NCCN VERSION 2 2015

NCCN Guidelines Version 2.2015 Breast Cancer

NCCN Guidelines Index Breast Cancer Table of Contents Discussion

average HER2 copy number ≥4.0 signals/cell; dual probe HER2/CEP17 ratio ≥2.0 with an average HER2 copy number <4.0 signals/cell; HER2/CEP17 ratio <2.0 with an average HER2 copy number ≥6.0 signals/cell). High average copy number of HER2 ( ≥6.0 signals/cell) is considered positive regardless of the HER2/CEP17 ratio. The rationale cited by the joint committee for including rare scenarios such as HER2 positivity when dual probe HER2/CEP17 ratio is ≥2.0 and average HER2 copy number is <4.0 signals/cell is that the first-generation trials of adjuvant trastuzumab included a small number of patients with a HER2 /CEP17 ratio ≥2.0 and an average HER2 copy number <4.0 signals/cell. There is no trend in these data, suggesting that these patients were not responsive to trastuzumab and the trastuzumab has a favorable safety profile. Equivocal Result The NCCN Panel agrees with the ASCO/CAP HER2 committee that weak/moderate and within >10% of the invasive tumor cells or complete and circumferential membrane staining that is intense and within ≤ 10% of the invasive tumor cells.” In such cases, the panel recommends reflex testing using the ISH method on the same specimen or repeating tests if a new specimen is available. Similarly, samples with equivocal results by an ISH assay (for example, single probe ISH average HER2 copy number ≥4.0 and <6.0 signals/cell; and dual probe HER/CEP17 ratio <2.0 with an average HER2 copy number ≥4.0 signals/cell) must be confirmed by reflex results of IHC are equivocal if scored as IHC 2+ “based on circumferential membrane staining that is incomplete and/or

Principles of HER2 Testing Along with ER and PR, the determination of HER2 tumor status is recommended for all newly diagnosed invasive breast cancers and for first recurrences of breast cancer whenever possible. The NCCN Breast Cancer Panel endorses CAP accreditation for anatomic pathology laboratories performing HER2 testing. HER2 status can be assessed by measuring the number of HER2 gene copies using in situ hybridization [ISH] techniques, or by a complementary method in which the quantity of HER2 cell surface receptors is assessed by IHC. 18 Assignment of HER2 status based on mRNA assays or multigene arrays is not recommended. The accuracy of HER2 assays used in clinical practice is a major concern, and results from several studies have shown that false-positive 19-22 as well as false-negative 19,23 HER2 test results are common. A joint panel from ASCO and CAP has issued updated HER2 testing guidelines to avoid such false-positive or false-negative results. These updated guidelines have been published in the Archives of Pathology & Laboratory Medicine and ASCO's Journal of Clinical Oncology. 24,25 The NCCN Panel endorses these updated ASCO/CAP recommendations for quality HER2 testing and have been outlined these recommendations in Principles of HER2 Testing . HER2-Positive Result Consistent with the ASCO/CAP guidelines, the NCCN Panel considers either IHC or ISH with either a single or dual probe as acceptable methods for making an initial determination of HER2 tumor status. Breast cancer tumors are classified as HER2-positive if they are scored as 3+ by an IHC method defined as uniform membrane staining for HER2 in 10% or more of tumor cells or demonstrate HER2 gene amplification by an ISH method (single probe, average HER2 copy number ≥6.0 signals/cell; dual probe HER2/CEP17 ratio ≥2.0 with an

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-4