Problematic breast tumors reassessed in light of novel molecular data

Breast cancer is a vastly heterogeneous disease encompassing a panoply of special histological subtypes. Although rare breast tumors have largely not been investigated systematically in large scale genomics series, recent studies have shed light on the genetic underpinnings of special histologic subtypes of breast cancer. Genomic analyses of estrogen receptor-positive special histologic types of breast cancer have not resulted in the identification of novel pathognomonic genetic alterations in addition to the confirmation of the presence ofCDH1loss-of-function mutations in invasive lobular carcinomas. By contrast, the analyses of triple-negative breast cancers have demonstrated that low-grade triple-negative breast cancers categorically differ from the common forms of high-grade triple-negative disease biologically and phenotypically and are underpinned by specific fusion genes or hotspot mutations. A subset of low-grade triple-negative disease has been shown to harbor highly recurrent if not pathognomonic genetic alterations, such asETV6-NTRK3fusion gene in secretory carcinomas, theMYB-NFIBfusion gene,MYBL1rearrangements orMYBgene amplification in adenoid cystic carcinomas, andHRASQ61 hotspot mutations coupled with mutations in PI3K pathway genes in estrogen receptor-negative adenomyoepitheliomas. A subset of these pathognomonic genetic alterations (e.g.,NTRK1/2/3fusion genes) now constitute an FDA approved indication for the use of TRK inhibitors in the advanced/metastatic setting. These studies have also corroborated that salivary gland-like tumors of the breast, other than acinic cell carcinomas, harbor the repertoire of somatic genetic alterations detected in their salivary gland counterparts. Reassuringly, the systematic study of special histologic types of breast cancer utilizing state-of-the-art sequencing approaches, rather than rendering pathology obsolete, has actually strengthened the importance of breast cancer histologic typing and is providing additional ancillary markers for the diagnosis of these rare but fascinating entities.

Automated summary

Breast cancer is a highly heterogeneous disease with special histological subtypes having different genetic underpinnings. Genetic analyses have shown specific alterations in different histologic types, providing insights into their biological and phenotypic differences.