Loss of HER2 in breast cancer: biological mechanisms and technical pitfalls

Abstract

Loss of HER2 in previously HER2-positive breast tumors is not rare, occurring in up to 50% of breast cancers; however, clinical research and practice underestimate this issue. Many studies have reported the loss of HER2 after neoadjuvant therapy and at metastatic relapse and identified clinicopathological variables more frequently associated with this event. Nevertheless, the biological mechanisms underlying HER2 loss are still poorly understood. HER2 downregulation, intratumoral heterogeneity, clonal selection, and true subtype switch have been suggested as potential causes of HER2 loss, but translational studies specifically investigating the biology behind HER2 loss are virtually absent. On the other side, technical pitfalls may justify HER2 loss in some of these samples. The best treatment strategy for patients with HER2 loss is currently unknown. Considering the prevalence of this phenomenon and its apparent correlation with worse outcomes, we believe that correlative studies specifically addressing HER2 loss are warranted.

Early Breast Cancer Risk Assessment: Integrating Histopathology with Artificial Intelligence

“…An accurate evaluation of human epidermal growth factor receptor 2 (HER2) expression is crucial for effective breast cancer treatment [ 93 , 94 , 95 , 96 ]. The current approach is transitioning from a binary HER2 assessment to recognizing HER2-low tumors (1+ or 2+ with negative in situ hybridization (ISH)), as emphasized by data with novel treatment, specifically trastuzumab deruxtecan in HER2-low BC [ 97 ].…”

Standardized pathology report for HER2 testing in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer

“…However, the potential challenges associated with HER2 IHC in the lower range of protein expression have not received sufficient attention [ 62 ]. It is now imperative to refine the performance of HER2 testing, considering all variables that may impact the documentation of HER2-low status in the pathology report [ 52 ]. By understanding the pitfalls of HER2 testing in light of the emerging clinical importance of HER2-low, improvements can be made in test sensitivity, specificity, and reproducibility [ 52 , 62 ].…”

“…It is now imperative to refine the performance of HER2 testing, considering all variables that may impact the documentation of HER2-low status in the pathology report [ 52 ]. By understanding the pitfalls of HER2 testing in light of the emerging clinical importance of HER2-low, improvements can be made in test sensitivity, specificity, and reproducibility [ 52 , 62 ]. In this article, we address the current issues related to identifying HER2-low BC and offer practical recommendations for optimal testing approaches.…”

Predicting Response to Antibody Drug Conjugates: A Focus on Antigens’ Targetability

“… 16 Besides heterogeneity, HER2 status is also dynamic, as demonstrated by the loss or gain of HER2 expression in both early and metastatic setting, 58-60 which may reflect tumor heterogeneity (ie, HER2 status is different between primary and metastatic tumor or between 2 different metastatic sites) but also the result of acquired resistance to previous treatments. BC can lose HER2-expression as a result of the selective pressure elicited by HER2-directed therapies 61 or, in case of HR-positive/HER2-negative mBC, BC cells can upregulate HER2 expression as a mechanism of resistance to endocrine agents, converting into HER2-positive tumors. 62 Therefore, rebiopsy and retest for pathology biomarkers on progressing lesions, including HER2, are crucial for some patients showing treatment resistance or a different disease trajectory, to capture potential heterogeneity and phenotype switch.…”