Paolo Cotzia: Insights into HER2-low breast cancers

Paolo Cotzia, Medical Director of Molecular Pathology and Head of Molecular Excellence at Sonic Healthcare USA, posted the following on LinkedIn:

“HER2-low breast cancers represent a subset of tumors previously classified as HER2-negative based on traditional diagnostic criteria, including immunohistochemistry and fluorescence in situ hybridization.

With the approval of trastuzumab deruxtecan, and the introduction of therapeutic strategies targeting low levels of HER2, there has been increased attention on this subgroup of tumors.

These breast neoplasms are distinguished by having low but detectable levels of HER2 expression, and though they were historically lumped together with HER2-negative tumors, emerging data suggest that they have distinct molecular features that influence treatment response and prognosis.

This recent study explores the genetic and molecular differences within HER2-low breast cancers and their clinical significance.

This study aimed to better understand the molecular and genetic variations within HER2-negative breast cancers stratifying them based on quantitative HER2 expression levels specifically by examining ERBB2 mRNA expression.

The authors used transcriptomic and genomic data from the Molecular Taxonomy of Breast Cancer International Consortium (Discovery Cohort) and The Cancer Genome Atlas (Independent Validation Cohort).

The HER2-negative tumors were categorized into three subgroups: minimal, moderate, and enhanced based on their ERBB2 mRNA levels.

Key findings included significant differences in mutational and transcriptional profiles across these subgroups:

Enhanced ERBB2 mRNA expression was linked to a higher prevalence of PIK3CA mutations and increased estrogen receptor (ER) signaling.
Minimal ERBB2 mRNA expression correlated with higher expression of genes related to cell proliferation and immune response.

A subgroup of breast cancers, characterized by a large deletion of chromosome 17q12 (17q12del), was identified. These tumors exhibited very low ERBB2 mRNA and HER2 protein expression and were enriched for heterozygous losses of TP53 and other tumor suppressor genes. This subgroup was associated with significantly poorer overall survival (OS) in two large real-world cohorts of patients with HER2-negative metastatic breast cancer (Dana-Farber Cancer Institute cohort n=1063 and Memorial Sloan Kettering MetTropism cohort n=1018).

This study identified a biologically and clinically distinct subgroup of HER2-negative breast cancers characterized by 17q12 deletion, heterozygous loss of ERBB2, and low HER2 expression.

This subgroup showed poorer survival outcomes. These findings underscore the need for further characterization of HER2-low tumors and suggest that molecular features, such as 17q12del and ERBB2 loss, may help predict prognosis and guide therapeutic strategies.

This research contributes to the growing evidence supporting the relevance of HER2-low breast cancers as a distinct entity with unique molecular characteristics.

Molecular profiling of these tumors may have important implications for treatment and patient management.”

Molecular characterization of HER2-negative breast cancers reveals a distinct patient subgroup with 17q12 deletion and heterozygous loss of ERBB2

Authors: X. Qiu, P. Tarantino, R. Li, A. Grinshpun, H. Gupta, M. E. Hughes, G. Kirkner, L. Scholl, B. E. Johnson, M. Meyerson, A. D. Cherniack, Y. Jiang, N. Zhou, N. U. Lin, H. W. Long, S. M. Tolaney, R. Jeselsohn