Updates in the Pathology and Therapy of BRCA Germline–Associated Breast Cancer with a Focus on HER2 Amplification

Germline pathogenic variants of the breast cancer type 1 or 2 susceptibility genes (BRCA1 or BRCA2) are associated with the majority of hereditary breast and ovarian cancer syndromes (HBOC). The prevalence of human epidermal growth factor receptor 2 (HER2) gene amplification or protein overexpression in BRCA1/2-associated breast cancers is low. Simultaneous BRCA1/2 pathogenic variants and HER2 alterations confer a poor prognosis. The purpose of this review is to evaluate the recent literature characterizing the concurrent presence of BRCA1/2 and HER2 alterations in breast cancer patients, current management, associated outcomes, and potential opportunities for novel therapeutic approaches.

Simultaneous BRCA1/2and HER2 alterations are uncommon, reporting a prevalence of up to 10% in BRCA1 and 13% in BRCA2-associated breast cancers. Available prognostic data is limited, with some series reporting lower invasive disease-free survival (iDFS) and overall survival (OS) in HER2-positive BRCA1/2-associated breast cancers compared to other tumor phenotypes. Current therapeutic guidelines in the non-metastatic setting recommend the combination of a cytotoxic regimen with HER2-directed therapy. BRCA1/2-mutated breast cancers are susceptible to platinum-based agents and poly(ADP-ribose) polymerase (PARP) inhibitors. Preclinical data shows increased antitumor response with HER2-targeted therapy in HER2-positive BRCA2-mutated cancer cell lines. These findings open the opportunity for combinatorial targeted therapies including anti-HER2 agents, PARP inhibitors, and/or platinum-based chemotherapy. Given that most BRCA-associated cancers are not HER2-amplified, treatment strategies for HER2-low breast cancer could also have applications to patients with BRCA pathogenic variants.