The Spectrum of Triple-Negative Breast Disease: High- and Low-Grade Lesions

Triple-negative breast cancer is viewed clinically as an aggressive subgroup of breast cancer. In fact, most triple-negative breast cancers are poor-prognosis tumors with a complex genomic landscape. However, triple-negative disease is vastly heterogeneous, encompassing multiple entities with marked genetic, transcriptional, histologic, and clinical differences, with neoplasms in this group ranging from low to high grade. Among the less common low-grade triple-negative lesions, two large subgroups, both with a rather indolent behavior, can be distinguished: a low-grade triple-negative breast neoplasia family, which includes nonobligate precursors of triple-negative breast cancer, and, despite being low-grade, harbors the complex genomic landscape of usual triple-negative breast cancer, and the salivary gland-like tumors of the breast, lacking all the cardinal molecular features of conventional triple-negative breast cancer and underpinned by specific fusion genes or hotspot mutations, which may be of diagnostic and possibly therapeutic utility. Progression to high-grade triple-negative breast cancer likely occurs in both subgroups but at different rates. In this review, we describe the heterogeneity of triple-negative disease, focusing on the histologic and molecular features of the low-grade lesions. Recognition that triple-negative breast cancer is an operational term and that triple-negative disease is heterogeneous and includes low-grade forms driven by distinct sets of genetic alterations is germane to the successful implementation of precision medicine.