Guideline Title
American Society of Clinical Oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction.
Bibliographic Source(s)
Visvanathan K, Chlebowski RT, Hurley P, Col NF, Ropka M, Collyar D, Morrow M, Runowicz C, Pritchard KI, Hagerty K, Arun B, Garber J, Vogel VG, Wade JL, Brown P, Cuzick J, Kramer BS, Lippman SM, American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol 2009 Jul 1;27(19):3235-58. [127 references] PubMed  |
Guideline Status
This is the current release of the guideline.
This guideline updates a previous version: Chlebowski RT, Col N, Winer EP, Collyar DE, Cummings SR, Vogel VG 3rd, Burstein HJ, Eisen A, Lipkus I, Pfister DG. American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol 2002 Aug 1;20(15):3328-43. [119 references] PubMed
UMLS Concepts ( what's this?)
Click to view all guideline(s) indexed with these concepts
Hide...
|
Guideline Category
Prevention
Risk Assessment
Technology Assessment
Treatment
Clinical Specialty
Endocrinology
Obstetrics and Gynecology
Oncology
Preventive Medicine
Intended Users
Physicians
Guideline Objective(s)
To update the 2002 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer risk reduction
Target Population
Women at increased risk of breast cancer
Interventions and Practices Considered
Pharmacologic Interventions for Breast Cancer Risk Reduction
- Tamoxifen
- Raloxifene
- Aromatase inhibitor/inactivator (not recommended outside of a clinical trial)
- Retinoids, such as fenretinide (not recommended outside of a clinical trial)
Major Outcomes Considered
- Incidence of breast cancer (invasive and noninvasive)
- Breast cancer-specific mortality
- Overall mortality
- Net health benefits
- Quality of life
- Adverse effects of therapy
|
Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence
For the 2009 update, the following electronic databases were searched for articles published from January 2002 to July 2007: MEDLINE, preMEDLINE, and the Cochrane Collaboration Library. Results were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Update Committee members’ personal files. Search terms included the agents considered in the guideline ("tamoxifen," "raloxifene," "fenretinide," and "aromatase inhibition") as well as all of the identified brand names (North American and European). These search terms were combined with "selective estrogen receptor modulators," "breast," "mammary," "neoplasms," "cancer," "primary prevention," "preventive medicine," "prophylaxis," "risk," and "risk reduction." Searches were limited to randomized controlled trials (phase II or III), meta-analyses, systematic reviews, and existing practice guidelines. Retrospective cohort studies were permitted if they were embedded within a randomized controlled trial. Other study designs, including prospective or retrospective cohort studies and phase I or phase I/II trials, were excluded. English-language studies available in full text and published in peer-reviewed journals were eligible.
Articles were selected for inclusion in the systematic review of the evidence if they met the following criteria: (1) the intervention consisted of one of the specified chemoprevention agents for the prevention of primary breast cancer; (2) participants were randomly assigned to a chemoprevention arm or a control arm (control arm could consist of no chemoprevention agent, a placebo, the same chemoprevention agent at an alternate dose/route, or a different chemoprevention agent); and (3) outcomes reported included at least one of the following: breast cancer incidence, breast cancer–specific mortality, overall mortality, net health benefits, or quality of life. The primary outcome of interest was incidence of invasive and noninvasive breast cancer (including ductal carcinoma in situ [DCIS] and lobular carcinoma in situ [LCIS]). The guideline is limited to pharmacologic interventions, and therefore evaluations of surgical and lifestyle interventions were excluded from consideration.
An initial article abstract screen was performed by two American Society of Clinical Oncology (ASCO) staff members who independently reviewed each abstract for inclusion criteria. Disagreements were resolved by consensus. The ASCO Update Committee cochairs reviewed the title lists of included and excluded abstracts, and full text articles were obtained for each included abstract. Full text review was undertaken by two ASCO staff, who independently reviewed each article for the inclusion criteria. Again, disagreements were resolved by consensus.
Preliminary searches identified 1,329 potential articles. The abstract screen eliminated 1,241 abstracts that failed to meet any of the inclusion criteria or were duplicates resulting from searching across more than one database. Full text reports were obtained for the remaining 88 abstracts, which were reviewed in full for the interventions and outcomes described previously. Seventy-one articles were excluded at the full text review stage. Fifty-four of those were excluded because there was no clinical end point, study design was nonrandomized, or there was no report of original data (e.g., reviews of previously reported trials, editorials/commentaries). The other 17 papers were systematic reviews or meta-analyses.
Seventeen articles met the inclusion criteria for randomized controlled trials for consideration and underwent data extraction. Of these 17 articles, two reported data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Study of Tamoxifen and RaloxifeneP2 (STAR) trial comparing tamoxifen and raloxifene. Six papers reported data from the Multiple Outcomes of Raloxifene Evaluation (MORE), Continuing Outcomes Relevant to Evista (CORE), and/or Raloxifene Use for The Heart (RUTH) trials, comparing raloxifene and placebo. The remaining nine articles reported data from trials comparing tamoxifen and placebo, including NSABP Breast Cancer Prevention Trial P1, the International Breast Intervention Study (IBIS-I), the Italian Randomized Tamoxifen Prevention Trial, and the Royal Marsden Tamoxifen Prevention Trial.
The literature search identified one article that combined the results from five randomized controlled trials that compared either tamoxifen or raloxifene with placebo for breast cancer prevention (NSABP-P1, Royal Marsden, Italian, IBIS-I, and MORE trials). Two other meta-analyses were identified that focused on side effects of tamoxifen and summarized data from both prevention and treatment trials.
Number of Source Documents
Seventeen articles met the inclusion criteria for randomized controlled trials for consideration and underwent data extraction.
Methods Used to Assess the Quality and Strength of the Evidence
Expert Consensus (Committee)
Rating Scheme for the Strength of the Evidence
Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence
In 2009, the working group identified specific questions to be addressed by the technology assessment, developed a strategy for completing the technology assessment, and reviewed the available literature and evidence.
The analytic framework outlined in Figure 1 of the current guideline describes the overall process involved in identifying women at increased breast cancer risk and informing them of available drug-based preventive options. This framework was used to guide the review of the literature, which included primary and secondary outcomes, as well as side effects from phase III randomized prevention trials, and risk communication.
Each article that met the inclusion criteria underwent data extraction for patient characteristics, study design and quality, interventions, outcomes, and adverse events. Evidence summary tables were developed based on data extracted from studies that met the criteria for inclusion. If not provided in published materials, values for absolute risk difference, number needed to treat, and number needed to harm were computed from incidence data or cumulative incidence rates provided in the published articles.
Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations
Consensus Development Based on Evidence
The Update Committee consisted of experts in clinical medicine, public health, clinical research, health services, and related disciplines (biostatistics, epidemiology, cancer prevention, patient-physician communication), with a focus on expertise in breast cancer prevention. The Update Committee also included a patient representative. A Steering Committee under the auspices of the Health Services Committee chose the Update Committee.
The entire Update Committee met once face-to-face. The purposes of the meeting were to review the evidence relating to each clinical question (see below), generate the recommendations, and establish writing assignments for the respective sections. Additional work on the guideline was completed through teleconferences and electronic mail. All members of the Update Committee participated in the preparation of the draft guideline.
The clinical questions addressed by the Update Committee:
- In women who were not previously diagnosed with breast cancer, do tamoxifen, raloxifene, aromatase inhibitors, and/or fenretinide reduce the risk of developing breast cancer (invasive or noninvasive) compared with no pharmacologic intervention? Factors considered include disease-specific and overall mortality, type or stage of breast cancer diagnosed, and net health benefit (i.e., the potential benefit of chemoprevention after taking into consideration potential harms).
- What is the comparative efficacy of tamoxifen, raloxifene, aromatase inhibitors, and fenretinide?
- What constitutes effective and responsible communication by physicians of issues regarding breast cancer risk reduction to women eligible to consider use of these agents?
Rating Scheme for the Strength of the Recommendations
Cost Analysis
A formal cost analysis was not performed and published cost analysis were not reviewed.
Method of Guideline Validation
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation
The complete draft was reviewed and received final approval from the entire Update Committee. The guideline was submitted to Journal of Clinical Oncology for peer review. Feedback from external reviewers was also solicited. The content of the guidelines and the manuscript were reviewed and approved by the Health Services Committee and by the American Society of Clinical Oncology (ASCO) Board of Directors before publication.
|
Major Recommendations
Tamoxifen
2009 Recommendation for the Use of Tamoxifen to Reduce the Risk of Developing Breast Cancer
Five years of tamoxifen (20 mg/d) may be offered to women at increased risk of breast cancer to reduce their risk of estrogen receptor (ER)–positive invasive breast cancers for up to 10 years. Eligible women include those with a 5-year projected breast cancer risk >1.66% (according to the National Cancer Institute [NCI] Breast Cancer Risk Assessment Tool based on the Gail model--available at http://www.cancer.gov/bcrisktool ) or women with lobular carcinoma in situ (LCIS). The benefit of taking tamoxifen for more than 5 years is unknown. The greatest clinical benefit and the fewest side effects were derived from the use of tamoxifen in younger (premenopausal) women 35 to 50 years of age who are unlikely to experience thromboembolic sequelae or uterine cancer, women without a uterus, and women at high risk of breast cancer. Vascular and vasomotor side effects were observed to decline post-treatment across all ages. Tamoxifen is not recommended in women with a prior history of deep vein thrombosis (DVT), pulmonary embolus (PE), stroke, or transient ischemic attack. Combined use of tamoxifen for breast cancer prevention and hormone therapy (HT) is currently not recommended. Follow-up should include a baseline gynecologic examination before initiation of treatment and annually thereafter, with a timely work-up for abnormal vaginal bleeding. The risks and benefits of tamoxifen should be given careful consideration during the decision-making process. There has been no mortality differences observed in the tamoxifen prevention trials so far, most likely because these trials were not powered to detect such outcomes. Nevertheless, a reduction in breast cancer incidence is considered to be an important health outcome in and of itself.
Raloxifene
2009 Recommendation for the Use of Raloxifene to Reduce the Risk of Developing Breast Cancer
For postmenopausal women at increased risk for breast cancer, raloxifene (60 mg/d) for 5 years may be offered as another option to reduce the risk of ER-positive invasive breast cancer. Raloxifene has been shown to be equally efficacious to tamoxifen in reducing breast cancer risk in postmenopausal women. However, raloxifene was not as effective in reducing the incidence of noninvasive breast cancer compared with tamoxifen, although the association was not statistically significant. In the Study of Tamoxifen and Raloxifene P2 (STAR) trial, raloxifene was associated with a more favorable side-effect profile compared with tamoxifen, including a statistically significant lower risk of thromboembolic disease, benign uterine complaints, and cataracts as compared with tamoxifen. Raloxifene, like tamoxifen, is not known to have an effect on overall or breast cancer–specific mortality in women at increased risk of breast cancer. However, the risk reduction trials were not powered to detect a reduction in breast cancer incidence rather than mortality, as it was felt to be an important end point in and of itself. Raloxifene may be used for longer than 5 years in women with osteoporosis in whom breast cancer risk reduction is an additional potential benefit. Raloxifene is not recommended in premenopausal women or in women with a prior history of DVT, PE, stroke, or transient ischemic attack. In postmenopausal women, the risks and benefits of both tamoxifen and raloxifene, including risks of noninvasive breast cancer, adverse events, and impact on quality of life, should be discussed in detail with women before coming to a decision about risk reduction strategies.
Aromatase Inhibitor/Inactivators
2009 Recommendation for the Use of Aromatase Inhibitors to Reduce the Risk of Developing Breast Cancer
The Update Committee does not recommend the use of any aromatase inhibitor to lower breast cancer risk outside of the investigational setting. Ongoing studies will offer more data for the next review of this area.
Retinoids
2009 Recommendation for the Use of Retinoids to Reduce the Risk of Developing Breast Cancer
The Update Committee does not recommend the use of retinoids, such as fenretinide, to lower breast cancer risk outside of the investigational setting.
|
Evidence Supporting the Recommendations
Type of Evidence Supporting the Recommendations
The recommendations are based primarily on published randomized trials.
|
Benefits/Harms of Implementing the Guideline Recommendations
Potential Benefits
In postmenopausal women, raloxifene and tamoxifen reduce the risk of estrogen receptor (ER)-positive invasive breast cancer with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women.
Potential Harms
Tamoxifen
- Tamoxifen is associated with an increased risk of endometrial cancer, thromboembolic events, stroke, and cataracts.
- Women should be made aware that vaginal discharge and other gynecologic symptoms may be an issue with tamoxifen use.
Raloxifene
Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women.
Refer to Tables 4-8 in the original guideline document for results of adverse events and side effects related to tamoxifen and raloxifene.
|
Contraindications
- Tamoxifen is contraindicated in women with a prior history of stroke or transient ischemic attack.
- Raloxifene and tamoxifen are not recommended for use in women with a prior history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack.
|
Qualifying Statements
- No evidence exists establishing whether a reduction in breast cancer risk from either tamoxifen or raloxifene translates into reduced breast cancer mortality.
- If a woman is identified to be at elevated risk for breast cancer, an informed discussion of risk reduction strategies, including disclosure of risks and benefits, should be initiated while being sensitive to her personal needs and values—including race, culture, and socioeconomic status. Specifically, the potential impact of each agent on the incidence of both noninvasive and invasive breast cancers should be addressed, because the efficacy of different agents varies for these end points, and the biologic potential of these two types of tumors differs. This discussion should include information on estrogen receptor (ER)-positive and ER-negative breast cancers.
- American Society of Clinical Oncology's (ASCO's) practice guidelines and technology assessments reflect expert consensus based on the best available evidence. They are intended to assist physicians and patients in clinical decision making and to identify questions and settings for further research. With the rapid flow of scientific information in oncology, new evidence can emerge between the time an updated guideline or assessment was submitted for publication and when it is read or appears in print. Guidelines and assessments are not continually updated and may not reflect the most recent evidence. Guidelines and assessments cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment with the patient. Accordingly, adherence to any guideline or assessment is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient’s individual circumstances and preferences. ASCO guidelines and assessments describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's guidelines or assessments, or for any errors or omissions.
Study Quality and Limitations of the Literature
There was heterogeneity across studies on key elements, such as participant characteristics and data reporting, which presented challenges for making comparisons between the risks and benefits of the individual agents. Additionally, meta-analyses were based on published data and not a reanalysis of original data.
|
Implementation of the Guideline
Description of Implementation Strategy
An implementation strategy was not provided.
Implementation Tools
Patient Resources
Personal Digital Assistant (PDA) Downloads
Quick Reference Guides/Physician Guides
Slide PresentationFor information about availability, see the Availability of Companion Documents and Patient Resources fields below.
|
Institute of Medicine (IOM) National Healthcare Quality Report Categories
IOM Care Need
Staying Healthy
IOM Domain
Effectiveness
Patient-centeredness
Safety
|
Identifying Information and Availability
Bibliographic Source(s)
| Visvanathan K, Chlebowski RT, Hurley P, Col NF, Ropka M, Collyar D, Morrow M, Runowicz C, Pritchard KI, Hagerty K, Arun B, Garber J, Vogel VG, Wade JL, Brown P, Cuzick J, Kramer BS, Lippman SM, American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol 2009 Jul 1;27(19):3235-58. [127 references] PubMed |
Adaptation
Not applicable: The guideline was not adapted from another source.
Date Released
1999 (revised 2009 Jul)
Guideline Developer(s)
American Society of Clinical Oncology - Medical Specialty Society
Source(s) of Funding
American Society of Clinical Oncology
Composition of Group That Authored the Guideline
Authors: Kala Visvanathan, Rowan T. Chlebowski, Patricia Hurley, Nananda F. Col, Mary Ropka, Deborah Collyar, Monica Morrow, Carolyn Runowicz, Kathleen I. Pritchard, Karen Hagerty, Banu Arun, Judy Garber, Victor G. Vogel, James L. Wade, Powel Brown, Jack Cuzick, Barnett S. Kramer, Scott M. Lippman
Update Committee Panel Members: Kala Visvanathan, MD, MHS, Co-Chair; Scott M. Lippman, MD, Co-Chair; Banu Arun, MD; Powel Brown, MD, PhD; Rowan Chlebowski, MD, PhD; Nananda F. Col, MD, MPH, MPP; Jack Cuzick, PhD; Judy Garber, MD, MPH; Barnett Kramer, MD, MPH; Monica Morrow, MD; Kathleen I. Pritchard, MD; Mary Ropka, PhD, RN; Carolyn Runowicz, MD; Victor G. Vogel III, MD; James L. Wade, MD
Financial Disclosures/Conflicts of Interest
All members of the Update Committee complied with American Society of Clinical Oncology (ASCO) policy on conflict of interest, which requires disclosure of any financial or other interest that might be construed as constituting an actual, potential, or apparent conflict. Members of the Update Committee completed ASCO's disclosure form and were asked to reveal ties to companies developing products that might be affected by promulgation of the guidelines. Information was requested regarding employment, consultancies, stock ownership, honoraria, research funding, expert testimony, and membership on company advisory committees. The cochairs of the Update Committee made decisions on a case-by-case basis regarding whether an individual’s role should be limited as a result of a conflict. No limiting conflicts were identified. All reported conflicts of interest are listed below.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors of the original journal of publication.
Employment or Leadership Position: Carolyn Runowicz, NSABP (C) Consultant or Advisory Role: Carolyn Runowicz, NSABP (C); Kathleen I. Pritchard, Roche, AstraZeneca, and Pfizer (C); Rowan T. Chlebowski, AstraZeneca (C), Novartis (C), Pfizer (C), Eli Lilly (C), Wyeth (C); Victor G. Vogel, Eli Lilly (C); Jack Cuzick, AstraZeneca (C) Stock Ownership: None Honoraria: Rowan T. Chlebowski, AstraZeneca, Novartis; Kathleen I. Pritchard, Pfizer, Roche, AstraZeneca; Banu Arun, Pfizer; Victor G. Vogel, Eli Lilly, AstraZeneca; Research Funding: Rowan T. Chlebowski, Amgen, Eli Lilly, Organon; Banu Arun, NCI, Pfizer, Novartis, AstraZeneca; Judy Garber, AstraZeneca; Victor G. Vogel, Eli Lilly, AstraZeneca; Powel Brown, Eli Lilly, AstraZeneca; Jack Cuzick, AstraZeneca Expert Testimony: None Other Remuneration: None
Guideline Status
This is the current release of the guideline.
This guideline updates a previous version: Chlebowski RT, Col N, Winer EP, Collyar DE, Cummings SR, Vogel VG 3rd, Burstein HJ, Eisen A, Lipkus I, Pfister DG. American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol 2002 Aug 1;20(15):3328-43. [119 references] PubMed
Availability of Companion Documents
Patient Resources
The following is available:
Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.
NGC Status
This NGC summary was completed by ECRI on February 27, 2003. The information was verified by the guideline developer on March 14, 2003. This NGC summary was updated by ECRI Institute on January 27, 2010.
Copyright Statement
This summary is based on the original guideline, which is subject to the American Society of Clinical Oncology's copyright restrictions.
|
NGC Disclaimer
The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site. Read full disclaimer...The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.
All guidelines summarized by NGC and hosted on our site are produced under the auspices of medical specialty societies, relevant professional associations, public or private organizations, other government agencies, health care organizations or plans, and similar entities.
Guidelines represented on the NGC Web site are submitted by guideline developers, and are screened solely to determine that they meet the NGC Inclusion Criteria which may be found at http://www.guideline.gov/about/inclusion-criteria.aspx.
NGC, AHRQ, and its contractor ECRI Institute make no warranties concerning the content or clinical efficacy or effectiveness of the clinical practice guidelines and related materials represented on this site. Moreover, the views and opinions of developers or authors of guidelines represented on this site do not necessarily state or reflect those of NGC, AHRQ, or its contractor ECRI Institute, and inclusion or hosting of guidelines in NGC may not be used for advertising or commercial endorsement purposes.
Readers with questions regarding guideline content are directed to contact the guideline developer. Hide...
|
