HER2-Low Breast Cancer: Molecular Characteristics and Prognosis

SIMPLE SUMMARY: The dichotomous classification of HER2 status is experiencing a paradigm change, leading to the identification of the so-called “HER2-low” category. The aim of our retrospective, observational study was to characterize intrinsic PAM50 subtypes within HER2-low primary breast tumors extracted from The Cancer Genome Atlas (TCGA) dataset and to describe the prognostic impact of HER2-low on survival outcomes. We evaluated 804 breast cancers and we identified 410 HER2-low tumors (336 with positive hormonal receptor status (HR+) and 74 with negative HR status (HR−)). HER2-enriched tumors were more frequent in HER2-low/HR− and HER2-low/HR+ subtypes, compared to HER2-negative/HR− and HER2-negative/HR+ subtypes, respectively (13.7% versus 1.6% and 1.2% versus 0.5%, respectively). We observed no significant differences in prognosis between HER2-low subtypes and each non-HER2-low subtype when paired by HR status. Our characterization of PAM50 intrinsic subtypes within HER2-low breast cancer ultimately supports further investigation of new treatment strategies in the HER2-low category, with new promising drugs being tested in the context. ABSTRACT: Background: We aimed to determine the distribution of intrinsic subtypes within HER2-low breast cancer (BC), and to describe the prognostic impact of HER2-low status on survival outcomes. Methods: This is a retrospective, observational study of primary BC extracted from The Cancer Genome Atlas dataset. We described the distribution of PAM50 intrinsic subtypes within HER2-low BC subtype according to hormonal receptor status (positive (HR+) and negative (HR−)). Secondly, we assessed the impact of HER2-low on survival outcomes (progression-free interval (PFI), disease-free interval (DFI), and overall survival (OS)). Results: We analyzed 804 primary BCs, including 410 (51%) HER2-low BCs (336 HR+ and 74 HR−). The proportion of HER2-enriched tumors was higher in the HER2-low/HR− group compared to HER2-low/HR+ (13.7% versus 1.2%, respectively). HER2-enriched tumors were more frequent in HER2-low/HR− and HER2-low/HR+ subtypes, compared to HER2-negative/HR− and HER2-negative/HR+ subtypes, respectively (13.7% versus 1.6% and 1.2% versus 0.5%, respectively). We observed no significant differences in PFI, DFI, and OS between HER2-low subtypes and each non-HER2-low subtype paired by HR status. Conclusions: Our characterization of PAM50 intrinsic subtypes within HER2-low breast cancer may explain the different clinical behaviors and responses to treatment, and ultimately support further investigation of new treatment strategies in the HER2-low category. Moreover, it highlights the importance of considering HR status in the HER2-low category.