NCCN VERSION 2 2015

NCCN Guidelines Version 2.2015 Breast Cancer

NCCN Guidelines Index Breast Cancer Table of Contents Discussion

long-term (greater than 5-year) safety and efficacy of these agents are still under investigation. The various studies are consistent in demonstrating that the use of a third-generation aromatase inhibitor in postmenopausal women with hormone receptor-positive breast cancer lowers the risk of recurrence, including IBTR, contralateral breast cancer, and distant metastatic disease when used as initial adjuvant therapy, sequential therapy, or extended therapy. The panel finds no compelling evidence that there is meaningful efficacy or toxicity differences between the aromatase inhibitors, anastrozole, letrozole, and exemestane. All three have shown similar anti-tumor efficacy and toxicity profiles in randomized studies in the adjuvant settings. The updated version of the NCCN Guidelines for Breast Cancer recommends the following adjuvant endocrine therapy options for women with early breast cancer who are postmenopausal at diagnosis: an aromatase inhibitor as initial adjuvant therapy for 5 years (category 1); tamoxifen for 2 to 3 years followed by one of the following options: an aromatase inhibitor to complete 5 years of adjuvant endocrine therapy (category 1) or 5 years of aromatase inhibitor therapy (category 2B); or tamoxifen for 4.5 to 6 years followed by 5 years of an aromatase inhibitor (category 1) or consideration of tamoxifen for up to 10 years. In postmenopausal women, the use of tamoxifen alone for 5 years (category1) or up to 10 years is limited to those who decline or who have a contraindication to aromatase inhibitors. In premenopausal women, the aromatase inhibitors are associated with the development of benign ovarian pathology and do not adequately suppress ovarian estrogen synthesis. Premenopausal women should not be given adjuvant initial therapy with an aromatase inhibitor outside the confines of a clinical trial. Women who are premenopausal at diagnosis and who become amenorrheic with chemotherapy may have continued estrogen production from the ovaries without menses. Serial

assessment of circulating LH, FSH, and estradiol to assure a true postmenopausal status is mandatory if this subset of women is to be considered for therapy with an aromatase inhibitor. 309,310 After 5 years of tamoxifen (category 1), for women postmenopausal at that time (including those who have become postmenopausal during the 5 years of tamoxifen therapy), the NCCN Panel recommends considering extended therapy with an aromatase inhibitor for up to 5 years (category 1) or based on the data from the ATLAS trial considering tamoxifen for an additional 5 years. For those who remain premenopausal after the initial 5 years of tamoxifen, the panel recommends considering continuing up to 10 years of tamoxifen therapy. The measurement of the nuclear antigen, Ki-67 by IHC, gives an estimate of the tumor cells in the proliferative phase (G1, G2, and M phases) of the cell cycle. Studies have demonstrated the prognostic value of Ki-67 as a biomarker and its usefulness in predicting response and clinical outcome. 311 One small study suggests that measurement of Ki-67 after short-term exposure to endocrine treatment may be useful to select patients resistant to endocrine therapy and those who may benefit from additional interventions. 312 However, these data require larger analytic and clinical validation. In addition, standardization of tissue handling and processing is required to improve the reliability and value of Ki-67 testing. At this time, there is no conclusive evidence that Ki-67 alone, especially baseline Ki-67 as an individual biomarker, helps to select the type of endocrine therapy for an individual patient. Therefore, the NCCN Breast Cancer Panel does not currently recommend assessment of Ki-67. The cytochrome P-450 (CYP450) enzyme , CYP2D6, is involved in the conversion of tamoxifen to endoxifen. Over 100 allelic variants of CYP2D6 have been reported in the literature. 313 Individuals with wild-type CYP2D6 alleles are classified as extensive metabolizers of

Version 2.2015, 03/11/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-33