Abstract P3-07-02: Metaplastic breast carcinomas and uterine carcinosarcomas are histologically and genetically related

Introduction: Metaplastic breast carcinomas (MBCs) and uterine carcinosarcomas (UCSs) are histologically similar, being often characterized by an admixture of adenocarcinoma areas with areas displaying sarcomatoid differentiation. We sought to investigate whether their histologic similarities would be paralleled by similar patterns of genetic alterations, and to determine whether the different histologic components of MBCs and UCSs would be clonally related. Methods: Whole exome sequencing (WES) data from 35 MBCs previously analyzed by our group and 57 UCSs from The Cancer Genome Atlas (TCGA) study were reanalyzed. Somatic single nucleotide variants were detected with MuTect and indels with Strelka, Varscan2, Scalpel and Lancet. Copy number alterations were inferred using FACETS and functional annotation of the non-synonymous somatic mutations, amplifications or homozygous deletions was performed. We further microdissected the histologically distinct components of 11 MBCs and six UCSs and subjected each component to WES. Clonal decomposition was performed using PyClone. Results: The most frequent somatic mutations identified in MBCs were TP53 (69%), PIK3CA (29%), FAT3 (26%) and PTEN (14%), whereas the most frequently mutated genes in UCSs were TP53 (84%), FBXW7 (35%), PIK3CA (29%), PTEN (15%) and PPP2R1A (15%). MBCs displayed a significantly higher frequency of mutations targeting FAT3 (26% vs 4%, P Conclusions: Our findings support the contention that UCSs constitute the uterine counterpart of MBCs due to their similar histology and patterns of genetic alterations affecting the same signaling pathways (i.e. TP53, PI3K, Wnt and Notch). In each MBC and UCS analyzed here, the histologically distinct components were found to be clonally related. Citation Format: Da Cruz Paula A, Brown D, Geyer FC, Smith E, Pareja F, Papanastasiou AD, Fusco N, Marchio C, Brogi E, Wen HY, Vincent-Salomon A, Norton L, Weigelt B, Reis-Filho JS. Metaplastic breast carcinomas and uterine carcinosarcomas are histologically and genetically related [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-07-02.