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Association of somatic ERCC2 mutations with cisplatin sensitivity in muscle-invasive urothelial carcinoma.
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: Cisplatin-based combination chemotherapy is the standard of care for patients with muscle invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although the molecular determinants of cisplatin sensitivity are incompletely understood. Recent reports have identified somatic mutations in ERCC2, a nucleotide excision repair gene, in 7-12% of bladder cancers. Preclinical evidence suggests that defects in the nucleotide excision repair (NER) pathway mediate cisplatin sensitivity. Methods: We performed whole exome sequencing of pre-treatment tumor and germline DNA from 51 patients with muscle invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (26 pT0/pTis “responders”, 25 pT2+ “non-responders”). Computational methods were employed to identify somatic mutations that occurred preferentially in cisplatin responders. Functional validation of significantly enriched mutations was performed using cellular cisplatin and UV sensitivity assays. Results: Somatic ERCC2 mutations were observed in 38.5% of responders and 0% of non-responders (q < 0.01). ERCC2 was the only gene enriched in the cisplatin responders compared with non-responders. ERCC2 mutations clustered within or near conserved helicase domains required for ERCC2 function. Expression of the identified ERCC2 mutants in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared to wild-type ERCC2. Conclusions: Somatic ERCC2 mutation is associated with cisplatin sensitivity in muscle invasive urothelial carcinoma. These results may inform the use of cisplatin-containing regimens in muscle invasive urothelial carcinoma, and potentially other ERCC2-mutated tumors.
Abstracts by Jonathan E. Rosenberg:
Comprehensive characterization of 412 muscle invasive urothelial carcinomas: Final analysis of The Cancer Genome Atlas (TCGA) project.Meeting: 2016 Genitourinary Cancers Symposium | Abstract No: 405
External beam radiotherapy and concurrent gemcitabine for muscle-invasive bladder cancer: Toxicities and early outcomes.Meeting: 2016 Genitourinary Cancers Symposium | Abstract No: 443
IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC).Meeting: 2016 Genitourinary Cancers Symposium | Abstract No: 355