SUMMARY CDK4/6 inhibitors (CDK4/6i) are effective in breast cancer, however drug resistance is frequently encountered and poorly understood. We conducted a genomic analysis of 348 estrogen receptor-positive breast cancers treated with CDK4/6i and identified loss of function mutations affecting FAT1 and RB1 linked to drug resistance. FAT1 loss led to marked elevations in CDK6 whose suppression restored sensitivity to CDK4/6i. The induction of CDK6 was mediated by the Hippo pathway with accumulation of YAP and TAZ transcription factors on the CDK6 promoter. Genomic alterations in other Hippo pathway components were also found to promote CDK4/6i resistance. These findings uncover a tumor suppressor function of Hippo signaling in ER+ breast cancer and establish FAT1 loss as a mechanism of resistance to CDK4/6i.

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Clear cell carcinoma of the endometrium is a rare type of endometrial cancer generally associated with an aggressive clinical behavior. Here we sought to define the repertoire of somatic genetic alterations in endometrial clear cell carcinomas (ECCs) and whether ECCs could be classified into the molecular subtypes described for endometrial endometrioid and serous carcinomas. We performed a rigorous histopathological review, immunohistochemical analysis and massively parallel sequencing targeting 300 cancer-related genes of 32 pure ECCs. Eleven (34%), seven (22%) and six (19%) ECCs displayed abnormal expression patterns of p53, ARID1A and at least one DNA mismatch repair protein, respectively. Targeted sequencing data were obtained from 30 of the 32 ECCs included in this study, which revealed that two ECCs (7%) were ultramutated and harbored mutations affecting the exonuclease domain of POLE. In POLE wild-type ECCs, TP53 (46%), PIK3CA (36%), PPP2R1A (36%), FBXW7 (25%), ARID1A (21%), PIK3R1 (18%) and SPOP (18%) were the genes most commonly affected by mutations, and 18% and 11% harbored CCNE1 and ERBB2 amplifications, respectively, while 11% showed DAXX homozygous deletions. In comparison to non-POLE endometrioid carcinomas from The Cancer Genome Atlas (TCGA), ECCs less frequently harbored mutations affecting CTNNB1 and PTEN but more frequently PPP2R1A and TP53 mutations. Compared to endometrial serous carcinomas (TCGA), ECCs less frequently harbored TP53 mutations. Using a surrogate model for the molecular-based TCGA classification, all molecular subtypes previously identified in endometrial endometrioid and serous carcinomas were present in the ECCs studied, including POLE, MMR-deficient, copy-number high (serous-like)/p53 abnormal and copy-number low (endometrioid)/p53 wild-type, which were significantly associated with disease-free survival in univariate analysis. These findings demonstrate that ECCs are a histologically and genetically heterogeneous group of tumors with varying outcomes. Furthermore, our data suggest that the classification of ECCs as being generally “high-grade” or “type II” tumors may not be warranted.

Adenomyoepithelioma of the breast is a rare tumor characterized by epithelial−myoepithelial differentiation, whose genetic underpinning is largely unknown. Here we show through whole-exome and targeted massively parallel sequencing analysis that whilst estrogen receptor (ER)-positive adenomyoepitheliomas display PIK3CA or AKT1 activating mutations, ER-negative adenomyoepitheliomas harbor highly recurrent codon Q61 HRAS hotspot mutations, which co-occur with PIK3CA or PIK3R1 mutations. In two- and three-dimensional cell culture models, forced expression of HRASQ61R in non-malignant ER-negative breast epithelial cells with or without a PIK3CAH1047R somatic knock-in results in transformation and the acquisition of the cardinal features of adenomyoepitheliomas, including the expression of myoepithelial markers, a reduction in E-cadherin expression, and an increase in AKT signaling. Our results demonstrate that adenomyoepitheliomas are genetically heterogeneous, and qualify mutations in HRAS, a gene whose mutations are vanishingly rare in common-type breast cancers, as likely drivers of ER-negative adenomyoepitheliomas.

Purpose: Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome.Experimental Design: We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advancedstage PDAC, who had both germline-and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated: BRCA1,