©American Society of Clinical Oncology All rights reserved American Society of Clinical Oncology Clinical Practice Guideline Update on Adjuvant Endocrine Therapy for Women with Hormone-Receptor Positive Breast Cancer

©American Society of Clinical Oncology All rights reserved INTRODUCTION ASCO initially published its first technology assessment for the use of aromatase inhibitors (AIs) in the adjuvant setting for women with hormone receptor-positive breast cancer in 2002 ASCO guidelines are updated at intervals by an Update Committee of the original Expert Panel; the last update was in 2004 For the 2010 update, the Update Committee reviewed literature published since May 2007

©American Society of Clinical Oncology All rights reserved Guideline Methodology: Systematic Review The Update Committee completed a systematic review and analysis of the medical literature, using the Cancer Care Ontario systematic review of literature through May 2007, and ASCO’s searches of literature from May 2007 to February 2009 Medline Pre-Medline Cochrane Collaboration Library ASCO and San Antonio Breast Cancer Symposium abstracts from

©American Society of Clinical Oncology All rights reserved Limitations of the literature Timing of randomization – patient populations in sequential, extended, and primary therapy trials may all differ from one another Longest median follow-up data available is 8 years, most studies less Median time to event yet to be achieved Modest # of events, including for subgroups Different definitions of study endpoints

©American Society of Clinical Oncology All rights reserved Clinical Questions 1a. What adjuvant endocrine treatments should be offered to postmenopausal women with hormone receptor-positive breast cancer? 1b. What is the appropriate duration of adjuvant endocrine therapy? 1c. If tamoxifen is administered first, how long should it be continued before the switch to an AI? 2. Are there specific patient populations that derive differing degrees of benefit from an aromatase inhibitor in comparison to tamoxifen?

©American Society of Clinical Oncology All rights reserved Clinical Questions, cont’d 3. What are the toxicities and risks of adjuvant endocrine therapy? 4. Are aromatase inhibitors effective adjuvant therapy for women who are premenopausal at the time of diagnosis? 5. Can the third-generation aromatase inhibitors be used interchangeably?

©American Society of Clinical Oncology All rights reserved Recommendations Recommendation 1a. The Update Committee recommends, based on data from randomized controlled trials, that most postmenopausal women consider taking an aromatase inhibitor during the course of adjuvant treatment to lower recurrence risk, either as primary therapy or after two to three years of tamoxifen, strategies that yield equivalent outcomes in prospective studies. Duration of aromatase inhibitor therapy should not exceed five years.

©American Society of Clinical Oncology All rights reserved Recommendations Recommendation 1b. Therapy with an aromatase inhibitor should not extend beyond five years in either the primary or extended adjuvant settings, outside of the clinical trials setting. In the sequential setting, the Update Committee recommends, based on available evidence from randomized controlled trials, that patients receive an AI after two or three years of tamoxifen for a total of five years of adjuvant endocrine therapy. The Update Committee recommends that patients who are initially treated with an AI but discontinue treatment before five years of therapy consider taking tamoxifen for a total of five years of adjuvant endocrine therapy.

©American Society of Clinical Oncology All rights reserved Recommendations Recommendation 1c. The Update Committee recommends that, based on available evidence from randomized controlled trials, patients who initially receive tamoxifen as adjuvant therapy may be offered an AI after two to three years (sequential) or after five years (extended) of therapy. 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 two to three years based on data from sequential trials that employed this strategy. Switching at five years is also a strategy supported by the extended adjuvant randomized trials.

©American Society of Clinical Oncology All rights reserved Clinical settingOptionsRecommended duration of tamoxifen Recommended duration of AI Recommended total duration of endocrine therapy If patient is commencing adjuvant endocrine therapy; (patient may have just finished surgery or chemotherapy) (P/S) AI monotherapy N/A5 years Tamoxifen  AI 2-3 years 5 years If patient in middle of tamoxifen (S) Tamoxifen  AI 2-3 years 5 years If patient in middle of AI (S) AI  tamoxifen 2-3 years (administer second) 2-3 years (administer first) 5 years If patient finishing five years of tamoxifen (E) Tamoxifen  AI 5 years3-5 years 8-10 years If patient is pre- or peri- menopausal Tamoxifen5 yearsNR5 years Strategies: (P)-primary; (S)-sequential; (E)-extended

©American Society of Clinical Oncology All rights reserved Recommendations 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 Committee encouraged caution with concurrent use of CYP2D6 inhibitors (such as bupropion, paroxetine, fluoxetine) and tamoxifen because of the known drug-drug interactions.

©American Society of Clinical Oncology All rights reserved Recommendations Recommendation 3. The Update Committee recommends that clinicians consider side effect profiles, patient preferences, and pre-existing conditions when recommending an adjuvant endocrine strategy for postmenopausal women. Clinicians should discuss side effect profiles when presenting available treatment options to patients. The Update Committee suggests that clinicians consider recommending that patients change treatment if side effects are intolerable or patients are persistently non-compliant with therapy.

©American Society of Clinical Oncology All rights reserved Recommendations Recommendation 4. The Update Committee recommends that women who are pre- or perimenopausal at the time of breast cancer diagnosis be treated with five years of tamoxifen. Additional considerations. The Update Committee recommends that clinicians use caution in evaluating menopausal status of patients who were pre- or perimenopausal at diagnosis. Unequivocal determination of menopausal status may be challenging to prove. Even among women who have not experienced menses for over one year, laboratory testing is inadequate as patients may recover ovarian function. This particularly applies to those patients who experience chemotherapy- or tamoxifen- induced amenorrhea.

©American Society of Clinical Oncology All rights reserved Recommendations 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 aromatase inhibitors have not been demonstrated to date. In the clinical opinion of the 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.

©American Society of Clinical Oncology All rights reserved Side-effects Comparison TamoxifenAI CVD√ (<1% difference in serious CVD incidence) Hypercholesterolemia√ Hypertension√ slight VTE√ Loss of BMD*√ Bone fracture√ Osteoporosis√ Musculoskeletal/arthralgia√ Gynecologic AEs√ (uterine cancer, benign endometrial pathology, hysterectomy, vaginal discharge) Hot flashes√ Please note: √ represents higher risk of side-effect in column of that particular agent.. *BMD-bone mineral density

©American Society of Clinical Oncology All rights reserved Guideline Methodology: Panel Members Panel MemberInstitution Harold Burstein, MD, PHD, co- chair Dana-Farber Cancer Institute Jennifer Griggs, MD, MPH, co- chair University of Michigan Comprehensive Cancer Center Holly Anderson, RN, BSN patient representative Breast Cancer Coalition of Rochester Thomas Buchholz, MDMD Anderson Cancer Center Nancy Davidson, MDUniversity of Pittsburgh Cancer Institute and UPMC Cancer Centers Karen Gelmon, MDBritish Columbia Cancer Agency Sharon Giordano, MDUniversity of Texas – MD Anderson Cancer Center Clifford Hudis, MDMemorial Sloan-Kettering Cancer Center

©American Society of Clinical Oncology All rights reserved Guideline Methodology: Panel Members, cont’d Panel MemberInstitution Jennifer Malin, MD, PhDGreater Los Angeles Veterans Affairs Healthcare System Eleftherios (Terry) Mamounas, MDAultman Health Foundation Diana Rowden, MS patient representative Susan G. Komen for the Cure Alexander Solky, MDInterlakes Oncology and Hematology PC MaryFran Sowers, PhDUniversity of Michigan Vered Stearns, MDJohns Hopkins School of Medicine Eric P. Winer, MDDana-Farber Cancer Institute

©American Society of Clinical Oncology All rights reserved Additional ASCO Resources The full text of the guideline, an abridged version of the guideline, a Journal of Oncology Practice Summary, this slide set, and additional clinical tools and resources can be found at: A patient guide, “What to Know” about this guideline, is available at:

©American Society of Clinical Oncology All rights reserved ASCO Guidelines