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Guideline Summary
Guideline Title
American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor–positive breast cancer.
Bibliographic Source(s)
Burstein HJ, Prestrud AA, Seidenfeld J, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Malin J, Mamounas EP, Rowden D, Solky AJ, Sowers MR, Stearns V, Winer EP, Somerfield MR, Griggs JJ, American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010 Aug 10;28(23):3784-96. [124 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, Chlebowski RT, Gelber R, Edge SB, Gralow J, Cobleigh MA, Mamounas EP, Goldstein LJ, Whelan TJ, Powles TJ, Bryant J, Perkins C, Perotti J, Braun S, Langer AS, Browman GP, Somerfield, MR. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005 Jan 20;23(3):1-11.

Scope

Disease/Condition(s)

Hormone receptor-positive breast cancer

Guideline Category
Prevention
Risk Assessment
Technology Assessment
Treatment
Clinical Specialty
Obstetrics and Gynecology
Oncology
Intended Users
Physicians
Guideline Objective(s)

To develop evidence-based guidelines, based on a systematic review, for endocrine therapy for postmenopausal women with hormone receptor–positive breast cancer

Target Population

Postmenopausal women with hormone receptor-positive breast cancer

Interventions and Practices Considered

Treatment/Management

Adjuvant endocrine therapy:

  • Use of a third-generation aromatase inhibitor (AI)
  • Standard therapy with tamoxifen
  • Combination therapy of tamoxifen and an AI
Major Outcomes Considered
  • Disease-free survival
  • Overall survival
  • Time to contralateral breast cancer
  • Adverse effects of therapy
  • Quality of life

Methodology

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

Literature Search Strategy

The literature search for this update was facilitated by the systematic review completed by Cancer Care Ontario (CCO) that reviewed available literature through May 2007. American Society of Clinical Oncology (ASCO) guidelines staff conducted additional searches of the MEDLINE, PREMEDLINE, and Cochrane Collaboration Library electronic databases for published articles from May 2007 through February 2009 (list of MEDLINE search terms, see the Appendix in the original guideline document). In addition, electronic databases for presentations, posters, and abstracts presented at the San Antonio Breast Cancer Symposium (SABCS) and ASCO Annual Meetings in 2007 and 2008 were searched. Additional sources were identified by hand-searching bibliographies of relevant articles. Search terms included all the agents under consideration ("tamoxifen," "anastrozole," "exemestane," "letrozole," and "aromatase inhibitors") along with identified brand names (including European and North American versions). These terms were combined with the disease terminology "breast neoplasms," "carcinoma," "adenocarcinoma," and "tumor." The search was limited to phase III randomized, controlled trials; meta-analyses; systematic reviews; and existing practice guidelines. Other trial designs, including phase I or II trials and either prospective or retrospective cohort studies, were excluded. English-language studies available in full text and published in peer-reviewed journals were included. Following the Update Committee meeting, ASCO staff searched the programs for ASCO's 2009 Annual Meeting and the 2009 SABCS meeting to include updated data from the trials described therein.

Inclusion and Exclusion Criteria

Articles identified for inclusion in this systematic review met the following criteria: (1) the intervention was for the adjuvant therapy of breast cancer, (2) participants were randomly assigned to any of the treatments described previously, and (3) reports included at least one of the following primary outcomes of interest: overall survival, disease-free survival, or breast cancer-specific survival. Three different treatment strategies were identified on the basis of the timing of aromatase inhibitor (AI) therapy: initial endocrine therapy (hereafter referred to as a primary adjuvant strategy), sequential therapy with treatment divergence if the patient was disease-free following 1 to 4 years of initial treatment with adjuvant endocrine agents (most often tamoxifen), or extended therapy with random assignment if the patient was disease-free following 5 years of treatment with adjuvant tamoxifen. Trials that used earlier generations of AIs, included neoadjuvant therapy, reported laboratory but not primary disease-related outcomes of interest, or were not randomized were excluded. Trials that treated patients with metastatic breast cancer were also excluded.

Number of Source Documents

Twelve prospective, randomized clinical trials originally identified by the co-chairs were the focus of this systematic review. Four meta-analyses identified from the search were also considered.

Methods Used to Assess the Quality and Strength of the Evidence
Expert Consensus (Committee)
Rating Scheme for the Strength of the Evidence

Not applicable

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

Data Extraction

Reports and publications that met inclusion criteria were identified in a first round of review by members of the American Society of Clinical Oncology (ASCO) staff. The Update Committee co-chairs subsequently reviewed the list of articles, and staff obtained full-text copies of papers that satisfied the inclusion criteria. ASCO staff completed full-text review of these articles, including assessment of inclusion and exclusion criteria. Articles that provisionally met inclusion criteria underwent data extraction for patient characteristics, study design and quality, interventions, outcomes, and adverse events. Evidence summary tables were reviewed for accuracy and completeness by an ASCO staff member who was not involved in their original preparation.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

The American Society of Clinical Oncology (ASCO) Guideline Update Panel reconvened to develop an update. The ASCO technology assessment in 2004 on the use of aromatase inhibitors (AIs) in the adjuvant setting identified multiple unanswered questions regarding optimal endocrine treatment for postmenopausal women. New data on these remaining questions formed the foundation for this guideline update. The Update Committee focused on the optimal adjuvant endocrine strategy with use of either tamoxifen, AIs, or both in sequence; the appropriate duration of AI therapy; the long-term adverse effects of AI therapy; identification of subpopulations who might derive selective benefit from either AI- or tamoxifen-based treatments; efficacy of AIs among premenopausal women; and similarities or differences among commercially available third-generation AIs.

Consensus Development Based on Evidence

The Update Committee met twice, first in San Antonio in December 2008 and again at ASCO Headquarters in April 2009. The Update Committee was charged with updating the clinical questions, reviewing evidence collected from the systematic review, and drafting the new recommendations. Additional work on the guideline was primarily completed by the co-chairs and ASCO staff. The draft guideline document was developed by the co-chairs and ASCO staff and reviewed by the entire Update Committee.

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
Internal Peer Review
Description of Method of Guideline Validation

Per standard American Society of Clinical Oncology (ASCO) practice, the guideline was submitted to the Journal of Clinical Oncology for peer review. The content of the guideline was reviewed and approved by both the ASCO Clinical Practice Guideline Committee and the Board of Directors before publication.

Recommendations

Major Recommendations

1a. What adjuvant endocrine treatments should be offered to postmenopausal women with hormone receptor–positive breast cancer?

Recommendation 1a. The Update Committee recommends, on the basis of data from randomized, controlled trials, that most postmenopausal women consider taking an aromatase inhibitor (AI) during the course of adjuvant treatment to lower recurrence risk, either as primary therapy or after 2 to 3 years of tamoxifen—strategies that yield equivalent outcomes in prospective studies. Duration of AI therapy should not exceed 5 years.

1b. What is the appropriate duration of adjuvant endocrine therapy?

Recommendation 1b. Therapy with an AI should not extend beyond 5 years in either the primary or extended adjuvant settings, outside of clinical trials. In the sequential setting, the Update Committee recommends, on the basis of available evidence from randomized, controlled trials, that patients receive an AI after 2 or 3 years of tamoxifen for a total of 5 years of adjuvant endocrine therapy. The Update Committee recommends that patients who are initially treated with an AI but discontinue treatment before 5 years of therapy consider taking tamoxifen for a total of 5 years of adjuvant endocrine therapy.

1c. If tamoxifen is administered first, how long should it be continued before the switch to an AI?

Recommendation 1c. The Update Committee recommends that, on the basis of available evidence from randomized, controlled trials, patients who initially receive tamoxifen as adjuvant therapy may be offered an AI after 2 to 3 years of therapy (sequential) or after 5 years of therapy (extended). The time to switch from an AI to tamoxifen (or the converse) that maximally improves outcomes is not known from available direct evidence. The Update Committee recommends switching at 2 to 3 years on the basis of data from sequential trials that used this strategy. Switching at 5 years is also a strategy supported by the extended adjuvant randomized trials.

2. Are there specific patient populations that derive differing degrees of benefit from an AI in comparison to tamoxifen?

Recommendation 2. Direct evidence from randomized trials does not identify a specific marker or clinical subset that predicted which adjuvant treatment strategy, tamoxifen or AI monotherapy or sequential therapy, would maximally improve outcomes for a given patient. Among men with breast cancer, tamoxifen remains the standard adjuvant endocrine treatment.

The Update Committee recommends against using CYP2D6 genotype to select adjuvant endocrine therapy. The Update Committee encourages caution with concurrent use of CYP2D6 inhibitors (such as bupropion, paroxetine, fluoxetine; see Table 5 in the original guideline document) and tamoxifen because of the known drug-drug interactions.

3. What are the toxicities and risks of adjuvant endocrine therapy?

Recommendation 3. The Update Committee recommends that clinicians consider adverse effect profiles, patient preferences, and pre-existing conditions when recommending an adjuvant endocrine strategy for postmenopausal women. Clinicians should discuss adverse effect profiles when presenting available treatment options to patients. The Update Committee suggests that clinicians consider recommending that patients change treatment if adverse effects are intolerable or if patients are persistently noncompliant with therapy.

4. Are AIs effective adjuvant therapy for women who are premenopausal at the time of diagnosis?

Recommendation 4. The Update Committee recommends that women who are pre- or perimenopausal at the time of breast cancer diagnosis be treated with 5 years of tamoxifen.

Additional considerations. The Update Committee recommends that clinicians use caution in evaluating menopausal status of patients who are pre- or perimenopausal at diagnosis. Unequivocal determination of menopausal status may be challenging to prove. Even among women who have not experienced menses for more than 1 year, laboratory testing is inadequate because patients may recover ovarian function. This particularly applies to those patients who experience chemotherapy- or tamoxifen-induced amenorrhea.

5. Can the third-generation AIs be used interchangeably?

Recommendation 5. In the absence of direct comparisons, the Update Committee interprets available data as suggesting that benefits of AI therapy represent a "class effect." Meaningful clinical differences between the commercially available third-generation AIs have not been demonstrated to date. In the clinical opinion of the Update Committee (rather than direct evidence from randomized trials), postmenopausal patients intolerant of one AI but who are still candidates for adjuvant endocrine therapy may be advised to consider tamoxifen or a different AI.

Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The recommendations are based on 12 randomized controlled trials and 4 meta-analyses. Refer to the "Literature update and discussion" sections of the original guideline document for specific evidence for each recommendation.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

An adjuvant treatment strategy incorporating an aromatase inhibitor (AI) as primary (initial endocrine therapy), sequential (using both tamoxifen and an AI in either order), or extended (AI after 5 years of tamoxifen) therapy reduces the risk of breast cancer recurrence compared with 5 years of tamoxifen alone. Data suggest that including an AI as primary monotherapy or as sequential treatment after 2 to 3 years of tamoxifen yields similar outcomes.

Potential Harms
  • The Update Committee encourages caution with concurrent use of CYP2D6 inhibitors (such as bupropion, paroxetine, fluoxetine) and tamoxifen because of the known drug-drug interactions.
  • Appendix Tables A4 through A8 in the original guideline document include an abbreviated list of the adverse effects tabulated from the therapies evaluated in the prospective, randomized trials discussed. Four main categories of symptoms are detailed: cardiovascular, musculoskeletal, gynecologic, and climacteric.

Contraindications

Contraindications

Aromatase inhibitors are contraindicated in premenopausal women.

Qualifying Statements

Qualifying Statements
  • American Society of Clinical Oncology's (ASCO's) practice guidelines reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and to identify questions and settings for further research. Because of the rapid flow of scientific information in oncology, new evidence may have emerged since the guideline was submitted for publication. Guidelines and assessments are not continually updated and may not reflect the most recent evidence. Guidelines address only the topics specifically identified in the guideline and are not applicable to interventions, disease, or stages of disease not specifically identified. Guidelines 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 for the patient. Accordingly, adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO guidelines describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these 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 for any errors or omissions.
  • Several important limitations of the existing literature were identified. Of particular note is the timing of random assignment (see Fig 1 in the original guideline document). Most of the sequential trials and all the extended trials randomly assigned women who were free of recurrence through multiple years of tamoxifen therapy, effectively excluding women with early recurrence. For this reason, the patient populations in the sequential and extended trials may differ importantly from one another and from those patients in the primary therapy studies. Another limitation is the relatively short follow-up time. Postmenopausal breast cancer is a disease with a long natural history, and disease recurrence decades after diagnosis is not uncommon. The longest available median follow-up in the trials included here is slightly more than 8 years; most studies have considerably shorter follow-up. For the majority of the efficacy outcomes across all studies, the median time to event has yet to be reached. The relatively modest number of events may also limit study conclusions.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Patient Resources
Quick Reference Guides/Physician Guides
Slide Presentation
For 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
Living with Illness
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Burstein HJ, Prestrud AA, Seidenfeld J, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Malin J, Mamounas EP, Rowden D, Solky AJ, Sowers MR, Stearns V, Winer EP, Somerfield MR, Griggs JJ, American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010 Aug 10;28(23):3784-96. [124 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2002 Aug 1 (revised 2010 Aug 10)
Guideline Developer(s)
American Society of Clinical Oncology - Medical Specialty Society
Source(s) of Funding

American Society of Clinical Oncology

Guideline Committee

American Society of Clinical Oncology (ASCO) Practice Guidelines Update Committee

Composition of Group That Authored the Guideline

Update Committee Members: Harold J. Burstein, MD, PhD (Co-Chair), Dana-Farber Cancer Institute; Jennifer J. Griggs, MD, MPH (Co-Chair), University of Michigan Comprehensive Cancer Center; Holly Anderson, RN, BSN, Patient Representative, Breast Cancer Coalition of Rochester; Diana Rowden, MS, Patient Representative, Susan G. Komen for the Cure; Thomas A. Buchholz, MD, M. D. Anderson Cancer Center; Nancy E. Davidson, MD, University of Pittsburgh Cancer Institute; Karen A. Gelmon, MD, British Columbia Cancer Agency; Sharon Hermes Giordano, MD, M. D. Anderson Cancer Center; Clifford Hudis, MD, Memorial Sloan-Kettering Cancer Center; Jennifer Malin, MD, PhD, Greater Los Angeles Veterans Affairs Healthcare System; Eleftherios P. Mamounas, MD, Aultman Health Foundation; Alexander J. Solky, MD, Interlakes Oncology and Hematology; MaryFran R. Sowers, PhD, University of Michigan; Vered Stearns, MD, Johns Hopkins School of Medicine; Eric P. Winer, MD, Dana-Farber Cancer Institute

Financial Disclosures/Conflicts of Interest

Guideline and Conflicts of Interest

The Update Committee was assembled in accordance with American Society of Clinical Oncology's (ASCO's) Conflict of Interest Management Procedures for Clinical Practice Guidelines ("Procedures," summarized at www.asco.org/guidelinescoi External Web Site Policy). Members completed ASCO's disclosure form, which requires disclosure of financial and other interests relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as the result of promulgation of the guideline. Categories for disclosure include employment relationships, consulting arrangements, stock ownership, honoraria, research funding, and expert testimony. In accordance with the Procedures, the majority of the members of the Update Committee did not disclose any such relationships.

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.

Employment or Leadership Position: None

Consultant or Advisory Role: Jennifer Malin, Pfizer (C); Eleftherios P. Mamounas, Novartis (C), Pfizer (C)

Stock Ownership: None

Honoraria: Karen E. Gelmon, Novartis, AstraZeneca, Pfizer; Eleftherios P. Mamounas, Pfizer, Novartis; Vered Stearns, AstraZeneca

Research Funding: Vered Stearns, Novartis, Pfizer

Expert Testimony: None

Other Remuneration: None

Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, Chlebowski RT, Gelber R, Edge SB, Gralow J, Cobleigh MA, Mamounas EP, Goldstein LJ, Whelan TJ, Powles TJ, Bryant J, Perkins C, Perotti J, Braun S, Langer AS, Browman GP, Somerfield, MR. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005 Jan 20;23(3):1-11.

Guideline Availability

Electronic copies: Available from the American Society of Clinical Oncology (ASCO) Web site External Web Site Policy.

Print copies: Available from American Society of Clinical Oncology, Cancer Policy and Clinical Affairs, 1900 Duke Street, Suite 200, Alexandria, VA 22314; E-mail: guidelines@asco.org.

Availability of Companion Documents

The following are available:

  • American Society of Clinical Oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone-receptor positive breast cancer. Slide set. Electronic copies: Available in Portable Document Format (PDF) External Web Site Policy and Power Point External Web Site Policy from the American Society of Clinical Oncology (ASCO) Web site.
  • American Society of Clinical Oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone receptor–positive breast cancer. Guideline summary. Electronic copies: Available in Portable Document Format (PDF) from the ASCO Web site External Web Site Policy.
Patient Resources

The following are 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 on May 6, 2005. The information was verified by the guideline developer on May 10, 2005. This NGC summary was updated by ECRI Institute on October 7, 2010.

Copyright Statement

This summary is based on the original guideline, which is subject to the American Society of Clinical Oncology's copyright restrictions.

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