Targeting HER2-low in metastatic breast cancer: an evolving treatment paradigm

Abstract

The results of the Phase III DESTINY-Breast04 trial of trastuzumab deruxtecan (T-DXd) are leading to a shift in both the classification and treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. In this trial, T-DXd was associated with a substantial survival benefit among patients with hormone receptor-positive and hormone receptor-negative disease and low expression of HER2, a biomarker previously considered unactionable in this treatment setting. Herein, we discuss the evolving therapeutic pathway for HER2-low disease, ongoing clinical trials, and the potential challenges and evidence gaps arising with treatment of this patient population.

Advancing HER2-low breast cancer management: enhancing diagnosis and treatment strategies

“… 44 , 53 New evidence indicates that patients with low HER2 expression (IHC 1+ or 2+ and ISH-negative) represent a new targetable category of BC. 3 In light of these changes, HER2 testing and reporting has become more complex. 54 …”

“…Another challenge is related to the companion diagnostic tests for evaluating 1+ and 2+/ISH-negative disease. 3 Assays used are either those approved and currently available on the market (with Ventana HER2/neu 4B5 [F. Hoffmann-La Roche Ltd] being more frequently used in the CEE area) or ones developed in-house. Besides temporal and spatial tumor heterogeneity, many other factors are known to impact the IHC scoring – from pre- and post-analytical factors to test sensitivity, type of specimen, and laboratory and/or reader experience.…”

“…Besides temporal and spatial tumor heterogeneity, many other factors are known to impact the IHC scoring – from pre- and post-analytical factors to test sensitivity, type of specimen, and laboratory and/or reader experience. 3 , 6 , 56 , 57 , 58 …”

“… 1 In breast cancer (BC), HER2 overexpression/gene amplification determined by immunohistochemistry (IHC) and/or in situ hybridization (ISH) is found in 15−20% of all tumors. 3 , 4 , 5 Anti-HER2-directed therapies have significantly improved the survival of patients with both early and metastatic HER2-positive BC and consequently changed the treatment paradigm, being accepted as the standard of care throughout the world. 5 , 6 The current pathology guidelines define HER2-positive tumors when the IHC score is 3+ or 2+ with the HER2 encoding gene (erb-b2 receptor tyrosine kinase 2 [ ERRB2 ]) amplification by ISH (ISH-positive), whereas HER2-negative tumors have IHC scores of 0+, 1+, or 2+/ISH-negative.…”

“…In light of recent evidence brought by novel anti-HER2 antibody-drug conjugates (ADCs) 5 , 8 , 9 , 10 , 11 , 12 , the current knowledge of HER2 expression range and its clinical applicability is changing since a significant proportion of HER2-negative tumors are in fact characterized by a spectrum of HER2 expression levels. 13 , 14 A new targetable category has been identified in patients whose tumors are scored IHC 1+ or 2+/ISH-negative 3 , and this low level of HER2 expression has been termed ‘HER2-low’. 15 HER2-low status is detected in 45−55% of all BC tumors: around two-thirds (65%) in hormone receptor-positive (HR+) BC and one-third (36%) in HR-negative (HR-) cancers.…”