Association of somatic ERCC2 mutations with cisplatin sensitivity in muscle-invasive urothelial carcinoma.

Genitourinary (Nonprostate) Cancer
Session Type and Session Title: 
Poster Highlights Session, Genitourinary (Nonprostate) Cancer
Abstract Number: 



J Clin Oncol 32:5s, 2014 (suppl; abstr 4510)


Jonathan E. Rosenberg, Eliezer Mendel Van Allen, Kent William Mouw, Philip H. Kim, Nikhil Wagle, Hikmat Al-Ahmadie, Cong Zhu, Irina Ostrovnaya, Gopa Iyer, Sabina Signoretti, Victor E. Reuter, Gad Getz, Philip W. Kantoff, Bernard H. Bochner, Toni K. Choueiri, Dean F. Bajorin, David B. Solit, Stacey B. Gabriel, Alan D. D'Andrea, Levi A. Garraway; Memorial Sloan Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; The Broad Institute, Cambridge, MA; Brigham and Women's Hospital/Harvard Medical School, Boston, MA; Broad Institute, Cambridge, MA

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Abstract Disclosures


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.