August 9, 2001 Access past issues

Reviewed by: Karen Steinberg,1 Mindy Clyne,2 and Marta Gwinn2 1. Division of Environmental Health Laboratory Sciences, CDC 2. Office of Genomics and Disease Prevention, CDC

The Health Outcome

In 2001, 192,200 new cases of invasive breast cancer will be diagnosed in the United States and, depending on the population studied, perhaps 3% - 5% of those cases will be associated with mutations to the BRCA1 or BRCA2 genes (1-4). In one study, more than half of the women who had a 50% risk of carrying these mutations said that they would chose to be tested for them (5).  Although there are risks as well as benefits associated with being tested, perhaps the strongest argument for genetic testing for these mutations is the availability of an effective prevention for women who test positive.  Strategies under investigation for prevention of breast cancer include prophylactic bilateral total mastectomy, oophrorectomy, and chemoprevention using drugs that block estrogen action on breast tissue.  Because questions remain about the efficacy of estrogen blocking agents, such as tamoxifen, in women with BRCA1 and BRCA2 mutations, information on the efficacy of prophylactic mastectomy is urgently needed.

The Finding

Meijers-Heijboer et al. (6), have reported a study of 139 women with documented BRCA1 or BRCA2 mutations, 76 of whom chose to have prophylactic bilateral mastectomy and 63 of whom chose surveillance with annual mammography, twice yearly physician breast examinations, and monthly self-examinations. A detailed abstract of this article is available online as part of the HuGENet™ e-journal club (7).  Beginning on January 1, 1992, all women with BRCA1 or BRCA2 mutations and a family history of breast cancer or ovarian cancer who were being monitored for breast cancer at the Daniel den Hoed Cancer Center in Rotterdam were considered for inclusion in the study.  Women with documented mutations who were diagnosed with breast cancer before January 1, 1992 were excluded, as was one woman whose breast cancer was detected at first screening. Follow-up ended March 1, 2001.  After approximately 3 years of follow-up, 8 cases of invasive breast cancer were observed in the surveillance group, a number that was consistent with what researchers expected, based on the estimated penetrance of BRCA1 and BRCA2 mutations (8).  No cases of breast cancer were observed in the group who chose mastectomy, a difference in incidence that remained significant even after adjusting for menopausal status.  

Surveillance did not appear to assure early diagnosis.  Of the eight women who developed breast cancer, half were diagnosed during screening sessions and half between screening sessions (from 2 to 5 months after screening).  In four patients, breast cancers were palpable when detected, and four were lymph-node positive.  Seven cancers were estrogen-and progesterone-receptor negative, and seven were histologically classified as grade 3. The authors concluded that prophylactic bilateral total mastectomy significantly decreased risk of breast cancer in women with BRCA1 or BRCA2 mutations after 3 years of follow-up

Public Health Implications

This is the first prospective study of the efficacy of prophylactic bilateral total mastectomy for preventing breast cancer.  Because women were allowed to choose their treatment, factors not measured in the study may have contributed to the lower incidence of breast cancer in the group that chose mastectomy.  The study cohort was small, and follow-up time was only three years.  More women and longer follow-up are needed to estimate the protective effect with certainty and to make public health recommendations.  These recommendations must consider the potential physical and psychological morbidity associated with prophylactic mastectomy and with alternative interventions. Although the results of this study suggest that heightened surveillance is not very effective, other interventions, such as chemoprevention with tamoxifen, should be evaluated in women with BRCA1 or BRCA2 mutations.

References  

1. Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, Easton DF, Evans C, Deacon J, Stratton MR.  Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.  J Natl Cancer Inst 1999 Jun 2;9(11):943-9.      
2. Weber BL.  Update on breast cancer susceptibility genes.  Recent Results Cancer Res 1998;152:49-59.  
3. Newman B, Mu H, Butler LM, Millikan RC, Moorman PG, King MC.  Frequency of breast cancer attributable to BRCA1 in a population-based series of American women.  JAMA 1998 Mar 25;279(12):915-21. 
4. Cancer Resource Center.  Cancer facts and figures
5. Matloff ET, Shappell H, Brierley K, Berhardt BA, McKinnin W, Peshkin BN. What would you do? Specialists’ perspectives on cancer genetic testing, prophylactic surgery, and insurance discrimination.  J Clin Oncol 2000 Jun;18(12):2484-92.  
6. Meijers-Heijboer H, Van Geel B, van Putten WLJ, Henzen-Logmans SC, Seynaeve C, Menke-Pluymers MBE, Bartels CCM, Verhoog LC, van den Ouweland AMW, Niermeijer MF, Brekelmans CTM, Klijn JGM.  Breast cancer after prophylactic mastectomy in women with a BRCA1 or BRCA2 mutation.  N Eng J Med 2001:345:159-64.  
7. Meijers-Heijboer, et al. Electronic journal club abstraction form
8. Whittemore AS, Gong G, Itnyre J.  Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from  U.S. population-based case-control studies of ovarian cancer.  Am J Hum Genet 1997:60:496-504.