The Landscape of Somatic Genetic Alterations in Metaplastic Breast Carcinomas.

Abstract

<b>Purpose:</b> Metaplastic breast carcinoma (MBC) is a rare and aggressive histologic type of breast cancer, predominantly of triple-negative phenotype, and characterized by the presence of malignant cells showing squamous and/or mesenchymal differentiation. We sought to define the repertoire of somatic genetic alterations and the mutational signatures of MBCs.<b>Experimental Design:</b> Whole-exome sequencing was performed in 35 MBCs, with 16, 10, and 9 classified as harboring chondroid, spindle, and squamous metaplasia as the predominant metaplastic component. The genomic landscape of MBCs was compared with that of triple-negative invasive ductal carcinomas of no special type (IDC-NST) from The Cancer Genome Atlas. Wnt and PI3K/AKT/mTOR pathway activity was assessed using a qPCR assay.<b>Results:</b> MBCs harbored complex genomes with frequent <i>TP53</i> (69%) mutations. In contrast to triple-negative IDC-NSTs, MBCs more frequently harbored mutations in <i>PIK3CA</i> (29%), <i>PIK3R1</i> (11%), <i>ARID1A</i> (11%), <i>FAT1</i> (11%), and <i>PTEN</i> (11%). <i>PIK3CA</i> mutations were not found in MBCs with chondroid metaplasia. Compared with triple-negative IDC-NSTs, MBCs significantly more frequently harbored mutations in PI3K/AKT/mTOR pathway-related (57% vs. 22%) and canonical Wnt pathway-related (51% vs. 28%) genes. MBCs with somatic mutations in PI3K/AKT/mTOR or Wnt pathway-related genes displayed increased activity of the respective pathway.<b>Conclusions:</b> MBCs are genetically complex and heterogeneous, and are driven by a repertoire of somatic mutations distinct from that of triple-negative IDC-NSTs. Our study highlights the genetic basis and the importance of PI3K/AKT/mTOR and Wnt pathway dysregulation in MBCs and provides a rationale for the metaplastic phenotype and the reported responses to PI3K/AKT/mTOR inhibitors in these tumors. <i>Clin Cancer Res; 23(14); 3859-70. ©2017 AACR</i>.