DNA damage response alterations are linked to improved responses to anti–PD-1/PD-L1 in urothelial carcinoma.
Major finding: DNA damage response alterations are linked to improved responses to anti–PD-1/PD-L1 in urothelial carcinoma.
Concept: Sequencing identified deleterious DNA damage response alterations in 80% of responding patients.
Impact: DNA damage response alterations may serve as biomarkers to predict responses to anti–PD-1/PD-L1.
Immune checkpoint inhibitors targeting PD-1 or PD-L1 provide clinical benefit in a subset of patients with metastatic urothelial carcinoma, but response rates are relatively low and biomarkers are needed to identify the patients most likely to benefit from immune checkpoint blockade (ICB). A high tumor mutation load has been linked to increased response rates, but does not sufficiently predict response. Urothelial carcinomas often have genomic alterations affecting genes involved in DNA damage response and repair (DDR), and these alterations are associated with an increased mutation load. Thus, Teo and colleagues hypothesized that DDR mutations might be associated with responses to immune checkpoint blockade. This hypothesis was tested in a study of 60 patients with metastatic urothelial carcinoma treated with anti–PD-1/PD-L1 antibodies on three separate prospective trials. All patients had targeted exon sequencing performed on preimmunotherapy tumor specimens. The primary objective was to determine the effect of DDR gene alterations on the overall response rate, and the secondary objective was to assess correlations between DDR alterations and both progression-free and overall survival. Overall, 74 alterations in DDR genes were identified in 28 patients (46.7%), and 27 of these mutations, observed in 15 patients (25%), were considered deleterious. The presence of a DDR alteration was linked to a higher response to ICB, with 67.9% of patients responding compared with 18.8% of patients lacking DDR alterations. Further, an 80% response rate was observed in patients with DDR alterations known or likely to be deleterious, compared with a 54% response rate for DDR alterations of unknown significance. DDR alterations were also associated with an increased progression-free and overall survival. Collectively, these findings suggest that alterations in DDR genes may serve as biomarkers of response to anti–PD-1/PD-L1 therapy, and thus may guide treatment selection for patients with metastatic urothelial carcinoma.
Teo MY, Seier K, Ostrovnaya I, Regazzi AM, Kania BE, Moran MM, et al. Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers. J Clin Oncol 2018 Feb 28 [Epub ahead of print].
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