Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKbH4TTImqenVPWx2hcEpdL/wMTQrdCOxrCTxQjKEBLaAP6qBxWn6lfeSgBOTk8Xfww= on 10/19/2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. C URRENT O PINION Targeting HER2 heterogeneity in early-stage breast cancer Sonia Pernas a and Sara M. Tolaney b Purpose of review HER2-positive (HER2þ) breast cancer is clinically and biologically a heterogenous disease and not all patients benefit to the same extent from current anti-HER2 therapies. Recent findings Among HER2þ breast cancer, molecular intrinsic subtypes, PIK3CA mutation status, levels of HER2 gene/ protein, immune infiltration, or intratumor heterogeneity modulate HER2-treatment sensitivity. HER2-enriched carcinomas, with high levels of HER2 and tumor-infiltrating lymphocytes (TILs) are highly sensitive to anti- HER2 therapies, regardless of chemotherapy. Luminal A/B tumors are more estrogen receptor-dependent than HER2-dependent, harbor higher rates of PIK3CA mutations, and are less responsive to anti-HER2 treatment. HER2 intratumoral heterogeneity that exists in approximately 10% of HER2þ disease may also cause treatment resistance. Early changes occur during neoadjuvant anti-HER2 therapy that can predict response. Importantly, HER2 expression is not a binary but rather a continuous variable. Overall, 34–63% of HER2-negative breast cancers express HER2, and HER2-low tumors have become a new entity, for which novel targeted therapies may be effective. Summary Although much of what is discussed currently remains investigational, it is clear that HER2þ breast cancer is a complex disease comprising different entities. Future strategies to escalate or de-escalate treatment in early-stage HER2þ disease should consider other biomarkers beyond HER2 and estrogen receptor status, including intrinsic subtype, HER2 levels, and TILs; and evaluate different treatment strategies among patients with estrogen receptor-positive/HER2þ and estrogen receptor-negative/HER2þ diseases. Keywords HER2, HER2-enriched, HER2-low, heterogeneity, immune-profile INTRODUCTION The introduction of HER2-targeting therapies to standard treatment has dramatically improved the prognosis for HER2-positive (HER2þ) breast cancer patients in both the early and metastatic settings. The discovery of the HER2 oncogene and the devel- opment of trastuzumab, a humanized mAb that binds to HER2 causing HER2 downregulation, were landmarks in the treatment of this disease. Pertuzu- mab, another mAb that binds to HER2 and prevents HER2/HER3 formation, one of the most powerful heterodimers that activates cell proliferation and survival, was the second anti-HER2 agent incorpo- rated into the treatment of early-stage HER2þ breast cancer. In the first-line treatment of advanced dis- ease, the combination of pertuzumab, trastuzumab, and docetaxel resulted in an 8-year landmark overall survival (OS) rate of 37% [1], and in the neoadjuvant setting, the introduction of pertuzumab to standard neoadjuvant treatment resulted in a significant increase in pathological complete response (pCR) rates. However, results in the adjuvant setting have been modest. The addition of pertuzumab to tras- tuzumab and adjuvant chemotherapy resulted in a 3-year rate of invasive disease-free survival (iDFS) benefit only observed in node-positive patients (92 vs. 90.2%; Hazard ratio 0.81; P ¼ 0.02). This benefit was maintained in the 6-year analysis with a 24% decrease in iDFS and an absolute risk reduction of a Department of Medical Oncology, Catalan Institute of Oncology (ICO)- H.U.Bellvitge-IDIBELL, Barcelona, Spain and b Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Correspondence to Sara M. Tolaney, MD, MPH, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Tel: +1 617 632 3800; e-mail: Sara_Tolaney@DFCI.HARVARD.EDU Curr Opin Oncol 2020, 32:545–554 DOI:10.1097/CCO.0000000000000685 1040-8746 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. www.co-oncology.com REVIEW