HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation

Abstract

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/ by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Human epidermal growth factor receptor 2 (HER2) is a protooncogene that encodes epidermal growth factor receptor with tyrosine kinase activity, located on chromosome 17 at q21. In breast cancers, HER2 gene is amplified in 15%-20% of invasive breast cancers and its amplification is closely linked to HER2 protein overexpression [1,2]. HER2 amplification is a poor prognostic factor associated with a high rate of recurrence and mortality, and is a predictive factor for response to anthracyclinebased chemotherapies in patients with breast cancer [1,2]. Most importantly, it is a sole predictive marker for treatment benefits from HER2-targeting agents such as trastuzumab, lapatinib, and pertuzumab. As HER2-targeted therapy is exclusively effective in HER2-overexpressed and/or HER2-amplified breast cancers, precise assessment of HER2 status is an essential step for treatment of breast cancer. In this review, we focused on changes in the American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) guidelines on HER2 interpretation and some pitfalls in the interpretation of HER2 status in breast cancers. METHODS OF HER2 TESTINGCurrently, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and chromogenic in situ hybridization (CISH) including silver in situ hybridization (SISH) are regarded as standard methods for determination of HER2 status in breast cancer, and some of them have been approved by the U.S. Food and Drug Administration (FDA) for HER2 testing in breast cancer since 1998.Although HER2 status can be directly tested by in situ hybridization (ISH), many laboratories have adopted IHC as a screening test, and FISH as a confirmation test for HER2 IHC equivocal cases, considering higher failure rate, longer procedure time and higher reagent cost of FISH, compared to that of IHC. Moreover, Human epidermal growth factor receptor 2 (HER2) protein overexpression and/or HER2 gene amplification is found in about 20% of invasive breast cancers. It is a sole predictive marker for treatment benefits from HER2 targeted therapy and thus, HER2 testing is a routine practice for newly diagnosed breast cancer in pathology. Currently, HER2 immunohistochemistry (IHC) is used for a screening test, and in situ hybridization is used as a confirmation test for HER2 IHC equivocal cases. Since the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines on HER2 testing was first released in 2007, it has been updated to provide clear instructions for HER2 testing and accurate determination of HER2 status in breast cancer. During HER2 interpretation, some pitfalls such as intratumoral HER2 heterogeneity and increase in chromosome enumeration probe 17 signals m...

Impact of the Updated Guidelines on Human Epidermal Growth Factor Receptor 2 (HER2) Testing in Breast Cancer

“…This difference in the percentages from other studies is not clear; nevertheless, we assume that SISH could have a role in this classification. The greatest advantage of bright field ISH is that it is possible to co-evaluate the histologic morphologies under conventional light microscopy [ 1 ]. It helps in distinguishing the tumor cells from normal background cells, which provides a more accurate copy number count than FISH.…”

“…The human epidermal growth factor receptor 2 ( HER2 ) gene, which encodes a transmembrane tyrosine kinase, is located on the chromosome 17q21. HER2 gene amplification and/or protein overexpression have been reported in 15%–20% of patients with invasive breast cancer (IBC) [ 1 ].…”

“…The HER2 gene amplification can be assessed by in situ hybridization (ISH), including fluorescence ISH (FISH), chromogenic ISH and silver-enhanced ISH (SISH). Moreover, the HER2 protein overexpression can be evaluated by immunohistochemistry (IHC) [ 1 ]. In Korea, IHC is applied as the primary test and SISH has been used for the confirmation of HER2 IHC equivocal cases since October 2013 [ 5 ].…”

UCNP-based Photoluminescent Nanomedicines for Targeted Imaging and Theranostics of Cancer

“…One of the most significant tumor markers is HER2, a human epidermal growth factor receptor, overexpression is directly related to the growth of various types of malignant tumors (breast and cervix adenocarcinoma, ovary and lung carcinoma, etc.) [ 20 ] and indicates their aggressiveness and high metastatic potential [ 29 , 30 , 31 ]. Therefore, the creation of HER2-specific complexes is an actual direction in diagnostics and therapy.…”

Standardized pathology report for breast cancer

“…IHC and in situ hybridization (ISH) are regarded as standard methods to assess HER2 status in breast cancer. The ASCO/CAP have jointly released guidelines and recommendations on HER2 testing in breast cancer since 2007, and, recently, have updated these guidelines to provide clear instructions for HER2 testing and accurate determination of HER2 status in breast cancer [ 49 ].…”