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Abstract 2165: Concurrent BRCA2 and PTEN mutations are associated with improved survival in endometrioid endometrial cancer

Objectives: In patients with high-grade serous ovarian cancer, those with BRCA mutations and resultant homologous recombination deficiency have shown improved responses to treatment with PARP inhibitors. PTEN mutations are frequently observed in endometrioid endometrial cancer, however, role of BRCA...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2015-08, Vol.75 (15_Supplement), p.2165-2165
Main Authors: Hansen, Jean M., Baggerly, Keith, Wang, Ying, Ivan, Cristina, Wu, Sherry, Previs, Rebecca, Zand, Behrouz, Dalton, Heather, Hu, Wei, Coleman, Robert L., Sood, Anil K.
Format: Article
Language:English
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Summary:Objectives: In patients with high-grade serous ovarian cancer, those with BRCA mutations and resultant homologous recombination deficiency have shown improved responses to treatment with PARP inhibitors. PTEN mutations are frequently observed in endometrioid endometrial cancer, however, role of BRCA mutations is not known in this disease. We sought to determine the frequency and clinical significance of BRCA mutations in patients with endometrioid endometrial cancer. Methods: We assessed PTEN, BRCA1 and BRCA2 mutation status for 248 uterine tumor samples using Level 3 data from The Cancer Genome Atlas (TCGA). We performed mutation analysis for PTEN, BRCA1 and BRCA2 for an additional 251 samples from TCGA using ANNOVAR. A total of 499 patients were included in the analysis. Clinical data including stage, tumor histology, and overall survival were also extracted. Fisher's exact tests were used to identify the association between mutation status and histologic subtype. Kaplan-Meier plots were constructed to demonstrate survival differences between groups. Next, we characterized a panel of uterine cell lines for PTEN, BRCA1 and BRCA2 mutation status using the Cancer Cell Line Encyclopedia. Gene and protein expression levels were determined by qPCR and Western Blot, respectively. MTT, a colorimetric cell viability assay, was used to determine viability of uterine cells treated with cisplatin or olaparib, a PARP-1 inhibitor. Results: Among the samples analyzed, 335 (67%) had endometrioid histology, 76 (15%) had serous histology, 18 (4%) had mixed histology, and in the remainder of cases, histology was unknown. Of the patients with endometrioid histology, 260 (78%) had a PTEN mutation, 23 (7%) had both BRCA1 and 2 mutations, 4 (1%) had mutations in BRCA1 only, and 25 (8%) had mutations in BRCA2 only. 52/335 patients (16%) had mutations in either BRCA1 or 2; 18/52 (35%) of these were stage II or above and the remainder were stage I. There was no survival advantage detected in patients with BRCA1 mutations over wild-type BRCA1, independent of PTEN mutation status (p = 0.16 and 0.19, respectively). Patients with both PTEN and BRCA2 mutations had improved overall survival as compared to those patients with wild-type PTEN and BRCA2 (p = 0.03, hazard ratio 0.242). A single mutation in BRCA1, BRCA2 or PTEN did not confer a significant survival advantage as compared to wild-type (p = 0.15). In vitro, Ishikawa (PTEN/BRCA1 double mutant) and Hec1b (wild-type for all three
ISSN:0008-5472
1538-7445
DOI:10.1158/1538-7445.AM2015-2165