HER2-Low Expression in Male Breast Cancer: Results from a Multicenter Series in Italy

Simple Summary In the evolving landscape of breast cancer care, recognizing HER2-low expression as a target for anti-HER2 therapies has revolutionized treatment approaches. This retrospective, observational, multicenter study, focusing on male breast cancer (MBC), aimed to characterize the HER2-low subtype. Of the 144 MBCs analyzed, 54.9% were HER2-0, 27.1% HER2-low, and 18% HER2-positive. Specifically, among hormone receptor-positive MBCs, 34.8% were HER2-low. Notably, the prevalence of HER2-low in MBC appears slightly lower than in females. HER2-low MBCs showed a higher likelihood of positive lymph node involvement. About 13% of HER2-low MBCs carried germline BRCA1/2 pathogenic variants, predominantly in BRCA2. Overall, our data derived from the largest MBC series to our knowledge, also characterized for germline pathogenic variants, support the recognition of the emerging category of HER2-low breast cancer. This study emphasizes the need for tailored understanding of HER2-low expression in MBC and underscores potential implications for refining therapeutic approaches based on distinct molecular profiles.Abstract In the field of breast cancer care, a significant breakthrough has occurred with the recognition of HER2-low expression as a target for novel anti-HER2 antibody-drug conjugates (ADC). This discovery is reshaping the treatment landscape, challenging previous perceptions that considered HER2-low as clinically insignificant. The ability to target HER2-low expression is expected to have substantial clinical implications, irrespective of gender, including in cases of male breast cancer (MBC). However, an estimate of the prevalence of the HER2-low subtype in MBC is missing. This retrospective, observational, multicenter study was aimed at characterizing the HER2-low subtype in MBC. For the purpose of this study, the three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) was used to reclassify the HER2-negative group into HER-0 or HER2-low subtypes. In the whole series of 144 invasive MBCs, 79 (54.9%) were HER2-0 (IHC scores of 0), 39 (27.1%) HER2-low (IHC scores of 1+/2+ with negative ISH), and 26 (18.0%) HER2-positive (IHC scores of 3+/2+ with positive ISH). Specifically, among hormone receptor-positive (HR+) HER2-negative invasive MBCs, 34.8% were HER2-low and 65.2% HER2-0. Compared with HER2-0, HER2-low subtype was associated with a positive lymph node involvement (p = 0.01). Other pathologic characteristics including histology, staging, and grading did not show notable variations between the two subtypes. The presence of germline BRCA1/2 pathogenic variants (PVs) did not significantly differ between HER2-0 and HER2-low MBCs. However, about 13% of HER2-low MBCs had germline PVs in BRCA1/2 genes, mainly BRCA2, a clinically relevant observation in the context of combined target therapy. Overall, our data, which focused on the largest gender-specific breast cancer series, to our knowledge, confirm that the emerging three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) can also be considered in MBC, to mitigate both the gender gap and the underrepresentation of males in clinical trials.