APOBEC-Driven Hypermutation in the Lymphocyte-Predominant Group of Triple-Negative Breast Cancer

This study aimed to evaluate the clinicopathologic and genomic characteristics of triple-negative breast cancer subclassification. Triple-negative breast cancer was classified into the luminal androgen receptor (LAR) subtype and the tumor-infiltrating lymphocytes (TILs) groups of the non-LAR subtype—lymphocyte predominant (LP), lymphocyte intermediate, and lymphocyte depleted—based on androgen receptor immunohistochemistry and TILs. Clinicopathologic and genomic characteristics were evaluated for these triple-negative breast cancer subclasses. The LP group was associated with a histologic type of carcinoma with medullary features, a higher tumor mutation burden, and increased APOBEC activity, indicative of APOBEC-driven hypermutation. The LAR subtype was characterized by a higher prevalence of PIK3CA mutations, lower homologous recombination deficiency scores, and associations with histologic types of invasive lobular carcinoma, and carcinoma with apocrine differentiation. This study demonstrated the distinct clinicopathologic and genomic characteristics of triple-negative breast cancer subclassifications. APOBEC activity–related hypermutation is a defining characteristic of the LP group.