in different studies and currently there is no one model that is clearly superior to others.[117-119] Most models do not include other cancers seen in the BRCA1 and BRCA2 spectrum such as pancreatic cancer and prostate cancer. Interventions that decrease the likelihood that an individual will develop cancer (such as oophorectomy and mastectomy) may influence the ability to predict BRCA1 and BRCA2 mutation status.[120]

Genetic testing for BRCA1 and BRCA2 has been available to the public since 1996. As more individuals have undergone testing, risk assessment models have improved. This in turn gives providers better data to estimate an individual patient’s risk of carrying a mutation. One study has shown that the risk models are sensitive to the amount of family history data available and perform less well with limited family information.[122] There remains an art to risk assessment in practitioners’ selection of the best model to fit their individual patient’s circumstances and consideration of factors that might limit the ability to provide an accurate risk assessment (i.e., small family size or paucity of women).

Given that germline mutations in BRCA1 or BRCA2 lead to a very high probability of developing breast and/or ovarian cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. Although somatic mutations in BRCA1 and BRCA2 are not common in sporadic breast and ovarian cancer tumors,[123-126] there is increasing evidence that downregulation of BRCA1 protein expression may play a role in these tumor types. Compared with normal breast epithelium, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter.[127-129] Similar findings have not been reported for BRCA2 mutations, although the BRCA2 locus on chromosome 13q is the target of frequent loss of heterozygosity (LOH) in breast cancer.[130,131] Approximately 10% to 15% of sporadic breast cancers appear to have BRCA1 promoter hypermethylation, and even more have downregulation of BRCA1 by other mechanisms. Basal-type breast cancers (estrogen receptor negative, progesterone receptor negative, HER2 negative, cytokeratin 5/6 positive), more commonly have BRCA1 dysregulation than other tumor types.[132-134] Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer,[135] and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease.[136,137] Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.[138]

Some genotype-phenotype correlations have been identified in both BRCA1 and BRCA2 mutation families. In 25 families with BRCA2 mutations, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629.[11,58] This is the region of the gene containing the BRC repeats, which have been shown to specifically interact with RAD51. A study of 164 families with BRCA2 mutations collected by the Breast Cancer Linkage Consortium confirmed the initial finding. Mutations within the ovarian cancer cluster region were associated with an increased risk of ovarian cancer and a decreased risk of breast cancer in comparison to families with mutations on either side of this region.[66] In addition, a study of 356 families with protein-truncating BRCA1 mutations collected by the Breast Cancer Linkage Consortium reported breast cancer risk to be lower with mutations in the central region (nucleotides 2,401-4,190) compared with surrounding regions. Ovarian cancer risk was significantly reduced with mutations 3’ to nucleotide 4,191.[139] These observations have generally been confirmed in subsequent studies.[68,69,140] Studies in Ashkenazim, in whom substantial numbers of families with the same mutation can be studied, have also found higher rates of ovarian cancer in carriers of the BRCA1:185delAG mutation, in the 5' end of BRCA1, compared with carriers of the BRCA1:5382insC mutation in the 3' end of the gene.[67,141] The risk of breast cancer, particularly bilateral breast cancer, and the occurrence of both breast and ovarian cancer in the same individual, however, appear to be higher in BRCA1:5382insC mutation carriers compared with carriers of BRCA1:185delAG and BRCA2:6174delT mutations. Ovarian cancer risk is considerably higher in BRCA1 mutation carriers, and it is uncommon before age 45 in BRCA2:6174delT mutation carriers.[67,141] None of the studies have had sufficient numbers of mutation-positive individuals to make definitive conclusions, and the findings are probably not sufficiently established to use in individual risk assessment and management.

The identification of a histologic pattern characterizing hereditary breast cancer has been elusive, though historically, medullary, tubular, and lobular histologies have been associated with familial breast cancer.[142] Other studies have noted an excess of medullary histology in multicase families.[143,144] Since the identification of the BRCA1 and BRCA2 genes, several studies have evaluated the distinct pathologic patterns seen in known hereditary breast cancers. Medullary histology was significantly more common (19% vs. 0%) in a series of BRCA1-associated breast cancer compared with sporadic cases in a study from France,[145] in carriers from the Breast Cancer Linkage Consortium,[146], in a Swedish population-based study of breast cancer cases from high-risk families,[147] and among women with early-onset breast cancer in a population-based study,[148] suggesting that medullary histology itself may be an indication for BRCA1 testing.

The prevalence of high-risk, preinvasive lesions in BRCA mutation carriers is controversial. The Breast Cancer Linkage Consortium reported a relative lack of an in situ component in BRCA1-associated breast cancers.[146] Data from the Mayo Clinic cohort of women undergoing mastectomy found a significantly lower prevalence of hyperplastic lesions among BRCA1/2 mutation carriers, but no difference in the prevalence of in situ lesions.[149] In contrast, one study from the United States and one study from the Netherlands reported a high rate of hyperplastic lesions in BRCA carriers.[150,151] A population-based case-control study of ductal carcinoma in situ (DCIS) patients found the prevalence of BRCA mutations to be similar, as previously reported in studies of invasive breast cancer patients.[152] A study of 199 Ashkenazi Jewish women with DCIS and 2,248 women with invasive cancers compared BRCA1/2 mutation prevalence, stratified by whether they were referred to a high-risk clinic or were unselected. The prevalence of founder mutations in DCIS cases was similar to that of invasive cases among referred patients, but was about one-third lower among unselected subjects.[153] A retrospective cohort study found that DCIS was equally common among patients with BRCA1/2 mutations as among women with a familial risk who were not mutation carriers.[154] Overall evidence suggests DCIS is part of the BRCA1/BRCA2 spectrum, however, the prevalence of mutations in DCIS patients, unselected for family history, is less than 5%.[152,153]

The development of gene-expression technology has created the potential to increase the specificity of the classification of breast cancer at the molecular level. Global gene expression profiles of tumors with BRCA1 and BRCA2 mutations and sporadic tumors differed significantly from each other in one small series.[155] Using comparative genomic hybridization (CGH), investigators from the Netherlands were able to develop a profile of distinct somatic genetic alterations, which can identify BRCA1-associated tumors with an accuracy of 84%.[156] Another study using tissue microarray technology to compare BRCA1, BRCA2, and sporadic tumors found that BRCA1 tumors were more likely to be BCL2-negative and to express high levels of P-cadherin.[157]

One potentially unifying hypothesis is that many BRCA1 tumors are derived from the basal epithelial layer of cells of the normal mammary gland, which account for 3% to 15% of unselected invasive ductal cancers. These tumors characteristically exhibit higher-grade features, areas of necrosis, and frequent TP53 mutations.[158] They are typically estrogen receptor–negative, are HER2-negative, and they stain positive for cytokeratin 5/6, 14, or 17, which are markers of basal epithelium.[159-161] A study of 76 estrogen receptor–negative breast cancers found that those occurring in BRCA1 mutation carriers were significantly more likely (88% vs. 45% in BRCA1-negative subjects) to have a basal epithelial phenotype as determined by cytokeratin 5/6 expression.[158] Two additional studies of invasive breast cancers occurring in BRCA1 mutation carriers not selected for estrogen receptor status found that 78% of 27 tumors [161] and 61% of 182 tumors [162] were positive for basal epithelial markers. Among a set of breast tumors studied by gene expression array to determine molecular phenotype, all tumors with BRCA1 alterations fell within the basal tumor subtype.[163] If, in fact, the basal epithelial cells of the breast represent the breast stem cells, the suggested regulatory role for wild-type BRCA1, it may partly explain the aggressive phenotype of BRCA1-associated breast cancer when BRCA1 function is damaged.[164] Further studies are needed to fully appreciate the significance of this subtype of breast cancer within the hereditary syndromes.

The phenotypic expression of BRCA1-related breast cancer indicates distinctive prognostic features. A large study of 1,555 women with invasive breast cancer in ten North American centers failed to find the expected correlation of tumor size with lymph node status among carriers of a deleterious BRCA1 mutation, suggesting that these tumors are characterized by an accelerated growth rate.[165] Investigators from the Mayo Clinic reached similar conclusions based on the risk-reducing mastectomy cohort, in whom both in situ and invasive lesions from BRCA1/2 carriers had higher-grade tumors and higher proliferation indices.[149] A Norwegian study reported that breast cancers occurring in BRCA1 mutation carriers were more likely to be invasive, high grade, and estrogen receptor negative.[166] A case-control study among women of Jewish descent also found that BRCA1-associated tumors were significantly more likely to be grade III and estrogen receptor negative.[167] Analysis of tumors from a North American study indicated that the estrogen receptor–negative status of the BRCA1 tumors is an intrinsic feature and not simply a correlate of younger age or higher grade.[168] The Breast Cancer Linkage Consortium compared the histopathologic features of breast cancer in women with BRCA1 mutations to a control group and found an excess of high-grade tumors, high mitotic rates, high proliferative fractions, and increased aneuploidy.[146] They also found an increased frequency of high-intensity immunostaining for p53 in tumors from BRCA1 mutation carriers.[169] A population-based study confirmed the excess of high-grade tumors with high mitotic rates in BRCA1 carriers, but did not find a relative absence of in situ cancers in this group.[148] In a separate study of tumors from women with one of the three Ashkenazi founder mutations, immunohistochemical analysis demonstrated a relatively low rate of HER2/neu positivity and no differences in p53, epidermal growth factor receptor, cathepsin D, bcl-2, or cyclin D staining compared to a control group.[170] A population-based study of incident cases of breast cancer among women in Israel failed to find a difference in prognosis for carriers of BRCA founder mutations compared with noncarriers.[171] Similar findings were seen in a European cohort with no differences in disease-free survival in BRCA1- or BRCA2-associated breast cancers.[172]

In accordance with the poor prognostic features noted histologically for BRCA1-related breast cancer, two European studies reported survival rates that were similar to or worse than sporadic cases, with a significantly increased risk of contralateral breast cancer.[173-175] A case series report found higher rates of both ipsilateral and contralateral breast cancers among BRCA1/2 mutation carriers than among mutation-negative cases.[176] Higher rates of ipsilateral and contralateral breast cancers were also seen in the cohort of Ashkenazi women with founder mutations.[177] That study failed, however, to show a significantly different event-free or overall survival at 5 years compared with nonmutation carriers. A retrospective cohort study of 496 Ashkenazi breast cancer patients from two centers compared the relative survival among the 56 BRCA1/2 mutation carriers followed for a median 116 months. BRCA1 mutations were independently associated with worse disease-specific survival; there was no effect for BRCA2. The poorer prognosis associated with BRCA1 was not observed in women who received chemotherapy.[178]

In summary, there is a growing consensus that BRCA1-related breast cancer presents with clinical, histopathologic, and molecular features, suggesting a more aggressive phenotype. Most clinical outcome studies are consistent with there being a somewhat worse prognosis, especially among women who do not receive chemotherapy. There is no consensus about whether these differences should alter the approach to treating women with BRCA1-related breast tumors.

The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well-characterized than that of BRCA1. A report from Iceland, where a BRCA2 founder mutation (999del5) accounts for nearly all hereditary breast cancer, found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors compared with sporadic controls.[179] A large case series from North America and Europe described a greater proportion of BRCA2 associated tumors with continuous pushing margins, fewer tubules and lower mitotic counts.[180] Other reports suggest that BRCA2 related tumors include an excess of lobular and tubulolobular histology.[148,181]

Studies of the prognosis of BRCA2 associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer.[182]

Ovarian cancer arising in women with BRCA1 and BRCA2 mutations is more likely to be invasive serous adenocarcinoma, and less likely to be mucinous or borderline.[183-185] Fallopian tube cancer and papillary serous carcinoma of the peritoneum are also part of the spectrum of BRCA-associated disease.[74,186] Approximately 60% of sporadic ovarian cancers have serous histology, but a survey of all published data shows that 94% of BRCA1 related ovarian cancers have this type of histology.[127] Serous carcinoma was also found to be the predominant histologic subtype of intraperitoneal carcinoma among BRCA1/2 carriers in a Dutch case-control study.[187] Both primary ovarian carcinomas and primary peritoneal carcinomas have a higher incidence of somatic TP53 mutations and exhibit relatively aggressive features, including higher grade and p53 overexpression.[183,188] The histopathologic profile of BRCA2 related ovarian cancer has not been well defined. The finding of differential expression of genes in BRCA1, BRCA2, and sporadic ovarian cancer, using DNA microarray technology suggests distinct molecular pathways of carcinogenesis, which may ultimately distinguish them histologically.[189]

Despite generally poor prognostic factors, several studies have found an improved survival among ovarian cancer patients with BRCA mutations.[189-194] A nationwide, population-based case-control study in Israel found 3-year survival rates to be significantly better for ovarian cancer patients with BRCA founder mutations, compared with controls.[191] In a retrospective, U.S., hospital-based study (n = 71), BRCA Ashkenazi heterozygotes had a better response to platinum-based chemotherapy, as measured by response to primary therapy, disease-free survival, and overall survival, compared with sporadic cases.[192] A similar study in Japanese patients also found a survival advantage in stage III BRCA1-associated ovarian cancers treated with cisplatin regimens compared with nonhereditary cancers treated in a similar manner.[193] In a U.S. study of Ashkenazi Jewish women with ovarian cancer, those with BRCA mutations had a longer median time to recurrence and an overall improved survival as compared with Ashkenazi Jewish women with ovarian cancer who did not have a BRCA mutation as well as two large groups of advanced stage ovarian cancer clinical trial patients.[194] A U.S. population–based study showed improvement in overall survival in BRCA2, but not in BRCA1, carriers.[195]

In contrast, several studies have not found improved overall survival among ovarian cancer patients with BRCA mutations.[174,196-198] A population-based study from Sweden noted an initial survival advantage in BRCA1-associated cases, but this advantage did not persist after 3 or 4 years.[174] Similarly, a case-control study from the Netherlands found an improvement in short-term (up to 5 years) survival among women with familial ovarian cancer compared to sporadic controls, but no difference in longer-term survival.[196] A study from the United Kingdom found a worse survival rate in ovarian cancer patients with a family history of ovarian cancer, whether or not they had a BRCA mutation, compared with sporadic controls.[197] Finally, a case-control study at the University of Iowa failed to find any survival advantage for women with BRCA1 inactivation, whether by germline mutation, somatic mutation, or BRCA1 promoter silencing.[198] In this study, however, cases (women with BRCA1 inactivation) were matched to controls on several variables, including tumor grade and p53 status, thus possibly minimizing any differences between the two groups.

Further large studies with appropriate control populations will be required to determine whether there is a survival advantage in either BRCA1- or BRCA2-related ovarian cancers.

Breast cancer is also a component of the rare Li-Fraumeni syndrome (LFS) (OMIM ⁴²), in which germline mutations of the TP53 gene (OMIM ⁴³) on chromosome 17p have been documented.[199] This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[200,201] Tumors in LFS families tend to occur in childhood and early adulthood, and often present as multiple primaries in the same individual. Evidence supports a genotype-phenotype correlation, with an association of the location of the mutation, the kind of cancer that develops, and the age of onset.[202] Brain and adrenal gland tumors were associated with specific sites of missense mutations. Age at onset of breast cancer was 34.6 years in families with a TP53 mutation compared with 42.5 years in those families without a mutation. A germline mutation in the TP53 gene has been identified in more than 50% of families exhibiting this syndrome, and inheritance is autosomal dominant, with a penetrance of at least 50% by age 50 years.

Located on chromosome 17p, TP53 encodes a 53kd nuclear phosphoprotein that binds DNA sequences and functions as a negative regulator of cell growth and proliferation in the setting of DNA damage. In response to DNA damage, p53 protein arrests cells in the G1 phase of the cell cycle, allowing DNA repair mechanisms to proceed before DNA synthesis. The p53 protein is also an active component of programmed cell death.[203] Inactivation of the TP53 gene or disruption of the protein product is thought to allow the persistence of damaged DNA and the possible development of malignant cells.[201] Evidence also exists that patients treated for a TP53-related tumor with chemotherapy or radiation therapy may be at risk of a treatment-related second malignancy. Germline mutations in TP53 are thought to account for fewer than 1% of breast cancer cases.[204]

One of the more than 50 cancer-related genodermatoses, Cowden syndrome (OMIM ⁴⁴) is characterized by multiple hamartomas, an excess of breast cancer, gastrointestinal malignancies, endometrial cancer, and thyroid disease, both benign and malignant.[205,206] Lifetime estimates for breast cancer among women with Cowden syndrome range from 25% to 50%. As in other forms of hereditary breast cancer, onset is often at a young age and may be bilateral.[207] Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. History or observation of the characteristic skin features raises a suspicion of Cowden syndrome. Central nervous system manifestations include macrocephaly, developmental delay, and dysplastic gangliocytomas of the cerebellum.[208,209] Germline mutations in PTEN (OMIM ⁴⁵), a protein tyrosine phosphatase with homology to tensin, located on chromosome 10q23, are responsible for this syndrome. Loss of heterozygosity at the PTEN locus observed in a high proportion of related cancers suggests that PTEN functions as a tumor suppressor gene. Its defined enzymatic function indicates a role in maintenance of the control of cell proliferation.[210] Disruption of PTEN appears to occur late in tumorigenesis and may act as a regulatory molecule of cytoskeletal function. Although PTEN mutations, which are estimated to occur in 1 in 200,000 individuals,[206] account for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into the signal pathway and the maintenance of normal cell physiology.[206,211] (Refer to the PDQ summary Genetics of Colorectal Cancer Major Genes ⁴⁶ section for more information on Cowden syndrome.)

Peutz-Jeghers syndrome (PJS) (OMIM ⁴⁷) is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, perioral, and buccal regions, and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[212-214] Mutations in the STK11 gene (OMIM ⁴⁸) at chromosome 19p13.3, which appears to function as a tumor suppressor gene,[215] have been identified as one cause of PJS.[216,217] Germline mutations in STK11, also known as LKB1, have been reported and appear to be responsible for about 50% of the cases of PJS.[216-221] A large series of 419 patients had a cumulative incidence of cancer of 85% by age 70 years, commonly affecting the GI tract. In addition, the cumulative risk of breast cancer was 31% by age 60 years; only two ovarian cancers were seen in this series.[222] Elevated cancer risks have also been seen in smaller series and a meta-analysis, including a higher risk of sex cord stromal tumors of the ovary.[223-227]

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174. Jóhannsson OT, Ranstam J, Borg A, et al.: Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. J Clin Oncol 16 (2): 397-404, 1998.  [PUBMED Abstract]
     
     
175. Stoppa-Lyonnet D, Ansquer Y, Dreyfus H, et al.: Familial invasive breast cancers: worse outcome related to BRCA1 mutations. J Clin Oncol 18 (24): 4053-9, 2000.  [PUBMED Abstract]
     
     
176. Haffty BG, Harrold E, Khan AJ, et al.: Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet 359 (9316): 1471-7, 2002.  [PUBMED Abstract]
     
     
177. Robson M, Levin D, Federici M, et al.: Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations. J Natl Cancer Inst 91 (24): 2112-7, 1999.  [PUBMED Abstract]
     
     
178. Robson ME, Chappuis PO, Satagopan J, et al.: A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res 6 (1): R8-R17, 2004.  [PUBMED Abstract]
     
     
179. Agnarsson BA, Jonasson JG, Björnsdottir IB, et al.: Inherited BRCA2 mutation associated with high grade breast cancer. Breast Cancer Res Treat 47 (2): 121-7, 1998.  [PUBMED Abstract]
     
     
180. Lakhani SR, Jacquemier J, Sloane JP, et al.: Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90 (15): 1138-45, 1998.  [PUBMED Abstract]
     
     
181. Marcus JN, Watson P, Page DL, et al.: Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 77 (4): 697-709, 1996.  [PUBMED Abstract]
     
     
182. Verhoog LC, Berns EM, Brekelmans CT, et al.: Prognostic significance of germline BRCA2 mutations in hereditary breast cancer patients. J Clin Oncol 18 (21 Suppl): 119S-24S, 2000.  [PUBMED Abstract]
     
     
183. Lakhani SR, Manek S, Penault-Llorca F, et al.: Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res 10 (7): 2473-81, 2004.  [PUBMED Abstract]
     
     
184. Evans DG, Young K, Bulman M, et al.: Probability of BRCA1/2 mutation varies with ovarian histology: results from screening 442 ovarian cancer families. Clin Genet 73 (4): 338-45, 2008.  [PUBMED Abstract]
     
     
185. Tonin PN, Maugard CM, Perret C, et al.: A review of histopathological subtypes of ovarian cancer in BRCA-related French Canadian cancer families. Fam Cancer 6 (4): 491-7, 2007.  [PUBMED Abstract]
     
     
186. Crum CP, Drapkin R, Kindelberger D, et al.: Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer. Clin Med Res 5 (1): 35-44, 2007.  [PUBMED Abstract]
     
     
187. Piek JM, Torrenga B, Hermsen B, et al.: Histopathological characteristics of BRCA1- and BRCA2-associated intraperitoneal cancer: a clinic-based study. Fam Cancer 2 (2): 73-8, 2003.  [PUBMED Abstract]
     
     
188. Schorge JO, Muto MG, Lee SJ, et al.: BRCA1-related papillary serous carcinoma of the peritoneum has a unique molecular pathogenesis. Cancer Res 60 (5): 1361-4, 2000.  [PUBMED Abstract]
     
     
189. Jazaeri AA, Yee CJ, Sotiriou C, et al.: Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J Natl Cancer Inst 94 (13): 990-1000, 2002.  [PUBMED Abstract]
     
     
190. Rubin SC, Benjamin I, Behbakht K, et al.: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 335 (19): 1413-6, 1996.  [PUBMED Abstract]
     
     
191. Ben David Y, Chetrit A, Hirsh-Yechezkel G, et al.: Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 20 (2): 463-6, 2002.  [PUBMED Abstract]
     
     
192. Cass I, Baldwin RL, Varkey T, et al.: Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 97 (9): 2187-95, 2003.  [PUBMED Abstract]
     
     
193. Aida H, Takakuwa K, Nagata H, et al.: Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clin Cancer Res 4 (1): 235-40, 1998.  [PUBMED Abstract]
     
     
194. Boyd J, Sonoda Y, Federici MG, et al.: Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 283 (17): 2260-5, 2000.  [PUBMED Abstract]
     
     
195. Pal T, Permuth-Wey J, Kapoor R, et al.: Improved survival in BRCA2 carriers with ovarian cancer. Fam Cancer 6 (1): 113-9, 2007.  [PUBMED Abstract]
     
     
196. Zweemer RP, Verheijen RH, Coebergh JW, et al.: Survival analysis in familial ovarian cancer, a case control study. Eur J Obstet Gynecol Reprod Biol 98 (2): 219-23, 2001.  [PUBMED Abstract]
     
     
197. Pharoah PD, Easton DF, Stockton DL, et al.: Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group. Cancer Res 59 (4): 868-71, 1999.  [PUBMED Abstract]
     
     
198. Buller RE, Shahin MS, Geisler JP, et al.: Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin Cancer Res 8 (5): 1196-202, 2002.  [PUBMED Abstract]
     
     
199. Garber JE, Goldstein AM, Kantor AF, et al.: Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res 51 (22): 6094-7, 1991.  [PUBMED Abstract]
     
     
200. Bottomley RH, Condit PT: Cancer families. Cancer Bull 20: 22-24, 1968. 
     
     
201. Malkin D: The Li-Fraumeni syndrome. Cancer: Principles and Practice of Oncology Updates 7(7): 1-14, 1993. 
     
     
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203. Harris CC, Hollstein M: Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329 (18): 1318-27, 1993.  [PUBMED Abstract]
     
     
204. Sidransky D, Tokino T, Helzlsouer K, et al.: Inherited p53 gene mutations in breast cancer. Cancer Res 52 (10): 2984-6, 1992.  [PUBMED Abstract]
     
     
205. Tsou HC, Teng DH, Ping XL, et al.: The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet 61 (5): 1036-43, 1997.  [PUBMED Abstract]
     
     
206. Pilarski R, Eng C: Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 41 (5): 323-6, 2004.  [PUBMED Abstract]
     
     
207. Olopade OI, Weber BL: Breast cancer genetics: toward molecular characterization of individuals at increased risk for breast cancer: part I. Cancer: Principles and Practice of Oncology Updates 12(10): 1-12, 1998. 
     
     
208. Nelen MR, Padberg GW, Peeters EA, et al.: Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet 13 (1): 114-6, 1996.  [PUBMED Abstract]
     
     
209. Lachlan KL, Lucassen AM, Bunyan D, et al.: Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet 44 (9): 579-85, 2007.  [PUBMED Abstract]
     
     
210. Lynch ED, Ostermeyer EA, Lee MK, et al.: Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis. Am J Hum Genet 61 (6): 1254-60, 1997.  [PUBMED Abstract]
     
     
211. Myers MP, Tonks NK: PTEN: sometimes taking it off can be better than putting it on. Am J Hum Genet 61 (6): 1234-8, 1997.  [PUBMED Abstract]
     
     
212. Peutz JL: On a very remarkable case of familial polyposis of the mucous membrane of the intestinal tract and nasopharynx accompanied by peculiar pigmentations of the skin and mucous membrane. Ned Tijdschr Geneeskd 10: 134-146, 1921. 
     
     
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216. Hemminki A, Markie D, Tomlinson I, et al.: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391 (6663): 184-7, 1998.  [PUBMED Abstract]
     
     
217. Jenne DE, Reimann H, Nezu J, et al.: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18 (1): 38-43, 1998.  [PUBMED Abstract]
     
     
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Low Penetrance Predisposition to Breast and Ovarian Cancer

Background

Mutations in BRCA1, BRCA2, and the genes involved in other rare syndromes discussed above account for less than 25% of the excess familial risk of breast cancer.[1] Despite intensive genetic linkage studies, there do not appear to be other BRCA1/BRCA2-like high-penetrance genes that account for a significant fraction of the remaining multiple-case familial clusters.[2] These observations suggest that the remaining breast cancer susceptibility is polygenic in nature, meaning that a relatively large number of low-penetrance genes are involved.[3] Each locus would be expected to have a relatively small effect on breast cancer risk and would not produce dramatic familial aggregation or influence patient management. However in combination with other genetic loci and/or environmental factors, particularly given how common these can be, variants of this kind might significantly alter breast cancer risk. These types of genetic variations are sometimes referred to as “polymorphisms”, meaning that the gene or locus occurs in several “forms” within the population (and more formally defined as polymorphic when at least 1% of chromosomes at a position vary from each other). Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed “disease-associated polymorphisms” or “functionally relevant polymorphisms.” This polygenic model of susceptibility is consistent with the observed patterns of familial aggregation of breast cancer.[4] Although the clinical significance and causality of associations with breast cancer are often difficult to evaluate and establish, genetic polymorphisms may account for why some women are more sensitive than others to environmental carcinogens.

Polymorphisms underlying polygenic susceptibility to breast cancer are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to “high-penetrance” variants or alleles that are typically associated with more severe phenotypes, for example those BRCA1/BRCA2 mutations leading to an autosomal dominant inheritance patterns in a family. The definition of a “moderate” risk of cancer is arbitrary, but it is usually considered to be in the range of a relative risk of 1.5–2.0. Because these types of sequence variants (also called low-penetrance genes, alleles, mutations, and polymorphisms) are relatively common in the population, their contribution to total cancer risk is estimated to be much higher than the attributable risk in the population from mutations in BRCA1 and BRCA2. For example, it is estimated by segregation analysis that half of all breast cancer occurs in 12% of the population that is deemed most susceptible.[3] There are no known low-penetrance variants in BRCA1/BRCA2. The N372H variation in BRCA2, initially thought to be a low-penetrance allele, was not verified in a large combined analysis.[5]

Two strategies have been taken to identify low-penetrance polymorphisms leading to breast cancer susceptibility: candidate gene and genome-wide searches. Both involve the epidemiologic case-control study design. The candidate gene approach involves selecting genes based on their known or presumed biological function, relevance to carcinogenesis or organ physiology, and searching for or testing known genetic variants for an association with cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and has been relatively disappointing despite some confirmed associations, as described below. It has largely been replaced by the genome-wide association studies (GWAS) in which a very large number of single nucleotide polymorphisms (SNPs) (potentially 1,000,000 or more) are chosen within the genome and tested largely without regard to their possible biological function, but instead to capture more uniformly all genetic variation throughout the genome.

CHEK2 (OMIM ⁵⁰), a gene involved in the DNA damage repair response pathway, was initially evaluated as a potential cause of Li-Fraumeni syndrome (LFS).[6] While it does not appear to be a common cause of LFS,[7] based on numerous studies, a single polymorphism, 1100delC, appears to be a rare, low-penetrance susceptibility allele.[8-13] The deletion was present in 1.2% of the European controls, 4.2% of the European BRCA1/2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases.[8] In a group of 1,479 Dutch women younger than 50 years with invasive breast cancer, 3.7% were found to have the CHEK2 1100delC mutation.[14] In both Europe and the United States (where the mutation appears to be slightly less common), additional studies, including a large prospective study,[15] have detected the mutation in 4% to 11% of familial cases of breast cancer and overall have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer[16-19]. A multicenter combined analysis and reanalysis of nearly 20,000 subjects from ten case-control studies, however, has verified a significant 2.3-fold excess of breast cancer among mutation carriers.[20] One study suggests the risk associated with a CHEK2 1100delC mutation was stronger in the families of probands ascertained because of bilateral breast cancer.[21] At least one study has also suggested that the mutation may be associated with both breast and colorectal cancer.[17] Although the initial report suggested that male mutation carriers were at a significantly increased risk of breast cancer,[13] several follow-up studies have failed to confirm the association.[22-25] The contribution of CHEK2 mutations to breast cancer may be dependent on the population studied. A study of 3,228 women diagnosed with breast cancer before age 51 years, and 5,496 population controls demonstrated that three founder alleles in CHEK2 contributed to 8% of early onset breast cancer in Poland.[26] Although a meta-analysis of 1100delC mutation carriers estimated the risk of breast cancer to be 42% by age 70 years in women with a family history of breast cancer,[27] the clinical applicability of this finding remains uncertain due to low mutation prevalence and lack of guidelines for clinical management.[28]

Ataxia telangiectasia (AT) (OMIM ⁵¹) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of ATM mutations(OMIM ⁵²).[29] More than 300 mutations in the gene have been identified to date, most of which are truncating mutations.[30] (Refer to the ATM online database ⁵³ for more information on AT mutations) ATM proteins have been shown to play a role in cell cycle control.[31-33] In vitro, AT cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[34]

Initial studies searching for an excess of ATM mutations among breast cancer patients provided conflicting results, perhaps due to study design and mutation testing strategies.[35-45] However, two large epidemiologic studies have demonstrated a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated relative risk of approximately 2.0.[45,46] Despite this convincing epidemiologic association, the clinical application of testing for ATM mutations is unclear due to the wide mutational spectrum and the logistics of testing. Because the presence of a mutation could pose a risk in screening-related radiation exposure, further work is needed.

BRIP1 (also known as BACH1) encodes a helicase that interacts with the BRCT domain of BRCA1. This gene also has a role in BRCA1-dependent DNA repair and cell cycle checkpoint function. Biallellic mutations in BRIP1 are a cause of Fanconi anemia,[47-49] much like such mutations in BRCA2. Inactivating mutations of BRIP1 are associated with an increased risk of breast cancer. Over 3,000 individuals from BRCA1/BRCA2 mutation negative families were examined for BRIP1 mutations. Mutations were identified in 9 of 1,212 individuals with breast cancer but in only 2 of 2,081 controls (P = 0.003). The relative risk of breast cancer was estimated to be 2.0 (95% confidence interval (CI), 1.2-3.2, P = 0.012). Of note, in families with BRIP1 mutations and multiple cases of breast cancer, there was incomplete segregation of the mutation with breast cancer, consistent with a low penetrance allele and similar to that seen with CHEK2.[50]

PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double stranded DNA repair. Similar to BRIP1 and BRCA2, biallelic mutations in PALB2 have also been shown to cause Fanconi anemia.[51] PALB2 mutations were found in 10 of 923 (1.1%) individuals with BRCA1 and BRCA2 mutation negative familial breast cancer, compared to none of 1084 (0%) controls (P = 0.0004). One of the ten families with a PALB2 mutation included a case of male breast cancer, raising the possibility that male breast cancer is included in the spectrum of PALB2. Similar to BRIP1 and CHEK2, there was incomplete segregation of PALB2 mutations in families with hereditary breast cancer.[52]

The Breast Cancer Association Consortium (BCAC) investigated single nucleotide polymorphisms identified in previous studies as possibly associated with excess breast cancer risk in 15,000 to 20,000 cases and 15,000 to 20,000 controls. Two SNPs, CASP80 D302H and TGFB1 L10P, were associated with invasive breast cancer with relative risks of 0.88 (95% CI, 0.84-0.92) and 1.08 (95% CI, 1.04-1.11) respectively.[53]

In contrast to assessing candidate genes and/or alleles, genome wide association studies involve comparing a very large set of genetic variants spread throughout the genome. The current paradigm uses sets of 100,000 to 1,000,000 SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap project.[54,55] By comparing allele frequencies between a large number of cases and controls, typically 1,000 or more of each, and validating promising signals in replication sets of subjects, very robust statistical signals of association have been obtained.[56-58] The strong correlation between many SNPs that are physically close to each other on the chromosome (linkage disequilibrium) allows one to “scan” the genome for susceptibility alleles even if the biologically relevant variant is not within the tested set of SNPs. While this between-SNP correlation allows one to interrogate the majority of the genome without having to assay every SNP, when a validated association is obtained, it is not usually obvious which of the many correlated variants is the causal one.

Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases[59] including breast cancer.[60-62] The first and most comprehensive study involved an initial scan in familial breast cancer cases followed by replication in two large sample sets of sporadic breast cancer, the final being a collection of over 20,000 cases and 20,000 controls from the BCAC, an international group of investigators.[60] Five distinct genomic regions were identified that were within or near the FGFR2, TNRC9, MAP3K1, and LSP1 genes or at the chromosome 8q region. Subsequent genome-wide studies from the Nurses Health Study, from an Icelandic study, and from a large cohort of Ashkenazi Jewish individuals, clearly replicated the FGFR2[62,63] and TNRC9[61] loci and pointed to additional susceptibility loci at chromosomes 2q35[61] and 6q22.33.[63]

Although the statistical evidence for an association between genetic variation at these loci and breast cancer risk is overwhelming, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk, with the largest odds ratio among heterozygous carriers being 1.23 (95% CI, 1.18–1.28). More risk variants are likely to be identified. Until their individual and collective influences on cancer risk are evaluated prospectively, they are not considered clinically relevant.

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24. Tsou HC, Teng DH, Ping XL, et al.: The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet 61 (5): 1036-43, 1997.  [PUBMED Abstract]
    
    
25. Olopade OI, Weber BL: Breast cancer genetics: toward molecular characterization of individuals at increased risk for breast cancer: part I. Cancer: Principles and Practice of Oncology Updates 12(10): 1-12, 1998. 
    
    
26. Cybulski C, Górski B, Huzarski T, et al.: CHEK2-positive breast cancers in young Polish women. Clin Cancer Res 12 (16): 4832-5, 2006.  [PUBMED Abstract]
    
    
27. Weischer M, Bojesen SE, Ellervik C, et al.: CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 26 (4): 542-8, 2008.  [PUBMED Abstract]
    
    
28. Offit K, Garber JE: Time to check CHEK2 in families with breast cancer? J Clin Oncol 26 (4): 519-20, 2008.  [PUBMED Abstract]
    
    
29. Savitsky K, Bar-Shira A, Gilad S, et al.: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268 (5218): 1749-53, 1995.  [PUBMED Abstract]
    
    
30. Telatar M, Teraoka S, Wang Z, et al.: Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet 62 (1): 86-97, 1998.  [PUBMED Abstract]
    
    
31. Uhrhammer N, Bay JO, Bignon YJ: Seventh International Workshop on Ataxia-Telangiectasia. Cancer Res 58 (15): 3480-5, 1998.  [PUBMED Abstract]
    
    
32. Ahmed M, Rahman N: ATM and breast cancer susceptibility. Oncogene 25 (43): 5906-11, 2006.  [PUBMED Abstract]
    
    
33. Khanna KK, Chenevix-Trench G: ATM and genome maintenance: defining its role in breast cancer susceptibility. J Mammary Gland Biol Neoplasia 9 (3): 247-62, 2004.  [PUBMED Abstract]
    
    
34. Gilad S, Chessa L, Khosravi R, et al.: Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 62 (3): 551-61, 1998.  [PUBMED Abstract]
    
    
35. FitzGerald MG, Bean JM, Hegde SR, et al.: Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 15 (3): 307-10, 1997.  [PUBMED Abstract]
    
    
36. Chen J, Birkholtz GG, Lindblom P, et al.: The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res 58 (7): 1376-9, 1998.  [PUBMED Abstract]
    
    
37. Bay JO, Grancho M, Pernin D, et al.: No evidence for constitutional ATM mutation in breast/gastric cancer families. Int J Oncol 12 (6): 1385-90, 1998.  [PUBMED Abstract]
    
    
38. Laake K, Vu P, Andersen TI, et al.: Screening breast cancer patients for Norwegian ATM mutations. Br J Cancer 83 (12): 1650-3, 2000.  [PUBMED Abstract]
    
    
39. Dörk T, Bendix R, Bremer M, et al.: Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 61 (20): 7608-15, 2001.  [PUBMED Abstract]
    
    
40. Teraoka SN, Malone KE, Doody DR, et al.: Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer 92 (3): 479-87, 2001.  [PUBMED Abstract]
    
    
41. Chenevix-Trench G, Spurdle AB, Gatei M, et al.: Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 94 (3): 205-15, 2002.  [PUBMED Abstract]
    
    
42. Thorstenson YR, Roxas A, Kroiss R, et al.: Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 63 (12): 3325-33, 2003.  [PUBMED Abstract]
    
    
43. Cavaciuti E, Laugé A, Janin N, et al.: Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families. Genes Chromosomes Cancer 42 (1): 1-9, 2005.  [PUBMED Abstract]
    
    
44. Olsen JH, Hahnemann JM, Børresen-Dale AL, et al.: Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia. Br J Cancer 93 (2): 260-5, 2005.  [PUBMED Abstract]
    
    
45. Renwick A, Thompson D, Seal S, et al.: ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38 (8): 873-5, 2006.  [PUBMED Abstract]
    
    
46. Thompson D, Duedal S, Kirner J, et al.: Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97 (11): 813-22, 2005.  [PUBMED Abstract]
    
    
47. Levitus M, Waisfisz Q, Godthelp BC, et al.: The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet 37 (9): 934-5, 2005.  [PUBMED Abstract]
    
    
48. Levran O, Attwooll C, Henry RT, et al.: The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet 37 (9): 931-3, 2005.  [PUBMED Abstract]
    
    
49. Litman R, Peng M, Jin Z, et al.: BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell 8 (3): 255-65, 2005.  [PUBMED Abstract]
    
    
50. Seal S, Thompson D, Renwick A, et al.: Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38 (11): 1239-41, 2006.  [PUBMED Abstract]
    
    
51. Reid S, Schindler D, Hanenberg H, et al.: Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 39 (2): 162-4, 2007.  [PUBMED Abstract]
    
    
52. Rahman N, Seal S, Thompson D, et al.: PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39 (2): 165-7, 2007.  [PUBMED Abstract]
    
    
53. Cox Angela, Dunning Alison, Garcia-Closas Montserrat, et al.: Nature genetics. Nat Genet 39 (5): 352-8, 2007. 
    
    
54. The International HapMap Consortium.: The International HapMap Project. Nature 426 (6968): 789-96, 2003.  [PUBMED Abstract]
    
    
55. Thorisson GA, Smith AV, Krishnan L, et al.: The International HapMap Project Web site. Genome Res 15 (11): 1592-3, 2005.  [PUBMED Abstract]
    
    
56. Evans DM, Cardon LR: Genome-wide association: a promising start to a long race. Trends Genet 22 (7): 350-4, 2006.  [PUBMED Abstract]
    
    
57. Cardon LR: Genetics. Delivering new disease genes. Science 314 (5804): 1403-5, 2006.  [PUBMED Abstract]
    
    
58. Chanock SJ, Manolio T, Boehnke M, et al.: Replicating genotype-phenotype associations. Nature 447 (7145): 655-60, 2007.  [PUBMED Abstract]
    
    
59. Wellcome Trust Case Control Consortium.: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (7145): 661-78, 2007.  [PUBMED Abstract]
    
    
60. Easton DF, Pooley KA, Dunning AM, et al.: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447 (7148): 1087-93, 2007.  [PUBMED Abstract]
    
    
61. Stacey SN, Manolescu A, Sulem P, et al.: Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39 (7): 865-9, 2007.  [PUBMED Abstract]
    
    
62. Hunter DJ, Kraft P, Jacobs KB, et al.: A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39 (7): 870-4, 2007.  [PUBMED Abstract]
    
    
63. Gold B, Kirchhoff T, Stefanov S, et al.: Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci U S A 105 (11): 4340-5, 2008.  [PUBMED Abstract]
    
    

Interventions

Few data exist on the outcomes of interventions to reduce risk in people with a genetic susceptibility to breast or ovarian cancer. As a result, recommendations for management are primarily based on expert opinion.[1-5] In addition, as outlined in other sections of this summary, uncertainty is often considerable regarding the level of cancer risk associated with a positive family history or genetic test. In this setting, personal preferences are likely to be an important factor in patients’ decisions about risk reduction strategies.

Refer to the PDQ summary on Screening for Breast Cancer ⁵⁴ for information on screening in the general population, and to the PDQ summary Cancer Genetics Overview ² for information on levels of evidence related to screening and prevention.

In the general population, evidence for the value of breast self-examination (BSE) is limited. Preliminary results have been reported from a randomized study of BSE being conducted in Shanghai, China.[6] At 5 years, no reduction in breast cancer mortality was seen in the BSE group compared with the control group of women, nor was a substantive stage shift seen in breast cancers that were diagnosed. (Refer to the PDQ summary on Screening for Breast Cancer ⁵⁴ for more information.)

Little direct prospective evidence exists regarding BSE among female carriers of a BRCA1 or BRCA2 high-risk mutation, male carriers of a BRCA2 mutation, or women at inherited risk of breast cancer. In the Canadian National Breast Screening Study, women with first-degree relatives with breast cancer had statistically significantly higher BSE competency scores than those without a family history. In a study of 251 high-risk women at a referral center, five breast cancers were detected by self-examination less than a year after a previous screen (as compared with one cancer detected by clinician exam and 11 cancers detected as a result of mammography). Women in the cohort were instructed in self-examination, but it is not stated whether the interval cancers were detected as a result of planned self-examination or incidental discovery of breast masses.[7] In another series of BRCA1/2 mutation carriers, four of nine incident cancers were diagnosed as palpable masses after a reportedly normal mammogram, further suggesting the potential value of self-examination.[8] A task force convened by the Cancer Genetics Studies Consortium has recommended “monthly self-examination beginning early in adult life (e.g., by age 18-21) to establish a regular habit and allow familiarity with the normal characteristics of breast tissue. Education and instruction in self-examination are recommended.”[9]

Level of evidence: 5

Few prospective data exist regarding clinical breast examination (CBE) among female carriers of a BRCA1 or BRCA2 high-risk mutation, male carriers of a BRCA2 mutation, or women at inherited risk of breast cancer.

The Cancer Genetics Studies Consortium task force concluded, “as with self-examination, the contribution of clinical examination may be particularly important for women at inherited risk of early breast cancer.” They recommended that female carriers of a BRCA1 or BRCA2 high-risk mutation undergo annual or semiannual clinical examinations beginning at age 25 to 35 years.[9]

Level of evidence: 5

In the general population, strong evidence suggests that regular mammography screening of women aged 50 to 59 years leads to a 25% to 30% reduction in breast cancer mortality. (Refer to the PDQ summary on Screening for Breast Cancer ⁵⁴ for more information.) For women who begin mammographic screening at age 40 to 49 years, a 17% reduction in breast cancer mortality is seen, which occurs 15 years after the start of screening.[10] Observational data from a cohort study of more than 28,000 women suggest that the sensitivity of mammography is lower for young women. In this study, the sensitivity was lowest for younger women (aged 30-49 years) who had a first-degree relative with breast cancer. For these women, mammography detected 69% of breast cancers diagnosed within 13 months of the first screening mammography. By contrast, sensitivity for women younger than 50 years without a family history was 88% (P = .08). For women aged 50 years and older, sensitivity was 93% at 13 months and did not vary by family history.[11] Preliminary data suggest that mammography sensitivity is lower in BRCA1 and BRCA2 carriers than in noncarriers.[8] Subsequent observational studies have found that the positive predictive value (PPV) of mammography increases with age and is highest among older women and among women with a family history of breast cancer.[12] Higher PPVs may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity.[13] One study found an association between the presence of pushing margins, a histopathologic description of a pattern of invasion, and false-negative mammograms in 28 women, 26 of whom had a BRCA1 mutation and two of whom had a BRCA2 mutation. Pushing margins, characteristic of medullary histology, is associated with an absence of fibrotic reaction.[14] In addition, rapid tumor doubling times may lead to tumors presenting shortly after an apparently normal study. In one study, mean tumor doubling time in BRCA1/2 carriers was 45 days, compared with 84 days in noncarriers.[15] Another study that evaluated mammographic breast density in women with BRCA mutations found no association between mutation status and mammographic density; however, in both carriers and noncarriers, increased breast density was associated with increased breast cancer risk.[16]

The randomized Canadian National Breast Screening Study-2 (NBSS2) compared annual CBE plus mammography to CBE alone in women aged 50 to 59 years from the general population. Both groups were given instruction in BSE.[17] Although mammography detected smaller primary invasive tumors and more invasive as well as ductal carcinomas in situ (DCIS) than CBE, the breast cancer mortality rates in the CBE-plus-mammography group and the CBE- alone group were nearly identical, and compared favorably with other breast cancer screening trials. After a mean follow-up of 13 years (range 11.3-16.0 years), the cumulative breast cancer mortality ratio was 1.02 (95% confidence interval (CI) = 0.78 to 1.33). One possible explanation of this finding was the careful training and supervision of the health professionals performing CBE.

In a prospective study of 251 individuals with BRCA mutations who received uniform recommendations regarding screening and risk-reducing, or prophylactic, surgery, annual mammography detected breast cancer in six women at a mean of 20.2 months after receipt of BRCA results.[7] The Cancer Genetics Studies Consortium task force has recommended for female carriers of a BRCA1 or BRCA2 high-risk mutation, “annual mammography, beginning at age 25 to 35 years. Mammograms should be done at a consistent location when possible, with prior films available for comparison.”[9] Data from prospective studies on the relative benefits and risks of screening with an ionizing radiation tool versus CBE or other nonionizing radiation tools would be useful.[18-20]

Certain observations have led to the concern that BRCA mutation carriers may be more prone to radiation-induced breast cancer than women without mutations. The BRCA1 and BRCA2 proteins are known to be important in cellular mechanisms of DNA damage repair, including those involved in repairing radiation-induced damage. Mouse embryos lacking Brca1 or Brca2 are hypersensitive to the effects of ionizing radiation. Some studies have suggested intermediate radiation sensitivity in cells that are heterozygous for a BRCA mutation, but this is not consistent and varies by experimental system and endpoint. A large international case-control study of 1,601 mutation carriers described an increased risk of breast cancer (hazard ratio (HR) = 1.54) among women who were ever exposed to chest x-rays, with risk being highest in women age 40 years and younger, born after 1949, and those exposed to x-rays only before age 20 years.[21] In contrast, two studies of the effect of mammogram exposure on carriers (n = 1,600, n = 162) did not support an association between such exposure and subsequent breast cancer risk.[22,23] In a small study,[23] there was a modest association between lifetime mammogram exposure and risk in BRCA1 mutation carriers (HR = 1.08, P = .03). No significant effect was seen after exclusion of postdiagnosis mammograms. At this time there is insufficient evidence to suggest that mutation carriers should avoid mammography.

Level of evidence: 3

The limited sensitivity of mammography and an interest in methods of screening that do not involve ionizing radiation has led to evaluation of other screening techniques, including magnetic resonance imaging (MRI), breast ultrasound, breast ductal lavage, and digital mammography.

Because of the relative insensitivity of mammography in women at hereditary risk for breast cancer, a number of screening modalities have been proposed and investigated in high-risk women, including BRCA mutation carriers. Several studies have described the experience with breast MRI screening in women at risk for breast cancer, including descriptions of relatively large multi-institutional trials.[24-30] Several considerations must be kept in mind when reviewing these reports:

• The studies are variable in terms of the underlying population being studied, equipment and signal processing protocols, the manner of reporting results, and the manner in which sensitivity and specificity are calculated.
• The different screening tests (MRI and mammogram with or without ultrasound) are performed nearly simultaneously in these studies, and the screening modalities are compared to each other. Therefore, sensitivity is defined somewhat differently in these studies than in the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) of follow-up and outcome reporting.
• The number of screening rounds is limited, and the distinction between prevalent (first round) and incident cancer detection rates is often unclear.

Despite these caveats, the reported studies consistently demonstrate that breast MRI is more sensitive than either mammography or ultrasound for the detection of hereditary breast cancer. The results of four large studies are presented in Table 5 ⁵⁵, Summary of MRI Screening Studies in Women at Hereditary Risk for Breast Cancer.[24-28] Most cancers in these programs were screen detected with only 6% of cancers presenting in the interval between screenings. The sensitivity of MRI (as defined by the study methodology) ranged from 71% to 100%. Of the combined studies, 82% of the cancers were identified by MRI compared with 40% by mammography.

Concerns have been raised about the reduced specificity of MRI compared with other screening modalities. In one study, after the initial MRI screen, 16.5% of the patients were recalled for further evaluation, and 7.6% of subjects were recommended to undergo a short-interval follow-up examination at 6 months.[28] These rates declined significantly during later screening rounds, with fewer than 10% of the subjects recalled for more detailed MRI and fewer than 3% recommended to have short interval follow-up. In a second study, Magnetic Resonance Imaging for Breast Screening (MARIBS), the recall rate for additional evaluation was 10.7% per year.[27] The benign biopsy rates in the first study were 11% at first round, 6.6% at second round, and 4.7% at third round.[28] In the MARIBS study, the aggregate surgical biopsy rate was 9 per 1,000 screening episodes, though this may underestimate the burden because follow-up ultrasounds, core-needle biopsies, and fine-needle aspirations have not been included in the numerator of the MARIBS calculation.[27] The PPV of MRI has been calculated differently in the various series and fluctuates somewhat, depending on whether all abnormal examinations or only the examinations that result in a biopsy are counted in the denominator. Generally, the PPV of a recommendation for tissue sampling (as opposed to further investigation) is in the range of 50% in most series.

These trials appear to establish that MRI is superior to mammography in the detection of hereditary breast cancer, and that women participating in these trials including annual MRI screening were less likely to have a cancer not detected by screening.[31] However, mammography clearly identifies some cancers that are not identified by MRI. Most of these mammographically detected cancers in women with a negative MRI appear to be ductal carcinomas in situ, presumably presenting as microcalcifications without significant ductal enhancement. While MRI does appear to be more sensitive than mammogram, it is unknown whether MRI screening results in a survival benefit or even in downstaging compared to mammography alone. One screening study demonstrated that patients were more likely to be diagnosed with small tumors and node-negative disease than women in two nonrandomized control groups.[25] However, a randomized study of screening with or without MRI using tumor stage or mortality as an endpoint has not been performed. Despite the apparent sensitivity of MRI screening, some women in MRI-based programs will nevertheless develop life-threatening breast cancer. The American Cancer Society and the National Comprehensive Cancer Network (NCCN) have recommended the use of annual MRI screening for women at hereditary risk for breast cancer.[3,32]

Level of evidence: 3

Several studies have reported instances of breast cancer detected by ultrasound that were missed by mammography, as discussed in one review.[34] In a pilot study of ultrasound as an adjunct to mammography in 149 women with moderately increased risk based on family history, one cancer was detected, based on ultrasound findings. Nine other biopsies of benign lesions were performed. One was based on abnormalities on both mammography and ultrasound, and the remaining eight were based on abnormalities on ultrasound alone.[34] However, ultrasound screening appears to have a limited benefit in combination with MRI. In a multicenter study of 171 women (92% of whom were BRCA1/2 mutation carriers) undergoing simultaneous mammography, MRI, and ultrasound, no cancers were detected by ultrasound alone.[29] Uncertainties about ultrasound include the effect of screening on mortality, the rate and outcome of false-positive results, and access to experienced breast ultrasonographers.

Level of evidence: None assigned

Digital mammography refers to the use of a digital detector to detect and record x-ray images. This technology improves contrast resolution,[35] and has been proposed as a potential strategy for improving the sensitivity of mammography. A screening study comparing digital with routine mammography in 6,736 examinations of women aged 40 years and older found no difference in cancer detection rates;[36] however, digital mammography resulted in fewer recalls. In another study (ACRIN-6652 ⁵⁷) comparing digital mammography to plain-film mammography in 42,760 women, the overall diagnostic accuracy of the two techniques was similar.[37] When Receiver Operating Characteristic (ROC) curves were compared, digital mammography was more accurate in women younger than 50 years, in women with radiographically dense breasts, and in premenopausal or perimenopausal women.

Level of evidence: 3

Refer to the PDQ summary on Prevention of Breast Cancer ²⁰ for information on prevention in the general population, and to the PDQ summary Cancer Genetics Overview ² for information on levels of evidence related to screening and prevention.

In the general population, breast cancer risk increases with early menarche and late menopause, and is reduced at early first full-term pregnancy. (Refer to the PDQ summary on Prevention of Breast Cancer ²⁰ for more information.) In the Nurses’ Health Study, these were risk factors among women who did not have a mother or sister with breast cancer.[38] Among women with a family history of breast cancer, pregnancy at any age appeared to be associated with an increase in risk of breast cancer, persisting to age 70 years.

One study evaluated risk modifiers among 333 female carriers of a BRCA1 high-risk mutation. In women with known mutations of the BRCA1 gene, early age at first live birth and parity of three or more have been associated with a lowered risk of breast cancer. A relative risk (RR) of 0.85 was estimated for each additional birth, up to five or more; however, increasing parity appeared to be associated with an increased risk of ovarian cancer.[39,40] In a case-control study from New Zealand, investigators noted no difference in the impact of parity upon the risk of breast cancer between women with a family history of breast cancer and those without a family history.[41]

Studies of the effect of pregnancy on breast cancer risk have revealed complex results. Although the relationship of parity has been inconsistent, several studies have shown that among parous women, an increased number of full-term births is associated with a decrease in breast cancer risk. The influence of age at first birth may differ between BRCA1 and BRCA2 mutation carriers.[42-44] Of note, neither therapeutic nor spontaneous abortions appear to be associated with an increased breast cancer risk.[42,45]

Level of evidence: 4aii

In the general population, breastfeeding has been associated with a slight reduction in breast cancer risk in a few studies, including a large collaborative reanalysis of multiple epidemiologic studies,[46] and at least one study suggests that it may be protective in BRCA1 mutation carriers. In a multicenter breast cancer case-control study of 685 BRCA1 and 280 BRCA2 mutation carriers with breast cancer and 965 mutation carriers without breast cancer drawn from multiple-case families, among BRCA1 mutation carriers, breastfeeding for 1 year or more was associated with approximately a 45% reduced risk of breast cancer.[47] No such reduced risk was observed among BRCA2 mutation carriers. A second study failed to confirm this association.[42]

Among the general population, oral contraceptives may produce a slight, short-term increase in breast cancer risk. (Refer to the PDQ summary on Prevention of Breast Cancer ²⁰ for more information.) In a meta-analysis of data from 54 studies, family history of breast cancer was not associated with any variation in risk associated with oral contraceptive use.[48] In a study of 50 Jewish women younger than 40 years with breast cancer, those with a BRCA1 or BRCA2 high-risk mutation had a higher likelihood of long-term oral contraceptive use (>48 months) before their first pregnancy.[49] The authors concluded that oral contraceptive use might increase the risk of breast cancer among carriers of a BRCA1 or BRCA2 mutation more than in noncarriers. In a case-control study of more than 1,300 pairs of women, each case was matched to a woman with a mutation in the same gene, born within 2 years of the case, and in the same country, who had not developed cancer. Oral contraceptive use was associated with a statistically significant 20% (CI, 2%-40%) increase in risk of breast cancer among BRCA1 mutation carriers, particularly if use:

• Began before 1975, a period when estrogen doses were relatively high (38% increase, CI 11%-72%).
• Began before age 30 years (29% increase, CI, 9%-52%).
• Lasted for 5 or more years (33% increase, CI, 11%-60%).[50]

There was no increased risk associated with use among BRCA2 mutation carriers. A Swedish population-based study of 245 women with breast cancer diagnosed before age 41 years, 19 of whom were BRCA1/BRCA2 mutation carriers, suggested that oral contraceptive use before age 20 years was associated with increased breast cancer risk in both mutation carriers and noncarriers, though the small number of carriers limits the conclusions for this subgroup.[51]

In contrast, a population-based study of 47 BRCA1 and 36 BRCA2 mutation carriers with breast cancer diagnosed before age 40 years, matched to population controls without mutations, found no increased risk of early-onset breast cancer associated with ever use of low-dose contraceptive pills for BRCA2 mutation carriers (odds ratio (OR) = 1.02) and a significantly reduced risk for BRCA1 mutation carriers (OR = 0.22; 95% CI, 0.10-0.49).[52]

One study examined proliferation of normal breast epithelium among women undergoing reduction mammoplasty.[53] The study found a substantially higher cellular proliferation rate among women who used oral contraceptives before their first full-term pregnancy. In addition, among women currently on oral contraceptives, women with a family history of breast cancer had much higher cellular proliferation rates than those women without a family history. These findings are consistent with increased breast cancer risk among women with a family history of breast cancer who use oral contraceptives.

In considering contraceptive options and preventive actions, the potential impact of oral contraceptive use upon the risk of both breast and ovarian cancer, as well as other health-related effects of oral contraceptives, needs to be considered. With regard to breast cancer risk associated with oral contraceptive use, despite conflicting results based on small numbers of carriers, several studies have found a significantly increased risk. A number of important issues remain unresolved including the potential differences between BRCA1/2 mutation carriers, age and duration of exposure, and formulation.

Level of evidence: 3aii

Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with hormone replacement therapy (HRT) in the general population.[54-57] The Women’s Health Initiative ⁵⁸ (WHI) is a randomized controlled trial of approximately 160,000 postmenopausal women investigating the risks and benefits of strategies that may reduce the incidence of heart disease, breast and colorectal cancer, and fractures, including dietary interventions and two trials of hormone therapy. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits.[56,57] One of the adverse outcomes prompting closure was a significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150) breast cancers (RR =1.24; 95% CI, 1.02-1.50, P <.001) in women randomized to receive estrogen and progestin.[57] HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms.[57]

Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased [58-60] or unaffected by a family history of breast cancer;[39,61,62] risk did not vary by family history in the meta-analysis.[48] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations.[57] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.[63]

The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 mutation has only been studied in the context of bilateral oophorectomy, a procedure known to reduce the risk of breast cancer. In a prospective study of 462 women with BRCA1 or BRCA2 mutations, 155 who had undergone bilateral oophorectomy (139 before age 50 years), the breast cancer risk reduction of 37% was essentially the same among the 93 women who took HRT compared with the reduction of 38% among those without HRT.[64] This finding needs to be confirmed in a larger study but suggests that HRT in this particular setting does not negate the protective effect of oophorectomy on breast cancer risk.

Level of evidence: 3aii

Tamoxifen (a synthetic antiestrogen) increases breast-cell growth inhibitory factors and concomitantly reduces breast-cell growth stimulatory factors. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (NSABP-P1 ⁵⁹), a prospective randomized double-blind trial, compared tamoxifen (20 mg/day) to placebo for 5 years. Tamoxifen was shown to reduce the risk of invasive breast cancer by 49%. The protective effect was largely confined to estrogen receptor–positive breast cancer, which was reduced by 69%. The incidence of estrogen receptor–negative cancer was not significantly reduced.[65] Similar reductions were noted in the risk of preinvasive breast cancer. Reductions in breast cancer risk were noted among women with a family history of breast cancer and in those without a family history. These benefits were associated with an increased incidence of endometrial cancers and thrombotic events among women older than 50 years. Interim data from two European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months [66] or 70 months,[67] respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used HRT.[66] These trials varied considerably in study design and populations. (Refer to the PDQ summary on Prevention of Breast Cancer ²⁰ for more information.)

A substudy of the NSABP-P1 trial evaluated the effectiveness of tamoxifen in preventing breast cancer in BRCA1/2 mutation carriers older than 35 years. BRCA2-positive women benefited from tamoxifen to the same extent as BRCA1/2 mutation–negative participants; however, tamoxifen use among healthy women with BRCA1 mutations did not appear to reduce breast cancer incidence. These data must be viewed with caution in view of the small number of mutation carriers in the sample (eight BRCA1 carriers and 11 BRCA2 carriers).[68]

Level of evidence: 1

In contrast to the very limited data on primary prevention in BRCA1 and BRCA2 mutation carriers with tamoxifen, several studies have found a protective effect of tamoxifen on the risk of contralateral breast cancer.[69-71] In one study involving approximately 600 BRCA1/2 mutation carriers, tamoxifen use was associated with a 51% reduction in contralateral breast cancer.[69] An update to this report examined 285 BRCA1/2 mutation carriers with bilateral breast cancer and 751 BRCA1/2 mutation carriers with unilateral breast cancer (40% of these patients were included in their initial study). Tamoxifen was associated with a 50% reduction in contralateral breast cancer risk in BRCA1 mutation carriers and a 58% reduction in BRCA2 mutation carriers. Tamoxifen did not appear to confer benefit in women who had undergone an oophorectomy, although the numbers in this subgroup were quite small.[71] Another study involving 160 BRCA1/2 mutation carriers demonstrated that tamoxifen use following treatment of breast cancer with lumpectomy and radiation was associated with a 69% reduction in the risk of contralateral breast cancer.[70] These studies are limited by their retrospective, case-control designs and the absence of information regarding estrogen-receptor status in the primary tumor.

The STAR trial ⁶⁰ (NSABP; P-2) included more than 19,000 women and compared 5 years of raloxifene with tamoxifen in reducing the risk of invasive breast cancer.[72] There was no difference in incidence of invasive breast cancer at a mean follow-up of 3.9 years; however, there were fewer noninvasive cancers in the tamoxifen group. The incidence of thromboembolic events and hysterectomy was significantly lower in the raloxifene group. Detailed quality of life data demonstrate slight differences between the two arms.[73] Data regarding efficacy in BRCA1 or BRCA2 mutation carriers are not available.

Level of Evidence: 1

In the general population, both subcutaneous mastectomy and simple (total) mastectomy have been used for prophylaxis. Only 90% to 95% of breast tissue is removed with subcutaneous mastectomy.[74] In a total or simple mastectomy, removal of the nipple-areolar complex increases the proportion of breast tissue removed compared with subcutaneous mastectomy. However, some breast tissue is usually left behind with both procedures. The risk of breast cancer following either of these procedures has not been well established.

The effectiveness of risk-reducing mastectomy (RRM) in women with BRCA1 or BRCA2 mutations has been evaluated in several studies. In one retrospective cohort study of 214 women considered to be at hereditary risk by virtue of a family history suggesting an autosomal dominant predisposition, three women were diagnosed with breast cancer after bilateral RRM, with a median follow-up of 14 years.[75] As 37.4 cancers were expected, the calculated risk reduction was 92% (95% CI, 76.6–98.3). In a follow-up subset analysis, 176 of the 214 high-risk women in this cohort study underwent mutation analysis of BRCA1 and BRCA2. Mutations were found in 26 women (18 deleterious, eight variants of uncertain significance). None of those women had developed breast cancer after a median follow-up of 13.4 years.[76] Two of the three women diagnosed with breast cancer after RRM were tested, and neither carried a mutation. The calculated risk reduction among mutation carriers was 89.5% to 100% (95% CI, 41.4%–100%), depending on the assumptions made about the expected numbers of cancers among mutation carriers and the status of the untested woman who developed cancer despite mastectomy. The result of this retrospective cohort study has been supported by a prospective analysis of 76 mutation carriers undergoing RRM and followed prospectively for a mean of 2.9 years. No breast cancers were observed in these women, whereas eight were identified in women undergoing regular surveillance (HR for breast cancer after RRM = 0 [95% CI, 0–0.36]).[77]

The Prevention and Observation of Surgical End Points (PROSE) study group estimated the degree of breast cancer risk reduction after RRM in BRCA1/2 mutation carriers. The rate of breast cancer in 105 mutation carriers who underwent bilateral RRM was compared with that in 378 mutation carriers who did not choose surgery. Bilateral mastectomy reduced the risk of breast cancer after a mean follow-up of 6.4 years by approximately 90%.[78]

Another study evaluated the effectiveness of contralateral RRM in affected women with hereditary breast cancer. In a group of 148 BRCA1 or BRCA2 mutation carriers, 79 of whom underwent RRM, the risk of contralateral cancer was reduced by 91% and was independent of the effect of risk-reducing oophorectomy. Survival was better among women undergoing RRM, but this result was apparently caused by higher mortality due to the index cancer or metachronous ovarian cancer in the group not undergoing surgery.[79]

Studies describing histopathologic findings in RRM specimens from women with BRCA1 or BRCA2 mutations have been somewhat inconsistent. In two series, proliferative lesions associated with an increased risk of breast cancer (lobular carcinoma in situ, atypical lobular hyperplasia, atypical ductal hyperplasia, DCIS) were noted in 37% to 46% of women with mutations undergoing either unilateral or bilateral RRM.[80-82] In these series, 13% to 15% of patients were found to have previously unsuspected DCIS in the prophylactically removed breast. Among 47 cases of risk-reducing bilateral or contralateral mastectomies performed in known BRCA1 or BRCA2 mutation carriers from Australia, 3 (6%) cancers were detected at surgery.[83] In a study from Sweden among 100 women with a hereditary risk of breast cancer, 50 of whom were BRCA1 or BRCA2 mutation carriers, unsuspected lesions were found in 18 women (3 invasive, 8 in situ, and 7 atypical hyperplasia), 13 of whom were mutation carriers.[84]

These findings were not replicated in a third retrospective cohort study. In this study, proliferative fibrocystic changes were noted in none of 11 bilateral mastectomies from patients with deleterious mutations and in only two of seven contralateral unilateral risk-reducing mastectomies in affected mutation carriers.[85]

Although data are sparse, the evidence to date indicates that while a substantial proportion of women with a strong family history of breast cancer are interested in discussing RRM as a treatment option, uptake varies according to culture, geography, healthcare system, insurance coverage, provider attitudes, and other social factors. For example, in one setting where the providers made one to two field trips to family gatherings for family information sessions and individual counseling, only 3% of unaffected carriers obtained RRM within 1 year of follow-up.[86] Among women at increased risk of breast cancer due to family history, fewer than 10% opted for mastectomy.[87] Selection of this option was related to breast cancer–related worry as opposed to objective risk parameters (e.g., number of relatives with breast cancer). In addition, self-perceived risk has been closely linked to interest in RRM.[87]

Assuming risk reduction in the range of 90%, a theoretical model suggests that for a group of 30-year-old women with BRCA1 or BRCA2 mutations, RRM would result in an average increased life expectancy of 2.9 to 5.3 years.[88] While these data are useful for public policy decisions, they cannot be individualized for clinical care as they include assumptions that cannot be fully tested. Another study of at-risk women showed a 70% time-tradeoff value, indicating that the women were willing to sacrifice 30% of life expectancy in order to avoid RRM.[89] A cost-effectiveness analysis study estimated that risk-reducing surgery (mastectomy and oophorectomy) is cost-effective compared with surveillance with regard to years of life saved, but not for improved quality of life.[90]

In contrast, in a Dutch study of highly motivated women being followed every 6 months at a high-risk center, more than half (51%) of unaffected carriers opted for RRM. Almost 90% of the RRM surgeries were performed within 1 year of DNA testing. In this study, those most likely to have RRM were women younger than 55 years and with children.[91]

The Society of Surgical Oncology has endorsed RRM as an option for women with BRCA1/2 mutations or strong family histories of breast cancer.[92]

Individual psychological factors have an important role in decision-making about RRM by unaffected women. Research is emerging about psychosocial outcomes of RRM. (Refer to the Psychological Aspects of Medical Interventions ⁶¹ section of this summary.)

Level of evidence: 3aii

In the general population, removal of both ovaries has been associated with a reduction in breast cancer risk of up to 75%, depending on parity, weight, and age at time of artificial menopause. (Refer to the PDQ summary on Prevention of Breast Cancer ²⁰ for more information.) A Mayo Clinic study of 680 women at various levels of familial risk found that in women younger than 60 years who had bilateral oophorectomy, the likelihood of breast cancers developing was reduced for all risk groups.[93] Ovarian ablation, however, is associated with important side effects such as hot flashes, impaired sleep habits, vaginal dryness, dyspareunia, and increased risk of osteoporosis and heart disease. A variety of strategies may be necessary to counteract the adverse effects of ovarian ablation.

In support of early small studies,[94,95] a retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (HR 0.47; 95% CI, 0.29–0.77) as well as ovarian cancer (HR 0.04, 95% CI, 0.01–0.16) after risk-reducing salpingo-oophorectomy (RRSO).[96] A prospective single-institution study of 170 women with BRCA1 or BRCA2 mutations showed a similar trend. With RRSO, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74).[97]

Level of evidence: 3aii

While lumpectomy plus radiation therapy has become standard local-regional therapy for women with early stage breast cancer, its use in women with a hereditary predisposition for breast cancer who do not choose immediate bilateral mastectomy is less clear. Concern about its use, particularly in women with deleterious BRCA1 and BRCA2 mutations, centers around two issues. The first is the potential for an increased rate of ipsilateral cancers in the treated breast. The second is the potential for therapeutic radiation to induce tumors in BRCA1/2 defective cells. Most of the early studies that used family history of breast/ovarian cancer as a surrogate for hereditary risk failed to find an increase in ipsilateral cancers in women treated with breast conservation.[98-102] However, with the availability of clinical genetic testing for BRCA1/2 mutations, treatment outcomes for carriers of deleterious mutations in BRCA1/2 can now be compared with those of noncarriers.

To understand the role of germline BRCA1/2 mutations in determining outcome among women treated conservatively for breast cancer, the records of Ashkenazi Jewish (AJ) women treated with lumpectomy and radiation therapy for invasive breast cancer were reviewed.[103] Archival pathology material was obtained for analysis of the three founder AJ mutations. Deleterious BRCA mutations were found in 56 (11.3%) of the cases. The rate of ipsilateral cancer for founder mutation carriers was 12% at 10 years compared with 8% for women without mutations (not statistically significant). Women with founder AJ mutations were over three times more likely than women without mutations to develop contralateral cancer, 27% versus 8% (P = .0001). The same investigators also described a separate case series of 87 women with BRCA mutations who were treated with breast conserving surgery.[104] They reported a 12.6% rate of ipsilateral breast cancer at a median of 51.8 months, and a 23% rate of contralateral breast cancer at a median of 67.4 months. No control group was included.[104]

A case-control study from the Netherlands compared women with hereditary breast cancer (identified as either BRCA1/2 positive, or by a strong family history) with women without hereditary breast cancer for treatment outcome after breast conservation therapy. Although rates of ipsilateral breast recurrence were similar at 2 years following diagnosis, by 5 years the rate was twice as high in the hereditary cases (14% vs. 7%), and remained twice as high at 10 and 15 years after diagnosis (30% and 49% in the hereditary group, and 16% and 20% in the sporadic group).[105]

A multi-institution retrospective cohort study compared outcomes after breast conserving treatment between women with known BRCA1/2 mutations and those whose family history was not suggestive of a hereditary pattern. At 10 years, overall rates of ipsilateral breast cancer were not significantly different. However, BRCA1/2 mutation status was significantly associated with a risk of ipsilateral breast cancer when those carriers who underwent oophorectomy were removed from the analysis (7.8% for noncarriers vs. 16.3% for carriers). The 10-year estimates for contralateral breast cancer were 3% for noncarriers and 26% for carriers.[70] One study reported an approximately 40% risk of contralateral breast cancer in BRCA mutation carriers, a risk which is reduced by taking tamoxifen or undergoing oophorectomy.[106]

A study of selected patients diagnosed at age 42 years or younger who had undergone conservative therapy were offered genetic testing for BRCA1/2 mutations. Of 127 participants, 22 were found to have deleterious mutations.[107] At a median of 12.7 years of follow-up, the rate of ipsilateral events was 49% in the mutation carriers and 21% in the noncarriers (P = .007). Clinical and pathological features of the ipsilateral tumors were more consistent with second primaries than with local recurrence. Similarly, the rate of contralateral cancers was 42% in the carriers and 9% in the noncarriers (P = .001). This study has been criticized as having an unacceptable rate of ipsilateral events overall, calling into question the adequacy of the local-regional treatment.[108]

As noted above, there is a growing indication that women with BRCA1/2 mutations who are treated conservatively have an increased, not decreased, rate of ipsilateral breast cancer, occurring usually after 5 years of follow-up.

The second concern stems from the emerging understanding of the role of the BRCA genes in DNA repair activities within the cell, and the implication of the loss of these functions for radiation hypersensitivity. Both BRCA1 and BRCA2 are involved in DNA double-strand break repair, and loss of function in these genes could potentially accelerate the rate of cell kill caused by ionizing radiation. Another potentially relevant mechanism is the defect in the G2-M phase checkpoint displayed by BRCA1-deficient cells, which also alters radiation sensitivity.[109] Furthermore, murine models of Brca1- and Brca2-deficient mice have demonstrated evidence of hypersensitivity to ionizing radiation.[18,110] Clinical manifestations of these findings could include:

1. An increased response to adjuvant radiation therapy with a decrease of in-breast recurrence rates.
2. An increase in ipsilateral and contralateral breast cancers secondary to genetic instability.
3. An increase in radiation-related toxicity.

In one study, the rate of local recurrence among women with strong family histories who were treated with lumpectomy was highest when radiation was omitted, suggesting that these tumors are radiosensitive.[100] Rates of contralateral disease are consistently elevated in this population, but are equal for women treated with conservative therapy and for those who chose mastectomy without radiation, indicating that the increased risk is due to the mutation, not the exposure to radiation. And finally, studies have failed to find an increase in either early acute radiation tissue reactions or late radiation reactions to the skin, underlying tissue or bone.[111-113]

These data are consistent with a model in which hereditary BRCA1/2 cancers are sterilized by radiation therapy equally well, but due to the underlying genetic predisposition, the increased risk of second primaries in the treated breast remains. The findings of a significantly increased risk of contralateral breast cancer in this population is consistent across studies, and increasingly women with BRCA1/2 mutations are considering bilateral mastectomy at the time of first diagnosis of breast cancer, regardless of stage. Finally, there is no evidence for an increase in radiation toxicity among BRCA1/2 mutation carriers.

Level of evidence: 3di

A small but growing body of preclinical and clinical literature suggests a differential response of BRCA-related breast cancers to systemic chemotherapy. This is based on the emerging understanding of the functions of these genes in response to DNA damage and mitotic spindle machinery control. As several chemotherapeutic agents target either DNA or mitotic spindle structural integrity, the lack of BRCA functions could alter response to these agents. The absence of BRCA-mediated DNA repair could potentially increase sensitivity to these agents, which induce DNA breaks. On the other hand, the failure to activate cell cycle checkpoints in response to DNA damage could allow damaged tumor cells to avoid apoptosis and survive, leading to chemotherapy resistance. In the case of spindle poisons, BRCA1 has a role in the detection of microtubule disruption and induces apoptosis to prevent aberrant mitosis. Its absence could circumvent this mitotic regulation and thereby enhance sensitivity to spindle poisons. Several in vitro studies have begun to explore potential mechanisms for a differential response of BRCA-related breast cancers to several classes of chemotherapy. There are no clinical data at this time indicating that BRCA-associated cancers should be treated with different chemotherapy than non-BRCA-associated cancers.

Cell lines with inducible expression of BRCA1 were generated to explore its potential role in the cellular response to various chemotherapeutic agents.[114] In the presence of the antimicrotubule agents Taxol and vincristine, expression of BRCA1 resulted in a significant increase in cell death associated with an acute arrest in G2/M, suggesting that BRCA1 expression may be an important mediator of response to antimicrotubule agents by preventing progression of the cell into mitosis. BRCA1-deficient tumors, therefore, may exhibit resistance to this class of drugs.

The ability of BRCA1 to sensitize breast cancer cell lines to G2/M arrest in response to antimicrotubule agents was confirmed in a second study.[115] In contrast, BRCA1 induced resistance to DNA-damaging agents that induce double-strand breaks in DNA. Both of these opposing effects were mediated by inhibition or induction of apoptosis.

It has been shown that cell lines deficient in BRCA1 are defective in homology-directed chromosomal break repair, and highly sensitive to the interstrand cross-linking agent mitomycin-C.[116] Additional evidence supporting a role of BRCA1 in response to DNA-damaging drugs is seen in cisplatinum-resistant breast and ovarian cancer cell lines, in which BRCA1 is overexpressed and DNA repair is enhanced.[117]

Decreasing expression of BRCA1 in cell lines has been associated with increased sensitivity to cisplatinum and etoposide, and resistance to the tubule-damaging agents Taxol and vincristine.[118] Resistance was linked to transcriptional modifications in the JNK pathway which mediates apoptosis. Increased sensitivity to cisplatinum was associated with a time-dependent and dose-dependent increase in apoptosis in a mouse mammary epithelial cell line.[119] Another mechanism suggested for increased cisplatinum sensitivity in BRCA mutant cells is the role of both BRCA1 and BRCA2 in the promotion of subnuclear Rad51 foci for DNA repair.[120] A cell culture model was used to study the interaction of cyclin-dependent kinase 2 (CDK2) inhibition and BRCA1 deficiency.[121] CDK2 is a serine/threonine kinase that has a role in cell cycle control. Inhibitors of CDK2 cause delays in DNA damage signaling. CDK2 inhibition was fourfold more toxic in the presence of BRCA1 mutations, suggesting that CDK2 inhibition may be a sensitive target in patients with BRCA1 mutations. Another specific pathway to exploit in BRCA1/2 deficient tumors is the poly (ADP-ribose) polymerase (PARP) pathway. PARP is active in the repair of double-strand breaks by homologous recombination. In vitro studies have shown that PARP inhibition kills BRCA mutant cells with high specificity. This specificity has not yet been demonstrated in vivo,[122] although phase I studies of PARP inhibitors in combination with chemotherapeutic agents are underway.

Overall, the preclinical data supports the conclusion that BRCA1 inhibits apoptosis after treatment with DNA-damaging agents, and its absence promotes apoptosis leading to increased sensitivity. In contrast, BRCA1 promotes apoptosis after exposure to spindle poisons and its absence supports survival of cells damaged by spindle poisons and thereby confers drug resistance.[123] Similarly, an animal model of Brca2 deficiency in murine small intestine showed a reduction in clonogenic survival after exposure to either cisplatinum or mitomycin C.[124]

Evidence of the role of BRCA1/2 mutations in human studies is retrospective in design and very preliminary. Among 38 women treated with neoadjuvant therapy for stages I-III breast cancer, those with BRCA1/2 mutations were significantly more likely to achieve a clinical and pathological complete response, independent of clinical stage.[125]

Thus the preclinical and clinical data are consistent with the emerging understanding of BRCA1 function in DNA-damage response as well as cell cycle regulation. While these findings raise the possibility that germline status may influence treatment choices, there is insufficient evidence at this time to support treating mutation carriers with different regimens.

Refer to the PDQ summary on Screening for Ovarian Cancer ⁶² for information on screening in the general population, and to the PDQ summary Cancer Genetics Overview ² for information on levels of evidence related to screening and prevention. The latter also outlines the five requirements that must be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice.

In the general population, clinical examination of the ovaries has neither the specificity nor the sensitivity to reliably identify early ovarian cancer. No data exist regarding the benefit of clinical examination of the ovaries (bimanual pelvic examination) in women at inherited risk of ovarian cancer.

Level of evidence: None assigned

In the general population, transvaginal ultrasound (TVUS) appears to be superior to transabdominal ultrasound in the preoperative diagnosis of adnexal masses. Both techniques have lower specificity in premenopausal women than in postmenopausal women, due to the cyclic menstrual changes in premenopausal ovaries (e.g., transient corpus luteum cysts) that can cause difficulty in interpretation. A screening trial of TVUS in 1,300 postmenopausal, asymptomatic women detected abnormalities in 2.5% of women. More than 90% of the lesions found were benign. Women with a family history of ovarian cancer were more likely to be found with an ovarian malignancy (RR = 4.0). No such association was noted for those with a family history of breast cancer or colon cancer.[126]

One study reported on the use of transvaginal color Doppler ultrasonography in the evaluation of 126 women with adnexal masses who subsequently underwent surgery. Twenty epithelial ovarian cancers were detected, as well as two dysgerminomas, two ovarian tumors of low malignant potential, one immature teratoma, and one Sertoli-Leydig cell tumor. It was concluded that color Doppler ultrasonography was able to increase the PPV and negative predictive value (NPV) due to increased sensitivity and specificity of ultrasound evaluation.[127]

Another study reported that the addition of color Doppler ultrasonography was able to increase the PPV of ultrasound imaging from 25% to 60% among women with a personal history of breast cancer undergoing screening for ovarian cancer.[128] As noted, however, clinical studies of color Doppler imaging have shown that normal physiologic changes in the premenopausal ovary near the time of ovulation have low impedance flow characteristics similar to those seen in malignancy.[129]

Data are limited regarding the potential benefit of pelvic ultrasound in screening women at inherited risk of ovarian cancer. A 10-year observational study in the United Kingdom of 2,500 asymptomatic women with at least one relative with ovarian cancer has evaluated TVUS and reported sensitivity and specificity with 10 years of follow-up and retrospective analysis of serum CA 125 levels.[130] Most women were screened once, unless the initial scan was positive or the family history was especially strong. There were 11 screening-detected cancers, one false-negative (a stage III cancer occurring within 12 months of ultrasound screening), and 93 false-positive tests, for a test sensitivity of 92% and a specificity of 97.8%. Among the 11 screening-detected cancers, four were stage IA invasive, four borderline stage IA, one invasive stage IC, and two stage II/III serous carcinomas. Sixty-five percent of the subjects were premenopausal, and 9 of the 12 cancers occurred in this group. TVUS was quite sensitive in this high-risk group, but there were still large numbers of women screened (n = 227) and false-positives (n = 9) for each cancer detected. The retrospective analysis of serum CA 125 levels in this study also allowed its evaluation as a potential first-stage screen to reduce the number of ultrasound tests required and the number of false-positives.[130] If only women with CA 125 levels of 20 or higher were to have undergone ultrasound screening, an additional four cancers would have been missed (sensitivity of 58%), but only 22% of the subjects would have been referred for ultrasound screening, reducing the number of false-positives to 21. Ultrasound screening only of those with CA 125 levels of 35 would have resulted in a sensitivity of 33% (seven additional cancers missed).

Another study evaluated 383 high-risk women (152 BRCA1/2 mutation carriers) with annual TVUS and CA 125.[131] Abnormal screening results were noted in 74 women (19.3%), but these resolved spontaneously in 47 women (63.5%). Of the 20 women undergoing exploratory surgery, only one had cancer, which proved to be a breast cancer metastatic to the ovary. No epithelial ovarian cancers were found as a result of screening.

Another study used gynecologic examination, TVUS, and CA 125 to screen 180 women at high risk of ovarian cancer with or without a prior history of breast cancer. (Refer to the Serum CA 125 ⁶³ section in this summary.) Abnormal ultrasounds were noted in all five women with invasive epithelial ovarian carcinomas. Of these, however, one had stage II disease and four had stage III disease.[132] A study from the Netherlands used annual TVUS and CA 125 to screen 269 women at high risk of hereditary ovarian cancer. Of the four prevalent and four incident cancers found, six were detected at an advanced stage.[133]

One study screened 597 women at risk of ovarian cancer with serum CA 125, TVUS, and color Doppler (described in the Serum CA 125 ⁶³ section). No epithelial ovarian cancers were found. However, one ovarian tumor of low malignant potential was identified.[129,134]

Another study reported screening 386 women with first- or second-degree relatives with ovarian cancer. The study used TVUS, color flow Doppler, and serum CA 125. Initial ultrasound was abnormal in 89 of 381 women (23%). Ovarian masses persisted in 15 patients; all of these were benign at surgery. CA 125 levels were higher than 35 U/mL in 42 of 386 women (11%). Two patients who underwent surgery for rising CA 125 levels had normal ovaries.[135]

Level of evidence: 4

Limited data are available on the potential benefit of screening with serum CA 125 in women at inherited risk of ovarian cancer. When 180 women considered at high risk of ovarian cancer based on family history were screened for ovarian cancer by gynecologic examination, TVUS, and serum CA 125, one granulosa cell tumor, three tumors of low malignant potential, and five epithelial ovarian tumors (one stage II and four stage III) were detected. CA 125 levels were elevated in one of the tumors of low malignant potential and in three of the four stage III ovarian carcinomas.[132]

A 10-year observational study of 2,500 asymptomatic women with a family history of ovarian cancer who underwent TVUS screening and retrospective analysis of serum CA 125 levels is described in more detail in the Pelvic Ultrasound ⁶⁴ section of this summary.[130]

Another study found elevated CA 125 levels in 68 of 597 (11.4%) women screened for ovarian cancer. Most of these women had a first-degree or second-degree relative with ovarian cancer, though 51 had a pedigree consistent with inherited susceptibility to breast or ovarian cancer, and seven had a pedigree consistent with Lynch syndrome. Among the premenopausal patients, the elevations in CA 125 were associated with ultrasonographic evidence of endometriosis, adenomyosis, or leiomyomas. Among the eight postmenopausal patients, all had normal ovarian architecture on ultrasound.[129,134] No data are available to address the effectiveness of ovarian cancer screening in preventing deaths from ovarian cancer.

Level of evidence: 5

The National Institutes of Health (NIH) Consensus Statement on Ovarian Cancer recommended against routine screening of the general population for ovarian cancer with serum CA 125. The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA 125 screening every 6 to 12 months, beginning at age 35 years.[136] The Cancer Genetics Studies Consortium task force has recommended that female carriers of a deleterious BRCA1 mutation undergo annual or semiannual screening using TVUS and serum CA 125 levels, beginning at age 25 to 35 years.[9] Both recommendations are based solely on expert opinion and best clinical judgment.

In the United States, the National Cancer Institute (NCI) is conducting a large controlled clinical trial in which 74,000 women were randomized to regular medical care or research-based screening for lung, colorectal, and ovarian cancer. The ovarian cancer screening consisted of serum CA 125 (baseline, and annually for 6 years) and TVUS (baseline, and annually for 4 years).[137] NCI's Clinical Genetics Branch, the Gynecologic Oncology Group, and the Cancer Genetics Network are collaborating on a prospective study (GOG-0199 ⁶⁵) of women at increased genetic risk of ovarian cancer in which risk-reducing surgery and a novel CA 125-based screening strategy are being evaluated.

The PDQ Cancer Screening and Prevention Board has reviewed the evidence related to the efficacy of pelvic examination, TVUS and serum CA 125 screening for ovarian cancer in the general population and concluded “There is inadequate evidence to determine whether routine screening for ovarian cancer…. would result in a decrease in mortality from ovarian cancer.” (Refer to the Ovarian Cancer Screening ⁶² summary for more information.)

Level of evidence: 5

The need for effective ovarian cancer screening is particularly important for women carrying mutations in BRCA1 and BRCA2, and the mismatch repair genes (e.g., MLH1, MSH2, MSH6, PMS2), disorders in which the risk of ovarian cancer is high. There is a special sense of urgency for BRCA1 mutation carriers, in whom cumulative lifetime risks of ovarian cancer may exceed 40%.

Thus, it is expected that many new ovarian cancer biomarkers (either singly or in combination) will be proposed as ovarian cancer screening strategies during the next 5 to 10 years. While this is an active area of research with a number of promising new biomarkers in early development, it is important to acknowledge that, at present, none of these biomarkers alone or in combination have been sufficiently well studied to justify their routine clinical use for screening purposes, either in the general population or in women at increased genetic risk.

Before addressing information related to emerging ovarian cancer biomarkers, it is important to consider the several steps that are required to develop and, more importantly, validate a new biomarker. One useful framework is that published by NCI Early Detection Research Network investigators.[138] They indicated that the goal of a cancer-screening program is to detect tumors at an early stage so that treatment is likely to be successful. The gold standard by which such programs are judged is whether the death rate from the cancer for which screening is performed is reduced among those being screened. In addition, the screening test must be sufficiently noninvasive and inexpensive to allow widespread use in the population to be screened. Maintaining high test specificity (i.e., few false-positive results) is essential for a population screening test, because even a low false-positive rate results in many people having to undergo unnecessary and costly diagnostic procedures and psychological stress. It is likely that the use of several such cancer biomarkers in combination will be required for a screening test to be both sensitive and specific.

Furthermore, a clinically useful test must have a high PPV (a parameter derived from sensitivity, specificity and disease prevalence in the screened population). Practically speaking, a biomarker with a PPV of 10% implies that ten surgical procedures would be required to identify one case of ovarian cancer; the remaining nine surgeries would represent false-positive test findings. In general, the ovarian cancer research community considers biomarkers with a PPV less than 10% to be clinically unacceptable, given the morbidity related to bilateral salpingo-oophorectomy. Finally, it is important to keep in mind that while novel biomarkers may be present in the sera of women with advanced ovarian cancer (which comprise the vast majority of cases analyzed in the early phases of biomarker development), they may or may not be detectable in women with early stage disease, which is essential if the screening test is to be clinically useful.

It has been suggested that there are five general phases in biomarker development and validation:

Phase I — Preclinical exploratory studies

• Identify potentially discriminating biomarkers.
• Usually done by comparing gene over- or under-expression in tumor compared with normal tissue.
• Since many exploratory analyses in large numbers of genes are performed at this stage, one or more may seem to have good discriminating ability between cancers and normal tissue by random chance alone.

Phase 2 — Clinical assay development for clinical disease

• Develop a clinical assay that can be obtained on noninvasively obtained samples (e.g., a blood specimen).
• Often the test targets the protein product of one of the genes found to be of interest in phase I.
• The goal is to describe the performance characteristics of the assay for distinguishing between subjects with and without cancer. At this point, the assay should be in its final configuration and remain stable throughout the following phases.
• IMPORTANT: Since the case subjects in a phase 2 study already have cancer, with assay results obtained at the time of disease diagnosis, one cannot determine if disease can be detected early with a given biomarker.

Phase 3 — Retrospective longitudinal repository studies

• Compare clinical specimens collected from cancer case subjects before their clinical diagnosis with specimens from subjects who have not developed cancer.
• Evaluate, as a function of time before clinical diagnosis, the biomarker’s ability to detect preclinical disease.
• Define the criteria for a positive screening test in preparation for phase 4.
• Explore the influence of other patient characteristics (e.g., age, gender, smoking status, medication use) on the ability of the biomarker to discriminate between those with and without preclinical disease.

Phase 4 — Prospective screening studies

• Determine the operating characteristics of the biomarker-based screening test in a population for which the test is intended.
• Measure the detection rate (number of abnormal tests among all those with the disease) and the false-positive rate (the number of abnormal tests among all those who do not have the disease).
• Evaluate whether the cancers detected by the test are being found at an early stage, a point at which treatment is more likely to be curative.
• Assess whether the test is acceptable in a population of persons for whom it is intended. Will subjects comply with the test schedule and results?

Phase 5 — Cancer control studies

• Ideally, randomized controlled clinical trials in clinically relevant populations, in which one arm is subjected to screening and appropriate intervention if screen-positive, while the other arm is not screened.
• Determine whether the death rate of the cancer being screened for is reduced among those who use the screening test.
• Obtain information about the costs of screening and treatment of screen-detected cancers.

Finally, for a validated biomarker test to be considered appropriate for use in a particular population, it must have been evaluated in that specific population without prior selection of known positives and negatives. In addition, the test must demonstrate clinical utility, that is, a positive net balance of benefits and risks associated with the application of the test. These may include improved health outcomes, as well as net psychosocial and economic benefits.[139]

Ovarian cancer poses a unique challenge relative to the potential impact of false-positive test results. There are no reliable noninvasive diagnostic tests for early stage disease, and clinically-significant early stage cancer may not be grossly visible at the time of exploratory surgery.[140] Consequently, it is likely that some patients will only be reassured that their abnormal test does not indicate the presence of cancer by having their ovaries and fallopian tubes surgically removed and examined microscopically. High test specificity (i.e., a very low false-positive rate) is required to avoid unnecessary surgery and induction of premature menopause in false positive women.

An ovarian cancer symptom index for predicting the presence of cancer was evaluated in 75 cases and 254 high-risk controls (BRCA mutation carriers or women with a strong family history of breast and ovarian cancer).[141] Women had a positive symptom index if they reported any of the predefined symptoms (bloating or increase in abdominal size, abdominal or pelvic pain, and difficulty eating or feeling full quickly) more than 12 times per month occurring only within the prior 12 months. CA 125 values greater than 30 U/mL were considered abnormal. The symptom index independently predicted the presence of ovarian cancer, after controlling for CA 125 levels (p < 0.05). The combination of an elevated CA 125 and a positive symptom index correctly identified 89.3% of the cases. The symptom index correlated with the presence of cancer in 50% of the affected women who did not have elevated CA 125 levels, but 11.8% of the high-risk controls without cancer also had a positive symptom index. The authors suggested that a composite index including both CA 125 and the symptom index had better performance characteristics than either test used alone, and that this strategy might be used as a first screen in a multi-step screening program. Additional test performance validation and determination of clinical utility are required in unselected screening populations.

Level of evidence: 5

A novel modification of CA 125 screening is based on the hypothesis that rising CA 125 levels over time may provide better ovarian cancer screening performance characteristics than simply classifying CA 125 as normal or abnormal, based on an arbitrary cut-off value. This has been implemented in the form of the Risk of Ovarian Cancer Algorithm (ROCA), an investigational statistical model that incorporates serial CA 125 test results and other covariates into a computation which produces an estimate of the likelihood that ovarian cancer is present in the screened subject. The first report of this strategy – based on reanalysis of 5,550 average-risk women from the Stockholm Ovarian Cancer screening trial – suggested that ovarian cancer cases and controls could be distinguished with 99.7% sensitivity, 83% specificity, and a PPV of 16%. That PPV represents an eight-fold increase over the 2% PPV reported with a single measure of CA 125.[142] This report was followed by applying the risk of ovarian cancer algorithm (ROCA) to 33,621 serial CA 125 values obtained from the 9,233 average-risk postmenopausal women in a prospective British ovarian cancer screening trial.[143] The area under the receiver operator curve increased from 84% to 93% (P = 0.01) for ROCA compared with a fixed CA 125 cutoff. These observations represented the first evidence that preclinical detection of ovarian cancer might be improved using this screening strategy. A prospective study of 13,000 normal volunteers aged 50 years and older in England used serial CA 125 values and the ROCA to stratify participants into low, intermediate and elevated risk subgroups.[144] Each had its own prescribed management strategy, including TVUS and repeat CA 125 either annually (low risk) or at 3 months (intermediate risk). Using this protocol, ROCA was found to have a specificity of 99.8% and a PPV of 19%.

Currently, there are two prospective trials underway in England which utilize the ROCA : the United Kingdom Collaborative Trial of Ovarian Cancer Screening targets normal-risk women randomized either to (1) no screening, (2) annual ultrasound or (3) multimodal screening using the ROCA (n = 202,638; accrual completed; follow-up ends in 2011); and the U.K. Familial Ovarian Cancer Screening Study which targets high-risk women (accrual ongoing). There are also two high-risk cohorts using the ROCA under evaluation in the United States: the Cancer Genetics Network ROCA Study ⁶⁶ (n = 2,500; follow-up complete; analysis underway), and the Gynecologic Oncology Group Protocol 199 (GOG-0199 ⁶⁵) (n = 1,575 screening subjects; enrollment complete; follow-up ends in late 2011).[145] Thus, additional data regarding the utility of this currently investigational screening strategy will become available within the next few years.

Level of evidence: 4

A wide array of new candidate ovarian cancer biomarkers has been described during the past decade, including HE4; mesothelin; kallekreins 6, 10, and 11; osteopontin; prostasin; M-CSF ;OVX1; lysophosphatidic acid; vascular endothelial growth factor (VEGF) B7-H4; and interleukins 6 and 8, to name just a few [reviewed in references 9-11].[146-148] These have been singly studied, in combination with CA 125, or in various other permutations. Most of the study populations are relatively small and comprise highly-selected known ovarian cancer cases and healthy controls of the type evaluated in early biomarker development phases I and II. Results have not been consistently replicated in multiple studies; presently, none are considered ready for widespread clinical application.

Level of evidence: 5

Initially, mass spectroscopy of serum proteins was combined with complex analytic algorithms to identify protein patterns that might distinguish between ovarian cancer cases and controls.[149] This approach assumed that pattern recognition alone would be sufficient to permit such discrimination, and that identification of the specific proteins responsible for the patterns identified was not required. Subsequently, this strategy has been modified, using similar laboratory tools, to identify finite numbers of specific known serum markers that may be used in place of, or in conjunction with, CA 125 measurements for the early detection of cancer.[150] These studies[148,151] have generally been small case-control studies that are limited by sample size and the number of early-stage cancer cases included. Further evaluation is needed to determine whether any additional markers identified in this fashion have clinical utility for the early detection of ovarian cancer in the unselected clinical population of interest.

Level of evidence: 5

Because individual biomarkers have not met the criteria for an effective screening test, it has been suggested that it may be necessary to combine multiple ovarian cancer biomarkers in order to obtain satisfactory screening test results. This strategy was employed to quantitatively analyze six serum biomarkers (leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA 125), using a multiplex, bead-based platform.[152] A similar assay was available commercially under the trade name OvaSure™ until its voluntary withdrawal from the market by the manufacturer.[Response to FDA Warning Letter ⁶⁷]

The cases in this study were newly-diagnosed ovarian cancer patients who had blood collected just prior to surgery: 36 were stage I/II; 120 were stage III/IV. The controls were healthy age-matched individuals who had not developed ovarian cancer within 6 months of blood draw. Neither cases nor controls in this study were well-characterized regarding their familial/genetic risk status, but they have been suggested to comprise a high-risk population.

First, 181 controls and 113 ovarian cancer cases were tested to determine the initial panel of biomarkers that best discriminated between cases and controls (training set). The resulting panel was applied to an additional 181 controls and 43 ovarian cancer cases (test set). Pooling both early and late stage ovarian cancer across the combined training and test sets, performance characteristics were reported as a sensitivity of 95.3% and a specificity of 99.4%, with a PPV of 99.3% and a NPV of 99.2%, using a formula that assumed an ovarian cancer prevalence of about 50%, as seen in the highly-selected research population. In order to avoid biases which may make test performance appear to be better than it really is, it is worth noting that combining training and test populations in analyses of this sort is generally not recommended.[153]

However, the most appropriate prevalence to use is the disease prevalence in the unselected population to be screened. The prevalence of ovarian cancer in the general population is 1 in 2,500. In a recently published correction to their manuscript,[152] the authors assumed that the prevalence of ovarian cancer in the screened population was 1/2,500 (0.04%) and recalculated the PPV to be only 6.5%, and on that basis the investigators have retracted their claim that this test is suitable for population screening. If this test were used in patients at increased risk of ovarian cancer, the actual prevalence in such a target population is likely to be higher than that observed in the general population, but well below the assumed 50% figure used in the published analysis. This revised PPV of 6.5% indicates that approximately 1 in 15 women with a positive test would in fact have ovarian cancer, and only a fraction of those with ovarian cancer would be stages I or II. The remaining 14 positive tests would represent false-positives, and these women would be at risk of exposure to needless anxiety and potentially morbid diagnostic procedures, including bilateral salpingo-oophorectomy.

Viewed in the context of the criteria previously described,[138] this assay would be classified as phase 2 in its development. While this appears to be a promising avenue of ovarian cancer screening research, additional validation is required, particularly in an unselected population representative of the clinical screening population of interest. A recent position statement ⁶⁸ by the Society of Gynecologic Oncologists regarding this assay indicated “it is our opinion that additional research is needed to validate the test’s effectiveness before offering it to women outside of the context of a research study conducted with appropriate informed consent under the auspices of an Institutional Review Board.”

Level of evidence: 5

Refer to the PDQ summary on Prevention of Ovarian Cancer ²⁴ for information on prevention in the general population, and to the PDQ summary Cancer Genetics Overview ² for information on levels of evidence related to screening and prevention.

It has been suggested that incessant ovulation, with repetitive trauma and repair to the ovarian epithelium, increases the risk of ovarian cancer. In epidemiologic studies in the general population, physiologic states that prevent ovulation have been associated with decreased risk of ovarian cancer. It has also been suggested that chronic overstimulation of the ovaries by luteinizing hormone (LH) plays a role in ovarian cancer pathogenesis.[154] Most of these data derive from studies in the general population, but some information suggests the same is true in women at high risk due to genetic predisposition.

Among the general population, parity decreases the risk of ovarian cancer by 45% compared with nulliparity. Subsequent pregnancies after the first appear to decrease ovarian cancer risk by 15%.[155] Earlier studies of women with BRCA1/2 mutations showed that parity decreases the risk of ovarian cancer.[156,157] In a large case-control study, parity was associated with a significant reduction in ovarian cancer risk in women with BRCA1 mutations, OR 0.67 (CI 0.46–0.96).[158] For each birth, BRCA1 mutation carriers had an OR of 0.87 (CI 0.79–0.95). In this same study, parity was associated with an increase in ovarian cancer risk in BRCA2 mutation carriers; however, there was no significant trend for each birth, OR 1.08 (0.90–1.29). Further studies are necessary to define the association of parity and risk of ovarian cancer in BRCA2 mutation carriers, but for BRCA1 carriers, each live birth significantly decreases risk of ovarian cancer, as it does in sporadic ovarian cancer.

In the general population, breast feeding is associated with a decrease in ovarian cancer risk.[159] In BRCA mutation carriers, data are limited. One study found no protective effect with breast feeding.[156] A case-control study among women with BRCA1 or BRCA2 mutations demonstrates a significant reduction in risk of ovarian cancer (OR = 0.39) for women who have had a tubal ligation. This protective effect was confined to those women with mutations in BRCA1 and persists after controlling for oral contraceptive pill use, parity, history of breast cancer, and ethnicity.[160] A case-control study of ovarian cancer in Israel found a 40% to 50% reduced risk of ovarian cancer among women undergoing gynecologic surgeries (tubal ligation, hysterectomy, unilateral oophorectomy, ovarian cystectomy, excluding bilateral oophorectomy).[161] The mechanism of protection is uncertain. Proposed mechanisms of action include decreased blood flow to the ovary, resulting in interruption of ovulation and/or ovarian hormone production; occlusion of the fallopian tube, thus blocking a pathway for potential carcinogens; or a reduction in the concentration of uterine growth factors that reach the ovary.[162] (Refer to the PDQ summary on Prevention of Ovarian Cancer ²⁴ for information relevant to the general population.)

Oral contraceptives have been shown to have a protective effect against ovarian cancer in the general population.[163] Several studies including a large, multicenter case-control study showed a protective effect,[54,158,160,164,165] while one population-based study from Israel failed to demonstrate a protective effect.[157]

A multicenter study of 799 ovarian cancer patients with BRCA1 or BRCA2 mutations, and 2,424 control patients without ovarian cancer but with a BRCA1 or BRCA2 mutation, showed a significant reduction in ovarian cancer risk with use of oral contraceptives, OR 0.56 (CI 0.45–0.71). Compared to never use of oral contraceptives, duration up to one year was associated with an OR of 0.67 (0.50–0.89). The OR for each year of oral contraceptive use was 0.95 (CI 0.92–0.97) with a maximum observed protection at 3 years to 5 years of use. This study included women from a prior study by the same authors and confirmed the results of that prior study.[54] A population-based case-control study of ovarian cancer did not find a protective benefit of oral contraceptive use in BRCA1 or BRCA2 mutation carriers, (OR = 1.07 for ≥5 years of use), though they were protective, as expected, among noncarriers (OR = 0.53 for ≥5 years of use).[157] A small population-based case-control study of 36 BRCA1 mutation carriers, however, observed a similar, protective effect in both mutation carriers and noncarriers (OR = approximately 0.5).[165] Finally, a multicenter study of subjects drawn from numerous registries observed a protective effect of oral contraceptives among the 147 BRCA1 or BRCA2 mutation carriers with ovarian cancer compared with the 304 matched mutation carriers without cancer (OR = 0.62 for ≥6 years of use).[164]

As noted under oral contraceptives in the Breast Cancer Risk Modification ⁶⁹ section of this summary, there are conflicting data regarding their effect on breast cancer risk, with some retrospective case-control studies suggesting that oral contraceptive use increases the risk of breast cancer in women at inherited risk of breast cancer,[49,166] including BRCA1 mutation carriers,[50] while a population-based study found a reduced risk among BRCA1 mutation carriers.[52]

Level of evidence: 3

Numerous studies have found that women at inherited risk of breast and ovarian cancer have a decreased risk of ovarian cancer following risk-reducing salpingo-oophorectomy (RRSO). A retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (HR = 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR = 0.04; 95% CI, 0.01–0.16) after bilateral oophorectomy.[96] A prospective single-institution study of 170 women with BRCA1 or BRCA2 mutations showed a similar trend.[97] With oophorectomy, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74). In a case-control study in Israel, bilateral oophorectomy was associated with reduced ovarian/peritoneal cancer risks (OR = 0.12; 95% CI, 0.06–0.24).[161]

In addition to a reduction in risk of ovarian and breast cancer, RRSO may also significantly improve overall survival, as well as breast and ovarian cancer specific survival. A prospective cohort study of 666 women with germline mutations in BRCA1 and BRCA2 found an HR for overall mortality of 0.24 (95% CI, 0.08–0.71) in women who had RRSO compared with women who did not.[167] This study provides the first evidence to suggest a survival advantage among women undergoing RRSO.

Studies on the degree of risk reduction afforded by RRSO have begun to clarify the spectrum of occult cancers discovered at the time of surgery. Primary fallopian tube cancers, primary peritoneal cancers, and occult ovarian cancers have all been reported. Several case series have reported a prevalence of malignant findings among mutation carriers undergoing risk-reducing oophorectomy to be in the range of 2.3% to 33%, with a median age of the affected women in the range of 42 to 48 years.[168-172] The wide variation in prevalence is likely due to differences in surgical technique and pathologic handling of the tissues. In addition to occult cancers, premalignant lesions have also been described in fallopian tube tissue removed for prophylaxis. In one series of 12 women with BRCA1 mutations undergoing risk-reducing surgery, 11 had hyperplastic or dysplastic lesions identified in the tubal epithelium. In several of the cases the lesions were multifocal.[173] These pathologic findings are consistent with the identification of germline BRCA1 and BRCA2 mutations in women affected with both tubal and primary peritoneal cancers.[172,174-179] One study suggests a causal relationship between early tubal carcinoma, or tubal intraepithelial carcinoma, and subsequent invasive serous carcinoma of the fallopian tube, ovary or peritoneum.[180]

These findings support the inclusion of fallopian tube cancers, which account for less than 1% of all gynecologic cancers in the general population, as a component of hereditary ovarian cancer, and underscore the need for the routine collection of peritoneal washings and careful pathologic evaluation of all tissue obtained at the time of risk-reducing surgery. They also raise questions about the optimal surgical approach to provide maximal cancer risk reduction. Some surgeons have recommended hysterectomy in addition to RRSO to remove the remnant of fallopian tube tissue embedded in the uterus, but there is no consensus on this issue, and most, if not all, fallopian tubes cancers appear to arise in the more distal segments of the tube.[172] Several studies have examined whether BRCA1 or BRCA2 mutation carriers are at increased risk of endometrial cancer.[181-185] While case reports and smaller studies suggested an association between BRCA mutations and a specific histology of endometrial cancer called uterine papillary serous cancer,[182] other studies have not found an increased risk of either uterine papillary serous cancer or endometrial cancer in BRCA1 or BRCA2 mutation carriers.[183,184] One cohort study of 857 BRCA1 or BRCA2 mutation carriers reported an increased endometrial cancer risk but found that this risk was largely due to tamoxifen use associated with breast cancer treatment.[185] Therefore, in the absence of tamoxifen use or other underlying uterine or cervical problems, hysterectomy is not a necessary component of risk–reducing salpingo-oophorectomy.

The peritoneum, however, appears to remain at low risk for the development of a Mullerian-type adenocarcinoma, even after oophorectomy.[186-190] Of the 324 women from the Gilda Radner Familial Ovarian Cancer Registry who underwent risk-reducing oophorectomy, six (1.8%) subsequently developed primary peritoneal carcinoma. No period of follow-up was specified.[191] Among 238 individuals in the Creighton Registry with BRCA1/2 mutations who underwent risk-reducing oophorectomy, five subsequently developed intra-abdominal carcinomatosis (2.1%). Of note, all five of these women had BRCA1 mutations.[192] A study of 1,828 women with a BRCA1 or BRCA2 mutation found a 4.3% risk of primary peritoneal cancer at 20 years after RRSO.[193]

Given the current limitations of screening for ovarian cancer and the high risk for the disease in BRCA1 and BRCA2 mutation carriers, NCCN Guidelines ⁷⁰ recommend RRSO between the ages of 35 and 40 years or upon completion of childbearing, as an effective risk-reduction option. Optimal timing of RRSO must be individualized, but evaluating a woman's risk for ovarian cancer based on mutation status can be helpful in the decision-making process. In a large study of U.S. BRCA1 and BRCA2 families, age-specific cumulative risk of ovarian cancer at age 40 years was 4.7% for BRCA1 mutation carriers and 1.9% for BRCA2 mutation carriers.[194] In a combined analysis of 22 studies of BRCA1 and BRCA2 mutation carriers, risk of ovarian cancer for BRCA1 mutation carriers increases most sharply between the ages of 40 years and 50 years, while for BRCA2 mutation carriers the risk is low before age 50 years, but increases sharply between the ages of 50 years and 60 years.[195] In a population-based study of BRCA mutations in ovarian cancer patients, patients with BRCA2 mutations had a significantly later age of onset than patients with BRCA1 mutations (57.3 years [40-72] vs. 52.6 [31-78]).[196] In summary, women with BRCA1 mutations may consider RRSO for ovarian cancer risk reduction at a somewhat earlier age than women with BRCA2 mutations; however, women with BRCA2 mutations may still consider early RRSO for breast cancer risk reduction.

For women who are premenopausal at the time of surgery, the symptoms of surgical menopause (e.g., hot flashes, mood swings, weight gain, and genitourinary complaints) can cause a significant impairment in their quality of life. To reduce the impact of these symptoms, providers have often prescribed a time-limited course of systemic HRT after surgery. The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 mutation has only been studied in the context of risk-reducing oophorectomy, a procedure known to reduce the risk of breast cancer. In a prospective study of 462 women with BRCA1 or BRCA2 mutations, 155 who had undergone bilateral oophorectomy (139 before age 50 years), the breast cancer risk reduction of 37% was essentially the same among the 93 women who took HRT compared with the reduction of 38% among those without HRT.[64] This finding needs to be confirmed in a larger study but suggests that HRT in this particular setting does not negate the protective effect of oophorectomy on breast cancer risk.

Studies have examined the effect of RRSO on quality of life (QOL). One study examined 846 high-risk women of whom 44% underwent RRSO and 56% had periodic screening.[197] Of the 368 BRCA1/2 mutation carriers, 72% underwent RRSO. No significant differences were observed in QOL scores (as assessed by the Short Form-36) between those with RRSO or screening or compared with the general population; however, women with RRSO had fewer breast and ovarian cancer worries (P < .001), more favorable cancer risk perception (P < .05) but more endocrine symptoms (P < .001) and worse sexual functioning (P < .05). Of note, 37% of women used HRT following RRSO, although 62% were either peri-menopausal or postmenopausal.[197] Researchers then examined 450 premenopausal high-risk women who had chosen either RRSO (36%) or screening (64%). Of those in the RRSO group, 47% used HRT. HRT users (n = 77) had fewer vasomotor symptoms than nonusers (n = 87) (p<0.05), although more vasomotor symptoms than women in the screening group (n = 286). Likewise, women who underwent RRSO and used HRT had more sexual discomfort due to vaginal dryness and dyspareunia than those in the screening group (p < 0.01). Therefore, while such symptoms are improved via HRT use, HRT is not completely effective and additional work needs to be done.

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164. Whittemore AS, Balise RR, Pharoah PD, et al.: Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer 91 (11): 1911-5, 2004.  [PUBMED Abstract]
     
     
165. McGuire V, Felberg A, Mills M, et al.: Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations. Am J Epidemiol 160 (7): 613-8, 2004.  [PUBMED Abstract]
     
     
166. Grabrick DM, Hartmann LC, Cerhan JR, et al.: Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer. JAMA 284 (14): 1791-8, 2000.  [PUBMED Abstract]
     
     
167. Domchek SM, Friebel TM, Neuhausen SL, et al.: Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Lancet Oncol 7 (3): 223-9, 2006.  [PUBMED Abstract]
     
     
168. Leeper K, Garcia R, Swisher E, et al.: Pathologic findings in prophylactic oophorectomy specimens in high-risk women. Gynecol Oncol 87 (1): 52-6, 2002.  [PUBMED Abstract]
     
     
169. Olivier RI, van Beurden M, Lubsen MA, et al.: Clinical outcome of prophylactic oophorectomy in BRCA1/BRCA2 mutation carriers and events during follow-up. Br J Cancer 90 (8): 1492-7, 2004.  [PUBMED Abstract]
     
     
170. Colgan TJ, Murphy J, Cole DE, et al.: Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status. Am J Surg Pathol 25 (10): 1283-9, 2001.  [PUBMED Abstract]
     
     
171. Powell CB, Kenley E, Chen LM, et al.: Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: role of serial sectioning in the detection of occult malignancy. J Clin Oncol 23 (1): 127-32, 2005.  [PUBMED Abstract]
     
     
172. Callahan MJ, Crum CP, Medeiros F, et al.: Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol 25 (25): 3985-90, 2007.  [PUBMED Abstract]
     
     
173. Piek JM, van Diest PJ, Zweemer RP, et al.: Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 195 (4): 451-6, 2001.  [PUBMED Abstract]
     
     
174. Paley PJ, Swisher EM, Garcia RL, et al.: Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol 80 (2): 176-80, 2001.  [PUBMED Abstract]
     
     
175. Rose PG, Shrigley R, Wiesner GL: Germline BRCA2 mutation in a patient with fallopian tube carcinoma: a case report. Gynecol Oncol 77 (2): 319-20, 2000.  [PUBMED Abstract]
     
     
176. Zweemer RP, van Diest PJ, Verheijen RH, et al.: Molecular evidence linking primary cancer of the fallopian tube to BRCA1 germline mutations. Gynecol Oncol 76 (1): 45-50, 2000.  [PUBMED Abstract]
     
     
177. Piek JM, Torrenga B, Hermsen B, et al.: Histopathological characteristics of BRCA1- and BRCA2-associated intraperitoneal cancer: a clinic-based study. Fam Cancer 2 (2): 73-8, 2003.  [PUBMED Abstract]
     
     
178. Levine DA, Argenta PA, Yee CJ, et al.: Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations. J Clin Oncol 21 (22): 4222-7, 2003.  [PUBMED Abstract]
     
     
179. Aziz S, Kuperstein G, Rosen B, et al.: A genetic epidemiological study of carcinoma of the fallopian tube. Gynecol Oncol 80 (3): 341-5, 2001.  [PUBMED Abstract]
     
     
180. Kindelberger DW, Lee Y, Miron A, et al.: Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol 31 (2): 161-9, 2007.  [PUBMED Abstract]
     
     
181. Thompson D, Easton DF; Breast Cancer Linkage Consortium.: Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94 (18): 1358-65, 2002.  [PUBMED Abstract]
     
     
182. Lavie O, Hornreich G, Ben-Arie A, et al.: BRCA germline mutations in Jewish women with uterine serous papillary carcinoma. Gynecol Oncol 92 (2): 521-4, 2004.  [PUBMED Abstract]
     
     
183. Levine DA, Lin O, Barakat RR, et al.: Risk of endometrial carcinoma associated with BRCA mutation. Gynecol Oncol 80 (3): 395-8, 2001.  [PUBMED Abstract]
     
     
184. Goshen R, Chu W, Elit L, et al.: Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome? Gynecol Oncol 79 (3): 477-81, 2000.  [PUBMED Abstract]
     
     
185. Beiner ME, Finch A, Rosen B, et al.: The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study. Gynecol Oncol 104 (1): 7-10, 2007.  [PUBMED Abstract]
     
     
186. Chen KT, Schooley JL, Flam MS: Peritoneal carcinomatosis after prophylactic oophorectomy in familial ovarian cancer syndrome. Obstet Gynecol 66 (3 Suppl): 93S-94S, 1985.  [PUBMED Abstract]
     
     
187. Lynch HT, Bewtra C, Lynch JF: Familial ovarian carcinoma. Clinical nuances. Am J Med 81 (6): 1073-6, 1986.  [PUBMED Abstract]
     
     
188. Lynch HT, Watson P, Bewtra C, et al.: Hereditary ovarian cancer. Heterogeneity in age at diagnosis. Cancer 67 (5): 1460-6, 1991.  [PUBMED Abstract]
     
     
189. Tobacman JK, Greene MH, Tucker MA, et al.: Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet 2 (8302): 795-7, 1982.  [PUBMED Abstract]
     
     
190. Truong LD, Maccato ML, Awalt H, et al.: Serous surface carcinoma of the peritoneum: a clinicopathologic study of 22 cases. Hum Pathol 21 (1): 99-110, 1990.  [PUBMED Abstract]
     
     
191. Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 71 (9): 2751-5, 1993.  [PUBMED Abstract]
     
     
192. Casey MJ, Synder C, Bewtra C, et al.: Intra-abdominal carcinomatosis after prophylactic oophorectomy in women of hereditary breast ovarian cancer syndrome kindreds associated with BRCA1 and BRCA2 mutations. Gynecol Oncol 97 (2): 457-67, 2005.  [PUBMED Abstract]
     
     
193. Finch A, Beiner M, Lubinski J, et al.: Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA 296 (2): 185-92, 2006.  [PUBMED Abstract]
     
     
194. Chen S, Iversen ES, Friebel T, et al.: Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol 24 (6): 863-71, 2006.  [PUBMED Abstract]
     
     
195. Antoniou A, Pharoah PD, Narod S, et al.: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72 (5): 1117-30, 2003.  [PUBMED Abstract]
     
     
196. Risch HA, McLaughlin JR, Cole DE, et al.: Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98 (23): 1694-706, 2006.  [PUBMED Abstract]
     
     
197. Madalinska JB, Hollenstein J, Bleiker E, et al.: Quality-of-life effects of prophylactic salpingo-oophorectomy versus gynecologic screening among women at increased risk of hereditary ovarian cancer. J Clin Oncol 23 (28): 6890-8, 2005.  [PUBMED Abstract]
     
     

Psychosocial Issues in Inherited Breast Cancer Syndromes

Introduction

Psychosocial research in the context of cancer genetic testing helps to define psychological outcomes, interpersonal and familial effects, and cultural and community responses. It also identifies behavioral factors that encourage or impede surveillance and other health behaviors. It can enhance decision-making about risk-reduction interventions, evaluate psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification and genetic testing, provide data to help resolve ethical concerns, and predict the interest in testing of various groups.

Research in these areas is limited by few randomized controlled trials, and many reports are based on uncontrolled studies of selected high-risk populations. Research is likely to expand considerably with access to larger populations of at-risk individuals.

There have been a number of descriptions of cancer genetics programs that provide genetic susceptibility testing.[1-9] The development of such programs was encouraged by federal funding of multidisciplinary research programs that offered intensive genetic counseling for hereditary cancer syndromes, psychological assessment and back-up, and physician involvement.[10]

Decisions about whether to pursue breast cancer genetic testing involve complex biologic, behavioral and social elements.[11] There are vast differences in interest in and actual uptake rates of testing reported in the literature. In a systematic review of 40 peer-reviewed primary clinical studies published between 1990 and May 2002,[12] it was reported that sampling frame and other methodological variables contributed to the wide variability. On average, interest in genetic testing was 66% (range 20%-96%), while actual uptake of genetic testing was 59% (range 25%-96%) (odds ratio [OR] 1.27; 95% confidence interval [CI], 1.16–1.39). In multivariate analysis, personal and family history of cancer, study recruitment and setting were all associated with testing uptake.

Furthermore, accrual statistics in different populations are difficult to compare because there are many points in the genetic risk assessment process at which a family member can decline, and no standard method of reporting these rates has been developed.[13] Factors that may influence uptake of testing include:

• Cost of genetic testing.
• How informative testing would be (e.g., presence of a known mutation in the family or ethnic group vs. lack of an identified mutation).
• Extent to which genetic test results are likely to influence clinical decision-making.[14]

Motivations for testing include the belief that testing positive would increase one’s motivation to get regular clinical breast examinations, to do breast self-exams, and to get recommended mammograms.[15] Women known to be at increased risk do not necessarily adhere to screening recommendations at higher rates than women at population risk, nor do they necessarily pursue or complete genetic testing, though the data on this subject are contradictory.[16-18] An additional motivation for testing is to receive information that would benefit other family members.[19] Another motivator for testing may be recommendation by a physician. In a retrospective study of 335 women considering genetic testing, 77% reported that they wanted the opinion of the genetics physician about whether they should be tested, and 49% wanted the opinion of their primary care provider.[20]

In one study of women who pursued BRCA1 and BRCA2 mutation testing and received uninformative test results, 45% (17/40) were interested in undergoing additional testing for five large rearrangements (deletions and insertions) in the BRCA1 gene. There were no significant differences in BRCAPRO scores, age at time of genetic testing, number of children, or number of siblings between individuals who chose to pursue additional testing and those who declined. Women who chose to undergo additional testing were significantly less likely to have a diagnosis of breast or ovarian cancer at the time of initial testing.[21]

Limited data are available about the characteristics of at-risk individuals who decline to be or have never been tested. It is difficult to access samples of test decliners since they are people who also may be reluctant to participate in research studies. Studies of testing are difficult to compare because people may decline at different points and with different amounts of pretest education and counseling. One study found that 43% of affected and unaffected individuals from hereditary breast/ovarian cancer families completing a baseline interview regarding testing declined. Most individuals declining testing chose not to participate in educational sessions. Decliners were more likely to be male and unmarried and had fewer relatives affected with breast cancer. Those decliners who had high levels of cancer-related stress had higher levels of depression. Decliners lost to follow-up were significantly more likely to be affected with cancer.[22] Another study looked at a small number (n = 13) of women decliners who carry a 25% to 50% probability of harboring a BRCA mutation and found that these nontested women were more likely to be childless and have a higher educational level. This study showed that most women had decided not to undergo the test after serious deliberation about the risks and benefits. Satisfaction with frequent surveillance was given as one reason for nontesting in most of these women.[23] Other reasons for declining included having no children and becoming acquainted with breast/ovarian cancer in the family relatively early in their lives.[22,23] A third study evaluated characteristics of 34 individuals who declined BRCA1/2 testing in a large multicenter study in the United Kingdom. Decliners were younger compared with a national sample of test acceptors, and female decliners had lower mean scores on a measure of cancer worry. Although 78% of test decliners/deferrers felt that their health was at risk, they reported that learning about their BRCA1/2 mutation status would cause them to worry about the following:

• Their children's health (76%).
• Their life insurance (60%).
• Their own health (56%).
• Loss of their job (5%).
• Receiving less screening if they did not carry a BRCA1/2 mutation (62%).

Apprehension about the impact of the test result was a more important factor in the reason to decline than concrete burdens such as time to travel to a genetics clinic and time away from work, family, and social obligations.[24] In 15% (n = 31) of individuals from 13 hereditary breast and ovarian cancer families who underwent genetic education and counseling and declined testing for a documented mutation in the family, positive changes in family relationships were reported, specifically greater expressiveness and cohesion, compared with those who pursued testing.[25]

Participation in breast cancer risk counseling among family relatives of breast cancer patients is positively associated with higher levels of education, income, and positive health behaviors (nonsmokers, any current alcohol use, recent clinical breast exam), and perceived and objective risk perception.[26,27] Other predictors of participation are being married, having a family history of cancer, presence of a daughter, fear of stigma, and believing there are more reasons to be tested than not to be tested.[28]

Women recruited from high-risk clinics, i.e., women who have expressed their concern about breast cancer by seeking specialized medical attention, are more likely than women recruited from registry sources to attend counseling and educational sessions about cancer genetics and genetic testing.[16,29] Genetic testing uptake was influenced by eligibility for free testing, history of breast or ovarian cancer, and Ashkenazi Jewish heritage.[14] Interest in testing declines sharply if it is not immediately available.[16] Knowledge about the details of cancer genetic testing is not associated with the decision to be tested,[30] suggesting a need for improved education about cancer genetics. Several studies suggest that interest in cancer genetic testing is generally high despite respondents' relative lack of knowledge regarding the pros and cons of attempting to learn one's mutation status.[27]

There are limited data on uptake of genetic counseling and testing among nonwhite populations, and further research will be needed to define factors influencing uptake in these populations.[29] In a study of African-American women at increased risk of breast cancer, those with a personal history of cancer or a greater perceived risk for developing cancer were more likely to report greater limitations or drawbacks of genetic testing. Those with more fatalistic beliefs about cancer, higher perceived risk of having a BRCA1/2 mutation, and more relatives affected with breast or ovarian cancer were more likely to consider undergoing BRCA1/2 testing.[31] In a case-control study of women who had been seen in a university-based primary care system, African-American women with a family history of breast or ovarian cancer were less likely to undergo BRCA1/2 testing compared with white women who had similar histories. Other predictors of testing used in that study include younger age, higher anxiety, belief that testing will provide reassurance, absence of concern about discrimination, and having had a primary care doctor or gynecologist discuss genetic testing with the patient.[32]

The emerging literature in this area suggests that risk perceptions, health beliefs, psychological status, and personality characteristics are important factors in decision-making about breast/ovarian cancer genetic testing. Many women presenting at academic centers for BRCA1/2 testing arrive with a strong belief that they have a mutation, having decided they want genetic testing, but possessing little information about the risks or limitations of testing.[33] Most mean scores of psychological functioning at baseline for subjects in genetic counseling studies were within normal limits.[34] Nonetheless, a subset of subjects in many genetic counseling studies present with elevated anxiety, depression, or cancer worry.[35] Identification of these individuals is essential to prevent adverse outcomes.

A general tendency to overestimate inherited risk of breast and ovarian cancer has been noted in at-risk populations,[36-38] in cancer patients,[37,39,40] in spouses of breast and ovarian cancer patients,[41] and among women in the general population.[42-44] This tendency may encourage a belief that BRCA1/2 genetic testing will be more informative than it is currently thought to be. There is some evidence that even counseling does not dissuade women at low to moderate risk from the belief that BRCA1 testing could be valuable.[29] Overestimation of both breast and ovarian cancer risk has been associated with nonadherence to physician-recommended screening practices.[45,46] A meta-analysis of 12 studies of outcomes of genetic counseling for breast/ovarian cancer showed that counseling improved the accuracy of risk perception.[47]

Women appear to be the prime communicators within families about the family history of breast cancer.[48] Higher numbers of maternal versus paternal transmission cases are reported,[49] likely due to family communication patterns, to the misconception that breast cancer risk can only be transmitted through the mother, and to the greater difficulty in recognizing paternal family histories because of the need to identify more distant relatives with cancer. Physicians and counselors taking a family history are encouraged to elicit paternal as well as maternal family histories of breast, ovarian, or other associated cancers.[48]

The accuracy of reported family history of breast or ovarian cancer varies; some studies found levels of accuracy above 90%,[50,51] with others finding more errors in the reporting of cancer in second-degree or more distant relatives[52] or in age of onset of cancer.[53] Less accuracy has been found in the reporting of cancers other than breast cancer. Ovarian cancer history was reported with 60% accuracy in one study compared with 83% accuracy in breast cancer history.[54] Providers should be aware that there are a few published cases of Munchausen syndrome in reporting of false family breast cancer history.[55] Much more common is erroneous reporting of family cancer history due to unintentional errors or gaps in knowledge, related in some cases to the early death of potential maternal informants about cancer family history.[48] (Refer to the Taking a Family History ³⁰ section of the Cancer Genetics Risk Assessment and Counseling ²⁹ summary.)

Targeted written,[56,57] video, CD-ROM, interactive computer program,[58-62] and culturally targeted educational materials [63] may be an effective and efficient means of increasing knowledge about the pros and cons of genetic testing. Such supplemental materials may allow more efficient use of the time allotted for pretest education and counseling by genetics and primary care providers and may discourage ineligible individuals from seeking genetic testing.[56]

Counseling for breast cancer risk typically involves individuals with family histories that are potentially attributable to BRCA1 or BRCA2. It also, however, may include individuals with family histories of Li-Fraumeni Syndrome, ataxia-telangiectasia, Cowden syndrome, or Peutz-Jeghers syndrome.[64] (See the Major Genes ¹⁷ section of this summary.)

Management strategies for carriers may involve decisions about the nature, frequency, and timing of screening and surveillance procedures, chemoprevention, risk-reducing surgery, and use of hormone replacement therapy. The utilization of breast conservation and radiation as cancer therapy for women who are carriers may be influenced by knowledge of mutation status. (See the Interventions ²¹ section of this summary.)

Counseling also includes consideration of related psychosocial concerns and discussion of planned family communication and the responsibility to warn other family members about the possibility of having an increased risk of breast, ovarian, and other cancers. Data are emerging that individual responses to being tested as adults are influenced by the results status of other family members.[65,66] Management of anxiety and distress are important not only as quality-of-life factors, but also because high anxiety may interfere with the understanding and integration of complex genetic and medical information as well as adherence to screening.[17,18,67] The limited number of medical interventions with proven benefit to mutation carriers provides further basis for the expectation that mutation carriers may experience increased anxiety, depression, and continuing uncertainty following disclosure of genetic test results.[68] Formal, objective evaluation of these outcomes are now emerging. (Refer to the sections below on Emotional Outcomes ⁷² and Behavioral Outcomes ⁷³.)

Published descriptions of counseling programs for BRCA1 (and subsequently for BRCA2) testing include strategies for gathering a family history, assessing eligibility for testing, communicating the considerable volume of relevant information about breast/ovarian cancer genetics and associated medical and psychosocial risks and benefits, and discussion of specialized ethical considerations about confidentiality and family communication.[3,69-75] Participant distress, intrusive thoughts about cancer, coping style, and social support were assessed in many prospective testing candidates. The psychosocial outcomes evaluated in these programs have included changes in knowledge about the genetics of breast/ovarian cancer after counseling, risk comprehension, psychological adjustment, family and social functioning, and reproductive and health behaviors.[76] A Dutch study of communication processes and satisfaction levels of counselees going through cancer genetic counseling for inherited cancer syndromes indicated that asking more medical questions (by the counselor), providing more psychosocial information, and longer eye contact by the counselor were associated with lower satisfaction levels. The provision of medical information by the counselor was most highly related to satisfaction and perception that needs have been fulfilled.[77] Additional research is needed on how to adequately address the emotional needs and feelings of control of counselees.

Many of the psychosocial outcome studies involve specialized, highly selected research populations, some of which were utilized to map and clone BRCA1 and BRCA2. One such example is K2082, an extensively studied kindred of more than 800 members of a Utah Mormon family in which a BRCA1 mutation accounts for the observed increased rates of breast and ovarian cancer. A study of the understanding that members of this kindred have about breast/ovarian cancer genetics found that, even in breast cancer research populations, there was incomplete knowledge about associated risks of colon and prostate cancer, the existence of options for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), and the complexity of existing psychosocial risks.[3] A meta-analysis of 21 studies found that genetic counseling was effective in increasing knowledge and improved the accuracy of perceived risk. Genetic counseling did not have a statistically significant long-term impact on affective outcomes including anxiety, distress, or cancer-specific worry and the behavioral outcome of cancer surveillance activities.[34] These prospective studies, however, were characterized by a heterogeneity of measures of cancer-specific worry and inconsistent findings in effects of change from baseline.[34]

It is not yet clearly established to what extent findings derived from special research populations, at least some of which have long awaited genetic testing for breast/ovarian cancer risk, are generalizable to other populations. For example, there are data to suggest that the BRCA1/2 penetrance estimates derived from these dramatically affected families are substantial overestimates and do not apply to most families presenting for counseling and possible testing.[78]

The few studies conducted to date of psychological outcomes associated with genetic testing for mutations in breast/ovarian cancer predisposition genes have shown low levels of distress among those found to be carriers and even lower levels among noncarriers.[56,79-82] A systematic review found that the studies assessing measures of distress (9 of 11 studies) found no change, or a decrease, in those parameters (including anxiety, depression, general distress, and situation distress) in people who had undergone testing at assessments done at 1 month or less, and 3 to 6 months later.[83] One follow-up study from the United Kingdom measured levels of cancer-related worry, general mental health, risk perception, intrusive or avoidant thoughts, and risk-management behaviors at baseline and 1, 4, and 12 months after results were provided. This study included 202 unaffected women and 59 unaffected men, of whom 91 tested positive and 170 tested negative. Results showed that while female noncarriers had significant (P <.001) reductions in cancer-related worry, female carriers younger than 50 years had an increase in cancer-related worry 1 month posttesting. These levels returned to baseline by 12 months but remained higher than noncarrier levels throughout the 12-month period. Female carriers engaged in more posttest screening than noncarriers (92% vs. 30%) within 12 months of test results disclosure. Thirty carriers had RRM and/or RRSO within the same time period.[84] A slightly smaller subset of this cohort was assessed again for cancer-related worry, general mental, health and risk-management behaviors at 3 years post-genetic test result disclosure. One hundred fifty-four women and 39 males, including 71 carriers and 122 noncarriers, returned the questionnaire. The level of distress and cancer worry was similar between carriers and noncarriers. Female carriers had higher distress levels at 3 years versus 1 year post-disclosure, but their level of cancer worry decreased significantly over the same time period. In female noncarriers, although the level of cancer worry had decreased from baseline to 1 year post-disclosure, these levels returned to baseline by 3 years.[85] The authors, however did not comment on contextual factors that might influence distress and cancer worry levels. Another study reported that, compared with pretest levels, mean scores on 1-year posttest measures of cancer-specific distress and state-anxiety decreased significantly among noncarriers, while scores on these measures as well as on a measure of general distress, did not change among BRCA1/2 carriers.[86] One long-term study of 65 female participants explored the psychosocial consequences of carrying a BRCA1/2 mutation 5 years after genetic testing. Carriers did not differ from noncarriers on several distress measures. Although both groups showed significant increases in depression and anxiety compared with 1 year postdisclosure, these scores remained within normal limits for the general population.[87] Caution is advised by authors of these studies in interpretation of the results as they are all from programs in which results disclosure was preceded by extensive genetic counseling about risks and benefits of BRCA1/2 testing, psychological assessment, and even, occasionally, exclusion of a few individuals who appeared highly distressed.[3] Intrusive thoughts (measured by the Impact of Event Scale [IES]) [88] about cancer diminished after results disclosure for both mutation-positive and mutation-negative individuals in one Dutch study.[89]

A prospective Australian study evaluated the psychological impact of genetic testing at baseline, 7 to 10 days, 4 months, and 12 months in 60 women of Ashkenazi Jewish heritage (ten with breast cancer, 50 unaffected). Of the 43 women who opted to learn their test results, 97% felt pleased to have had the test and, at 12 months of follow-up, none regretted having been tested. Seventeen women opted not to receive their results and had significantly lower levels of breast cancer anxiety than did those who opted to receive their results. Women with no history of cancer who opted to learn their results showed a progressive decrease in breast cancer anxiety over the 12-month study period compared with baseline measures. There was also no statistically significant difference in measures of depression and generalized anxiety from baseline to the follow-up assessments.[90] However, these results must be interpreted in light of the fact that only 7 of 43 women had deleterious mutations.

Despite generally positive findings regarding diminished distress in tested individuals, most studies also report increased distress among small subsets of tested individuals. Most, but not all, of these increases are within the normal range of distress. Increased distress has been noted by individuals receiving both positive and negative test results. Studies suggest that the psychological impact of an individual test result is highly influenced by the test result status of other family members. A 1999 study found that an individual’s response to learning his or her own BRCA1/2 test result was significantly influenced by his or her gender and by the genetic test result status of other family members. Adverse, immediate outcomes were experienced by male carriers who were the first tested in their family or by noncarrier men whose siblings were all positive. In addition, female carriers who were the first in their families to be tested or whose siblings were all negative had significantly higher distress than other female carriers.[65] Another study found that spousal anxiety about genetic testing and supportiveness differentiated the impact of BRCA1/2 test results. When the spouse was highly anxious and unsupportive in style, the mutation carrier had significantly higher levels of distress. These studies illustrate that genetic test results are not received in a vacuum, and that researchers need to consider the context of the tested individual in determining which individuals applying for genetic testing may require additional emotional support.[66]

In another study, depression rates postdisclosure were unchanged for mutation carriers and markedly decreased for noncarriers.[22] An analysis of the distress of individuals receiving BRCA1 results in the context of their siblings' results, however, revealed patterns of response suggesting that certain subgroups of tested individuals have markedly increased levels of distress after disclosure that were not apparent when the analysis focused only on comparing the mean scores for carriers versus noncarriers.[65] Early optimistic findings may not sufficiently reflect the true complexity of response to disclosure of BRCA1/2 test results. Female carriers who had no carrier siblings had distress scores (IES) similar to those found in cancer patients 10 weeks after their diagnosis. The distress of male subjects was highly correlated with the status of their siblings’ test results or lack thereof.[65] One pilot study suggested that women diagnosed more recently were more distressed after counseling.[91] A survey of women enrolled in a high-risk clinic found that heightened levels of distress may be more related to living with the awareness of a familial risk for cancer than with the genetic testing process itself. Obtaining genetic testing may be less stressful than living with the awareness of familial risk for cancer.[92] (Note: For more detailed information about depression and anxiety associated with a cancer diagnosis, refer to the PDQ Supportive Care summaries on Anxiety Disorder ⁷⁴; Depression ⁷⁵; and Normal Adjustment and the Adjustment Disorders ⁷⁶.) Case descriptions have supported the importance of family relationships and test outcomes in shaping the distress of tested individuals.[93,94]

Although there are not yet reports of large-scale studies of the reactions of affected individuals to genetic testing, there are indications from several smaller studies that affected individuals who undergo genetic counseling and testing experience more distress than had been expected by professionals [95,96] and are less able themselves to anticipate the intensity of their reactions following result disclosure.[97] Female mutation carriers who have had breast cancer are often surprised by their high level of risk for ovarian cancer. Women mutation carriers who have had breast cancer worried more than unaffected women about developing ovarian cancer, though, in general, worry about ovarian cancer risk was found to be unrealistically low.[96] In addition, some distress related to the burden of conveying genetic information to relatives has been noted among those who are the first in their families to be tested.[95,98]

Several studies have compared the provision of breast cancer genetics services by different providers and the psychological impact on women at high and low risk for cancer. In a study of 735 women at all levels of risk for hereditary breast/ovarian cancer, the services of a multidisciplinary team of genetics specialists was compared with services provided by surgeons. There were no significant differences between groups in anxiety, cancer worry, or perceived risk.[99] In a Scottish study of 373 participants, an alternative model of cancer genetics services using genetics nurse specialists in community-based services was compared with standard genetics regional services. There was no difference in cancer worry or change in health behaviors between the two groups. Cancer worry decreased for both groups over a 6-month period. Women who dropped out of the study tended to be in the nurse provider arm or were at low risk of breast cancer.[100] In a small U.S. study, an evaluation of nurses and genetic counselors as providers of education about breast cancer susceptibility testing was conducted to compare outcomes of pretest education about breast cancer susceptibility. Four genetic counselors and two nurses completed specialized training in cancer genetics. Women receiving pretest education from nurses were as satisfied with information received and had equal degrees of perceived autonomy and partnership. The study findings suggest that with proper training and supervision, both genetic counselors and nurses can be effective in providing pretest education to women considering genetic susceptibility testing for breast cancer risk.[101]

There has been little empirical research in the communication of risk assessments to individuals at risk of breast/ovarian cancer syndromes. When asked to choose a preferred method, individuals undergoing genetic counseling for breast and ovarian cancer appear to prefer quantitative to qualitative presentation of risk information.[102,103] One study indicated that most women wanted information given both ways.[39] Information about the risk of developing breast cancer among women with a family history of breast cancer may be more accurately recalled when presented as odds ratios rather than in other forms.[104]

There is a small but growing body of literature on the use of decision aids as an adjunct to standard genetic counseling to assist patients in making informed decisions about genetic testing. One study measured the effectiveness of a decision aid for BRCA1/2 genetic testing given to women at the end of their first genetic counseling consultation. At 1 week and 6 months follow-up, the decision aid had no effect on informed choice, post-decisional regret or actual genetic testing decision. However, women who received the decision aid had significantly higher knowledge levels and felt more informed about genetic testing than women who received the control pamphlet. The decision aid also helped those women who did not have their blood drawn for genetic testing at the first visit to clarify their values about their testing decision.[105]

Preferences for delivery of breast cancer genetic testing are reported in one study [103] to include counseling conducted by a genetic counselor (42%) or oncologist (22%) rather than by a primary care physician (6%), nurse (12%), or gynecologist (5%). Patients in that study preferred results disclosure by an oncologist. Younger women especially expressed a need for individual consideration of their personal values and goals or potential emotional reactions to testing; 67% believed emotional support and counseling were a necessary part of posttest counseling. Most women (82%) wanted to be able to self-refer for genetic testing, without a physician referral.

Family communication about genetic testing for cancer susceptibility, and specifically about the results of BRCA1/2 genetic testing, is complex; there are few systematic data available on this topic. Gender appears to be an important variable in family communication and psychological outcomes. One study documented that female carriers are more likely to disclose their status to other family members (especially sisters and children aged 14-18 years) than are male carriers.[106] Among males, noncarriers were more likely than carriers to tell their sisters and children the results of their tests. BRCA1/2 carriers who disclosed their results to sisters had a slight decrease in psychological distress, compared with a slight increase in distress for carriers who chose not to tell their sisters. Findings from other studies suggest that there may be more communication about inherited breast and ovarian cancer risk among female family members than between female and male relatives (e.g., between brothers and sisters and/or mothers and sons).[48,107]

Family communication of BRCA1/2 test results to relatives is another factor affecting participation in testing. There have been more studies of communication with first-degree and second-degree relatives than with more distant family members. One study investigated the process and content of communication among sisters about BRCA1/2 test results.[108] Study results suggest that both mutation carriers and women with uninformative results communicate with sisters to provide them with genetic risk information. Among relatives with whom genetic test results were not discussed, the most important reason given was that the affected women were not close to their relatives. Studies found that women with a BRCA mutation more often shared their results with their mother and adult sisters and daughters than with their father and adult brothers and sons.[109-111] A study that evaluated communication of test results to first-degree relatives at 4 months postdisclosure found that women aged 40 years or older were more likely to inform their parents of test results compared with younger women. Participants also were more likely to inform brothers of their results if the BRCA mutation was inherited through the paternal line.[110] Another study found that disclosure was limited mainly to first-degree relatives, and dissemination of information to distant relatives was problematic.[112] Age was a significant factor in informing distant relatives with younger patients being more willing to communicate their genetic test result.[108,109,112]

A few in-depth qualitative studies have looked at issues associated with family communication about genetic testing. Although the findings from these studies may not be generalizable to the larger population of at-risk persons, they illustrate the complexity of issues involved in conveying hereditary cancer risk information in families.[113] On the basis of 15 interviews conducted with women attending a familial cancer genetics clinic, the authors concluded that while women felt a sense of duty to discuss genetic testing with their relatives, they also experienced conflicting feelings of uncertainty, respect, and isolation. Decisions on whom in the family to inform and how to inform them about hereditary cancer and genetic testing may be influenced by tensions between women's need to fulfill social roles and their responsibilities toward themselves and others.[113] Another qualitative study of 21 women who attended a familial breast and ovarian cancer genetics clinic suggested that some women may find it difficult to communicate about inherited cancer risk with their partners and with certain relatives, especially brothers, because of those persons’ own fears and worries about cancer.[107] This study also suggested that how genetic risk information is shared within families may depend on the existing norms for communicating about cancer in general. For example, family members may be generally open to sharing information about cancer with each other, may selectively avoid discussing cancer information with certain family members to protect themselves or other relatives from negative emotional reactions, or may ask a specific relative to act as an intermediary to disclosure of information to other family members.[114] The potential importance of persons outside the family, such as friends, as both confidantes about inherited cancer risk information and as sources of support for coping with this information was also noted in the study.[107]

A study of 31 mothers with a documented BRCA mutation explored patterns of dissemination to children.[115] Of those who chose to disclose test results to their children, age of offspring was the most important factor. Fifty percent of the children who were told were between ages 20 years and 29 years and slightly more than 25% of the children were aged 19 years or younger. Sons and daughters were notified in equal numbers. More than 70% of mothers informed their children within a week of learning their test result. Ninety-three percent of mothers who chose not to share their results with their children indicated that it was because their children were too young. These findings were consistent with two other studies showing that children younger than 13 years were less likely to be informed about test results compared with older children.[110,116] Another study of 187 mothers undergoing BRCA1/2 testing evaluated their need for resources to prepare for a facilitated conversation about sharing their BRCA1/2 testing results with their children. Seventy-eight percent of mothers were interested in three or more resources, including literature (93%), family counseling (86%), talk to prior participants (79%), and support groups (54%).[116]

A longitudinal study of 153 women self-referred for genetic testing for BRCA1 and BRCA2 mutations and 118 of their partners evaluated communication about genetic testing and distress before testing and at 6 months posttesting.[117] The study found that most couples discussed the decision to undergo testing (98%), most test participants felt their partners were supportive, and most women disclosed test results to their partners (97%, n = 148). Test participants who felt their partners were supportive during pretest discussions experienced less distress after disclosure, and partners who felt more comfortable sharing concerns with test participants pretest experienced less distress after disclosure. Six-month follow-up revealed that 22% of participants felt the need to talk about the testing experience with their partners in the week before the interview. Most participants (72%, n = 107) reported comfort in sharing concerns with their partners, and 5% (n = 7) reported relationship strain as a result of genetic testing. In couples in which the woman had a positive genetic test result, more relationship strain, more protective buffering of their partners, and more discussion of related concerns were reported than in couples in which the woman had a true-negative or uninformative result.[117]

There is a small but growing body of literature regarding psychological effects in men who have a family history of breast cancer and who are considering or have had BRCA testing. A qualitative study of 22 men from 16 high-risk families in Ireland revealed that more men in the study with daughters were tested than men without daughters. These men reported little communication with relatives about the illness, with some men reporting being excluded from discussion about cancer among female family members. Some men in the study also reported actively avoiding open discussion with daughters and other relatives.[118] In contrast, a study of 59 men testing positive for a BRCA1/2 mutation found that most men participated in family discussions about breast and/or ovarian cancer. However, fewer than half of the men participated in family discussions about risk-reducing surgery. The main reason given for having BRCA testing was concern for their children and a need for certainty about whether they could have transmitted the mutation to their children. In this study, 79% of participating men had at least one daughter. Most of these men described how their relationships had been strengthened after receipt of BRCA results, helping communication in the family and greater understanding.[119] Men in both studies expressed fears of developing cancer themselves. Irish men especially reported fear of cancer in sexual organs.

In a study of 212 individuals from 13 hereditary breast and ovarian cancer families who received genetic counseling and were offered BRCA1/2 testing for documented mutation in the family, individuals who were not tested were found 6 to 9 months later to have significantly greater increases in expressiveness and cohesiveness compared with those who were tested. Persons who were randomized to a client-centered versus problem-solving genetic counseling intervention had a significantly greater reduction in conflict, regardless of the test decision.[25]

Many studies have looked at the psychological effects in women of having a high risk of developing cancer, either on the basis of carrying a BRCA1/2 mutation or having a strong family history of cancer. However, few studies have looked at the effects on the partners of such women.

A Canadian study assessed 59 spouses of women found to have a BRCA1/2 mutation. All were supportive of their spouses’ decision to undergo genetic testing and 17% wished they had been more involved in the genetic testing process. Spouses who reported that genetic testing had no impact on their relationship had long-term relationships (mean duration 27 years). Forty-six percent of spouses reported that their major concern was of their partner dying of cancer. Nineteen percent were concerned their spouse would develop cancer and 14% were concerned their children would also be BRCA1/2 mutation carriers.[120]

In a U.S. study, 118 partners of women undergoing genetic testing for mutations in BRCA1 and BRCA2 completed a survey prior to testing and then again 6 months following result disclosure. At 6 months, only 10 partners reported that they had not been told of the test result. Ninety-one percent reported that the testing had not caused strain on their relationship. Partners who were comfortable sharing concerns prior to testing experienced less distress following testing. Protective buffering was not found to impact distress levels of partners.[117]

An Australian study of 95 unaffected women at high risk of developing breast and/or ovarian cancer (13 mutation carriers and 82 with unknown mutation status) and their partners showed that although the majority of male partners had distress levels comparable to a normative population sample, 10% had significant levels of distress that indicated the need for further clinical intervention. Men with a high monitoring coping style and greater perceived breast cancer risk for their wife reported higher levels of distress. Open communication between the men and their partners and the occurrence of a cancer-related event in the wife’s family in the last year were associated with lower distress levels. When men were asked what kind of information and support they would like for themselves and their partners, 57.9% reported that they would like more information about breast and ovarian cancer, and 32.6% said they would like more support in dealing with their partner's risk. Twenty-five percent of men had suggestions on how to improve services for partners of high-risk women, including strategies on how to best support their partner, greater encouragement from healthcare professionals to attend appointments, and meeting with other partners.[121]

A study of Dutch men at increased risk of having inherited a BRCA1 mutation reported a tendency for the men to deny or minimize the emotional effects of their risk status, and to focus on medical implications for their female relatives. Men in these families, however, also reported considerable distress in relation to their female relatives.[122] In another study of male psychological functioning during breast cancer testing, 28 men belonging to 18 different high-risk families (with a 25% or 50% risk of having inherited a BRCA1/2 mutation) participated. The study purpose was to analyze distress in males at risk of carrying a BRCA1/2 mutation who applied for genetic testing. Of the men studied, most had low pretest distress; scores were lowest for men who were optimistic or who did not have daughters. Most mutation carriers had normal levels of anxiety and depression and reported no guilt, though some anticipated increased distress and feelings of responsibility if their daughters developed breast or ovarian cancer. None of the noncarriers reported feeling guilty.[123] In one study,[119] adherence to recommended screening guidelines after testing was analyzed. In this study, more than half of male carriers of mutations did not adhere to the screening guidelines recommended after disclosure of genetic test results. These findings are consistent with those for female carriers of BRCA1/2 mutations.[119,124]

A multicenter U.K. cohort study examined prospective outcomes of BRCA1/2 testing in 193 individuals, of which 20% were men aged 28 to 86 years. Men’s distress levels were low, did not differ among carriers and noncarriers, and did not change from baseline (pre-genetic testing) to the 3-year follow-up. Twenty-two percent of male mutation carriers received colorectal cancer screening and 44% received prostate cancer screening;[85] however, it is unclear whether men in this study were following age-appropriate screening guidelines.

Several studies have explored communication of BRCA test results to at-risk children. Across all studies, the rate of disclosure to children ranging in age from 4 to 25 years is approximately 50%.[109,110,112,116,125-128] In general, age of offspring was the most important factor in deciding whether to disclose test results. In one study of 31 mothers disclosing their BRCA test results, 50% of the children who were informed of the results were aged 20 to 29 years and slightly more than 25% of the children were aged 19 years or younger. Sons and daughters were notified in equal numbers.[115] Similarly, in another study of 42 female BRCA mutation carriers, 83% of offspring older than age 18 years were told of the results, while only 21% of offspring aged 13 years or younger were told.[116]

Several studies have also looked at the timing of disclosure to children after parents receive their test results. Although the majority of children were told within a week to several months after results disclosure,[110,115,116] some parents chose to delay disclosure.[116] Reasons for delaying disclosure included waiting for the child to get older, allowing time for the parent to adjust to the information, and waiting until results could be shared in person (in the case of adult children living away from home).[116]

One study looked at the reaction of children to results disclosure or the effect on the parent-child relationship of communicating the results.[116] With regard to offspring’s understanding of the information, almost half of parents from one study reported that their child did not appear to understand the significance of a positive test result, although older children were reported to have a better understanding. This same study also showed that 48% of parents reported at least one negative reaction in their child, ranging from anxiety or concern (22%) to crying and fear (26%). It should be noted, however, that in this study children's level of understanding and reactions to the test result were measured qualitatively and based only on the parents' perception. Also, given the retrospective design of the study, there was a potential for recall bias. There were no significant differences in emotional reaction depending on age or gender of the child. Lastly, 65% of parents reported no change in their relationship with their child, while 5 parents (22%) reported a strengthening of their relationship.

Another study of 187 mothers undergoing BRCA1/2 testing evaluated their need for resources to prepare for a facilitated conversation about sharing their BRCA1/2 testing results with their children. Seventy-eight percent of mothers were interested in three or more resources, including literature (93%), family counseling (86%), talking to prior participants (79%), and support groups (54%).[129]

Testing for BRCA1/2 has been almost universally limited to adults older than 18 years. The risks of testing children for adult-onset disorders (such as breast and ovarian cancer), as inferred from developmental data on children’s medical understanding and ability to provide informed consent, have been outlined in several reports.[130-133] Surveys of parental interest in testing children for adult-onset hereditary cancers suggest that parents are more eager to test their children than to be tested themselves for a breast cancer gene, suggesting potential conflicts for providers.[134,135] In a general population survey in the United States, 71% of parents said that it was moderately, very, or extremely likely that if they carried a breast-cancer predisposing mutation, they would test a 13-year-old daughter now to determine her breast cancer gene status.[134] To date, no data exist on the testing of children for BRCA1/2, though some researchers believe it is necessary to test the validity of assumptions underlying the general prohibition of testing of children for breast/ovarian cancer and other adult-onset disease genes.[136-138] In one study, 20 children (aged 11 to 17 years) of a selected group of mothers undergoing genetic testing (80% of whom previously had breast cancer and all of whom had discussed BRCA1/2 testing with their children) completed self-report questionnaires on their health beliefs and attitudes toward cancer, feelings related to cancer, and behavioral problems.[139] Ninety percent of children thought they would want cancer risk information as adults; half worried about themselves or a family member developing cancer. There was no evidence of emotional distress or behavioral problems. Another study by this group [127] found that 1 month after disclosure of BRCA1/2 genetic test results, 53% of 42 enrolled mothers of children aged 8 to 17 years had discussed their result with one or more of their children. Age of the child rather than mutation status of the mother influenced whether they were told, as did family health communication style.

In one study, participants who told children younger than 13 years about their carrier status had increased distress, and those who did not tell their young children experienced a slight decrease in distress. Communication with young children was found to be influenced by developmental variables such as age and style of parent/child communication.[127]

Prenatal diagnosis of breast/ovarian cancer predisposition is generally discouraged.[140] Adult age at onset, good prognosis for many breast cancer patients, and the expectation of greater medical progress by the time disease onset might be expected decades into the future make the prospect of prenatal diagnosis an uncomfortable one for many geneticists, leading potentially to charges of eugenics.[134,141] Limited data on the use of this technology are available. In a small series, 26 mutation carriers indicated that pregnancy termination based on mutation status would not be acceptable. Interestingly, a small percentage of nonmutation carriers felt that termination of a pregnancy, where the fetus was a mutation carrier was acceptable.[142] Historically, in Huntington disease, the uptake of prenatal diagnosis and termination is low.[143,144]

The U.K. Human Fertilization and Embryology authority has approved the use of preimplantation genetic diagnosis (PGD) for hereditary breast and ovarian cancer. In a sample of 102 women with a BRCA mutation, most were supportive of PGD but only 38% of the women who had completed their families would consider it for themselves and only 14% of women who were contemplating a future pregnancy would consider it.[145]