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DDR Alterations and Outcomes With Immunotherapy for Advanced Urothelial Cancer

By: Kelly M. Hennessey, PhD
Posted: Wednesday, December 23, 2020

The prognosis of urothelial cancer is influenced by gene alterations caused by the DNA damage response (DDR). A study conducted by Ming Yin, MD, of The Ohio State University College of Medicine, Columbus, and colleagues explored the role of ATM mutations in patients with advanced urothelial cancer who were treated with anti–PD-1/PD-L1 therapies. They found that patients with urothelial cancer who had DDR alterations and received anti–PD-1/PD-L1 therapy achieved a higher objective response rate as well as longer overall survival compared with patients who did not have ATM alterations. Their results were reported in Cancer Medicine.

“Further studies are needed to assess the clinical utility of DDR alterations in directing therapies in urothelial cancer,” the investigators concluded.

This retrospective study examined 53 patients in the treatment cohort and 38 patients in the nonrandomized control population who had advanced urothelial cancer. Of the patients in the treatment cohort, 49% (n = 26) presented with DDR alterations.

Patients who received immunotherapy had longer overall survival than those who did not (hazard ratio = 0.43). Patients with at least three DDR gene mutations had a significantly higher tumor mutation burden, higher objective response rates, and seemed to benefit the most from anti–PD-1/PD-L1 therapy compared with patients who had fewer than three alterations. The objective response rate was higher with the presence of more mutations (including ATM) with PD-1/PD-L1 blockade. Overall survival in patients with DDR alterations (including ATM) was similar to those without DDR alterations. However, patients with DDR alterations (without ATM) seemed to have longer overall survival, but significance was not reached (hazard ratio = 0,53). ATM alterations were associated with a nonsignificantly higher objective response rate (40% vs. 29%) and significantly shorter overall survival. According to the study authors, patients harboring ATM mutations may need additional therapeutic approaches.

Disclosure: For full disclosures of the study authors, visit

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