1. American Society of Clinical Oncology Endorsement of the Cancer Care Ontario (CCO) Practice Guideline on Adjuvant Ovarian Ablation (OA) in the Treatment of Premenopausal Women with Early Stage Invasive Breast Cancer

2. Introduction Cancer Care of Ontario (CCO) published a guideline, “Adjuvant Ovarian Ablation in the Treatment of Premenopausal Women with Early Stage Invasive Breast Cancer,” in July 2010 Ovarian ablation or suppression includes all methods: surgical oophorectomy, medical suppression, and ovarian irradiation. Guideline considered for endorsement, requiring both methodologic and content review

3. Guideline Clinical Questions Question 1: How does adjuvant ovarian ablation (OA) as systemic therapy improve clinically meaningful outcomes (disease-free survival, overall survival, quality of life and toxicity) when compared with and/or added to other systemic therapies, specifically chemotherapy and tamoxifen? Question 2: What is the best way to ablate or suppress ovarian function: surgical oophorectomy, ovarian irradiation or medical suppression

4. CCO Guideline Development Guideline developed by the CCO Program in Evidence-Based Care (PEBC) Guideline staff included members of the PEBC Breast Cancer Disease Site Group and systematic review/guideline methodologists Target population includes premenopausal women with hormone receptor-positive early- stage invasive breast cancer

5. CCO Guideline Development Databases searched: MEDLINE searched from 1966 – September 2009 Cochrane Library search through September 2009 Online conference proceedings, all searched through September 2009: ASCO Annual Meeting San Antonio Breast Cancer Symposium Canadian Medical Association Infobase National Guideline Clearing House

6. ASCO Methods Review Appraisal of Guidelines for Research and Evaluation (AGREE) II - tool used by guideline developers, evaluators Three ASCO senior guideline staff members completed “Rigour of Development” subscale of the AGREE II Seven-item subscale assesses both: – quality of approach to gather and synthesize data, and – methods to create the guideline recommendations Literature search updated since CCO guideline published – No trials met inclusion/exclusion criteria

7. ASCO Content Review Ad Hoc Panel of subject matter experts, primarily breast oncologists Panel members completed 8-item Guideline Endorsement Content Review Form – Assesses clarity, clinical utility of recommendations – Evaluates consistency of recommendations with available data Form adapted by ASCO from the CCO PEBC Practitioner Feedback instrument

8. Recommendations Clinical Question 1: What is the clinical efficacy of OA versus other systemic therapy +/- OA? – OA should not be routinely added to systemic therapy with chemotherapy, tamoxifen, or the combination of tamoxifen and chemotherapy. – OA alone is not recommended as an alternative to any other form of systemic therapy except in the specific case of patients who are candidates for other forms of systemic therapy but who for some reason will not receive any other systemic therapy (e.g., patients who cannot tolerate other forms of systemic therapy or patients who choose no other form of systemic therapy).

9. Recommendations Clinical Question 2. If indicated, What is best method of OA? – When chemical suppression using LHRH agonists is the chosen method of OA, in the opinion of the Breast Cancer DSG monthly injection is the recommended mode of administration. The mode of administration in nearly all of the available trials has been monthly administration.

10. Qualifying Statements CCO Guideline includes qualifying statements; these were also endorsed. OA was not compared with current systemic regimens; difficult to contextualize available data. EBCTCG meta-analysis is foundation for recommendation to use OA in patients who refuse systemic therapy. Patients might not be representative.

11. Qualifying Statements OA may be non-inferior to CMF chemotherapy; thus, OA may be reasonable alternative to CMF. However, trials were not designed to assess non- inferiority/equivalency No evidence available to suggest optimal method to achieve ovarian ablation

12. ASCO Ad Hoc Panel Updates ASCO panel members made the following points, in addition to endorsing CCO guideline: 1)In patients who do embark upon ovarian suppression using LHRH agonists, ovarian suppression is not always successfully achieved. Ovarian suppression cannot be confirmed by cessation of menses alone, and estradiol assays are not always reliable indicators of ovarian function.

13. ASCO Ad Hoc Panel Updates 2) Many of the studies that address the role of OA in premenopausal women with breast cancer included women with hormone receptor- negative disease or unknown hormone receptor status. There is no evidence of benefit of OA in these patients.

14. ASCO Ad Hoc Guideline Content Review Panel Panel MemberInstitution Jennifer J. Griggs, M.D., M.P.H, ChairUniversity of Michigan Holly Anderson, R.N., B.S.N.Breast Cancer Coalition of Rochester Nancy E. Davidson, M.D.University of Pittsburgh N. Lynn Henry, M.D., Ph.D.University of Michigan Clifford A. Hudis, M.D.Memorial Sloan-Kettering Cancer Center James L. Khatcheressian, M.D.Virginia Commonwealth University Ann H. Partridge, M.D., M.P.H.Dana Farber Cancer Institute

15. ASCO Guidelines This resource is a practice tool for physicians based on an ASCO® practice guideline. The practice guideline and this presentation are not intended to substitute for the independent professional judgment of the treating physician. Practice guidelines do not account for individual variation among patients and may not reflect the most recent evidence. This presentation does not recommend any particular product or course of medical treatment. Use of the practice guideline and this resource is voluntary. The full practice guideline and additional information are available at http://www.asco.org/endorsements/OA. Copyright © 2011 by American Society of Clinical Oncology®. All rights reserved.