Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1/PD-L1 Blockade in Advanced Urothelial Cancers

Purpose Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. Methods Detailed...

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Published in:	Journal of clinical oncology Vol. 36; no. 17; pp. 1685 - 1694
Main Authors:	Teo, Min Yuen, Seier, Kenneth, Ostrovnaya, Irina, Regazzi, Ashley M, Kania, Brooke E, Moran, Meredith M, Cipolla, Catharine K, Bluth, Mark J, Chaim, Joshua, Al-Ahmadie, Hikmat, Snyder, Alexandra, Carlo, Maria I, Solit, David B, Berger, Michael F, Funt, Samuel, Wolchok, Jedd D, Iyer, Gopa, Bajorin, Dean F, Callahan, Margaret K, Rosenberg, Jonathan E
Format:	Journal Article
Language:	English
Published:	United States American Society of Clinical Oncology 10-06-2018
Subjects:	Adult Aged Aged, 80 and over Antibodies, Monoclonal - therapeutic use Antineoplastic Agents, Immunological - therapeutic use B7-H1 Antigen - antagonists & inhibitors B7-H1 Antigen - immunology Biomarkers, Tumor - genetics DNA Damage - genetics DNA Repair - genetics Female Humans Male Middle Aged Mutation ORIGINAL REPORTS Programmed Cell Death 1 Receptor - antagonists & inhibitors Programmed Cell Death 1 Receptor - immunology Progression-Free Survival Prospective Studies Urologic Neoplasms - drug therapy Urologic Neoplasms - genetics Urologic Neoplasms - immunology
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Summary:	Purpose Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. Methods Detailed demographic, treatment response, and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens. Presence of DDR alterations was correlated with best objective response per Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free and overall survival. Results Sixty patients with urothelial cancer enrolled in prospective trials of anti-PD-1/PD-L1 antibodies met inclusion criteria. Any DDR and known or likely deleterious DDR mutations were identified in 28 (47%) and 15 (25%) patients, respectively. The presence of any DDR alteration was associated with a higher response rate (67.9% v 18.8%; P < .001). A higher response rate was observed in patients whose tumors harbored known or likely deleterious DDR alterations (80%) compared with DDR alterations of unknown significance (54%) and in those whose tumors were wild-type for DDR genes (19%; P < .001). The correlation remained significant in multivariable analysis that included presence of visceral metastases. DDR alterations also were associated with longer progression-free and overall survival. Conclusion DDR alterations are independently associated with response to PD-1/PD-L1 blockade in patients with metastatic urothelial carcinoma. These observations warrant additional study, including prospective validation and exploration of the interaction between tumor DDR alteration and other tumor/host biomarkers of immunotherapy response.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0732-183X 1527-7755 1527-7755
DOI:	10.1200/jco.2017.75.7740