Characterization of HER2 Expression Levels, Including HER2-Ultralow, in a Retrospective Male Breast Cancer Cohort

Male breast cancer (maleBC) is an orphan disease. Aside from age, risk factors include genetic mutations and conditions like Klinefelter syndrome or other reasons of hypogonadism. Treatment is based on standards in women, but biological differences may exist, with maleBC exhibiting higher rates of hormone-receptor expression. Limiting data exists regarding the rate of low/ultralow HER2 expression, a predictive biomarker for the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in HER2-negative disease in women.

We conducted a retrospective single-center analysis of clinicopathological features of maleBC at a tertiary cancer center. We identified a cohort of 57 maleBC patients, described demographic, pathological, prognostic and surgical and systemic treatment data and evaluated frequencies of low and ultralow HER2 expression.

The mean age was 64.3 (SE ± 1.79) years; 94.7% (n = 54) of patients presented with early/nonmetastatic breast cancer and 40.7% (22 of 54) of patients exhibited nodal involvement. Most patients (92.6%, 50 of 54 patients) had luminal disease and approximately one third of patients received chemotherapy. Endocrine therapy was administered in 87.7% (n = 50/57) of cases. For 52 of the patients included, full receptor status data including HER2 IHC scoring and/or histological specimens were available. IHC slides of tumor specimens from 24 patients with either historically reported "HER2 negative" or "HER2 0" expression were available for reassessment; 79.2% (n = 19 of 24) of these tumors exhibited either HER2-low or -ultralow expression. In the whole cohort, rates of HER2-low and -ultralow expression were 75.0% (39 of 52) and 5.8% (3 of 52 patients), respectively. The median follow-up was 7 years. Six deaths occurred in the total population (n = 57). The median event-free survival (EFS) was 8.39 years (95% CI 7.36-11.35). No statistically significant associations were observed between HER2 expression categories and clinicopathological variables including grade, ER status, nodal status, genetic variant status, age, Ki67 index, or overall survival events.

In this cohort of maleBC patients, high rates of combined HER2-low and -ultralow expression were observed upon reassessment of tumors with historically negative HER2 status, shedding light on potential ADC eligibility in male breast cancer.