Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers Journal Article


Authors: Teo, M. Y.; Seier, K.; Ostrovnaya, I.; Regazzi, A. M.; Kania, B. E.; Moran, M. M.; Cipolla, C. K.; Bluth, M. J.; Chaim, J.; Al-Ahmadie, H.; Snyder, A.; Carlo, M. I.; Solit, D. B.; Berger, M. F.; Funt, S.; Wolchok, J. D.; Iyer, G.; Bajorin, D. F.; Callahan, M. K.; Rosenberg, J. E.
Article Title: Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers
Abstract: 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. (c) 2018 by American Society of Clinical Oncology.
Keywords: chemotherapy; tumors; carcinoma; trial; sensitivity; invasive bladder-cancer; multicenter; mutational landscape; phase-2; pd-1 blockade; single-arm
Journal Title: Journal of Clinical Oncology
Volume: 36
Issue: 17
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2018-06-10
Start Page: 1685
End Page: 1694
Language: English
ACCESSION: WOS:000434770500007
DOI: 10.1200/jco.2017.75.7740
PROVIDER: wos
PUBMED: 29489427
Notes: Article -- Source: Wos
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MSK Authors
  1. Joshua Chaim
    17 Chaim
  2. Dean Bajorin
    382 Bajorin
  3. Jedd D Wolchok
    607 Wolchok
  4. David Solit
    420 Solit
  5. Mark J Bluth
    11 Bluth
  6. Gopakumar Vasudeva Iyer
    121 Iyer
  7. Michael Forman Berger
    373 Berger
  8. Ashley Regazzi
    30 Regazzi
  9. Jonathan Eric Rosenberg
    210 Rosenberg
  10. Maria Isabel Carlo
    21 Carlo
  11. Samuel Aaron Funt
    18 Funt
  12. Brooke Elizabeth Kania
    4 Kania
  13. Min Yuen   Teo
    27 Teo
  14. Kenneth Seier
    18 Seier
  15. Meredith Maisie Moran
    2 Moran