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BACKGROUND: Malignant phyllodes tumors (MPT) are rare fibroepithelial breast cancers with no known effective systemic therapy; metastatic progression portends a dismal prognosis. We sought to describe the genomic landscape of MPTs through genomic profiling and immunotherapeutic biomarker analysis. MATERIALS AND METHODS: Cases of sequenced MPT were identified from a Clinical Laboratory Improvement Amendments-certified, College of American Pathologists-accredited laboratory (Foundation Medicine). All cases underwent genomic profiling using adaptor ligation-based, next-generation sequencing assay of 324 genes. Tumor agnostic immunotherapy biomarkers, microsatellite instability, tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression were evaluated. Fisher's Exact Tests and analysis of variance were used to test for differences between groups and for continuous variables as appropriate. RESULTS: Of 135 MPT cases identified; 94 (69.6%) were localized/locally recurrent and 41 (30.4%) were metastatic. Median age was 54 years (range 14-86). The median TMB was 2.5 mut/Mb and 3 were TMB-high (≥10 mut/Mb). 21.4% were PD-L1+ via Dako 22C3 assay (CPS ≥1). Most commonly altered genes included TERT-promoter (69.7%), CDKN2A (45.9%), TP53 (37.8%), NF1 (35.6%), CDKN2B (33.3%), MED12 (28.9%), MTAP (27.7%), KMT2D (22.2%), PIK3CA (20.0%), PTEN (18.5%), and RB1 (18.5%). Several tumors harboring genomic alterations with US Food and Drug Administration-approved indications in other tumor types were found including NF1, PIK3CA, EGFR Exon 19/20 insertions, and BRAF V600E mutations. CONCLUSIONS: In the largest genomic evaluation of MPT to date, multiple clinically actionable mutations were found. Routine sequencing of metastatic MPT may provide additional information to guide treatment decisions and clinical trial enrollment.
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OBJECTIVES: Endometrial serous carcinoma (EMSC) is an aggressive variant of uterine cancer with limited therapeutic options. We sought to define distinct clinicopathologic and genomic EMSC subgroups. METHODS: We retrospectively analyzed 2159 EMSC and 2346 endometrioid-type endometrial carcinomas (EEC) tissue specimens that had undergone comprehensive genomic profiling (CGP) via the FoundationOne CDx assay during routine clinical care. High tumor mutational burden (TMB) was defined as ≥10mut/Mb using the FDA-approved CDx cutoff for pembrolizumab. Microsatellite instability (MSI) was determined on 95 loci. Evidence of homologous recombination deficiency (HRD) was determined via genomic loss of heterozygosity (gLOH), a validated HRD detection method for predicting PARP inhibitor effectiveness in ovarian carcinoma. High gLOH was defined as ≥16%. RESULTS: A genomic analysis of 2159 EMSCs revealed a predominance of TP53 mutations, microsatellite stability, low tumor mutational burden (TMB), and recurrent alterations of PIK3CA, PPP2R1A, ERBB2, CCNE1, FBXW7 and MYC. Evidence of HRD via high gLOH was identified in 22% of EMSCs. BRCA1 and BRCA2 alterations, as well as unique SET (solid, pseudo-endometrioid, and transitional cell-like) variant morphology, were enriched in HRD-EMSC. There was an increased frequency of CCNE1 amplification, a lower prevalence of PIK3CA and PPP2R1A alterations, and no differences in HRD, MSI or TMB biomarker frequencies in patients of predicted African ancestry. EMSC exhibited distinct gene mutation frequencies and MSI, TMB and gLOH biomarker signatures compared to a cohort 2346 EEC. CONCLUSIONS: Molecularly defined subgroups provide a framework to test the susceptibility of EMSC to targeted therapies in specific genetic settings (e.g. HRD, PIK3CA, PPP2R1A, ERBB2, MYC, CCNE1).