Synapse - DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma

DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma Journal Article

Authors:	Teo, M. Y.; Bambury, R. M.; Zabor, E. C.; Jordan, E.; Al-Ahmadie, H.; Boyd, M. E.; Bouvier, N.; Mullane, S. A.; Cha, E. K.; Roper, N.; Ostrovnaya, I.; Hyman, D. M.; Bochner, B. H.; Arcila, M. E.; Solit, D. B.; Berger, M. F.; Bajorin, D. F.; Bellmunt, J.; Iyer, G.; Rosenberg, J. E.
Article Title:	DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma
Abstract:	Purpose: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. Experimental Design: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features. Results: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, logrank P = 0.007) and overall survival (23.7 vs. 13.0 months, logrank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable impact on clinical outcomes. Conclusions: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment. (C) 2017 AACR.
Keywords:	gemcitabine; endometrial cancer; invasive; mutations; phase-iii; expression; transitional-cell carcinoma; bladder-cancer; sensitivity; cisplatin-based chemotherapy; long-term-survival; ercc1
Journal Title:	Clinical Cancer Research
Volume:	23
Issue:	14
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2017-07-15
Start Page:	3610
End Page:	3618
Language:	English
ACCESSION:	WOS:000405678400017
DOI:	10.1158/1078-0432.ccr-16-2520
PROVIDER:	wos
PMCID:	PMC5511570
PUBMED:	28137924
Notes:	Article -- Source: Wos