<i>CDKN2A</i> Alterations and Response to Immunotherapy in Solid Tumors.

Abstract

Immune checkpoint inhibitors (ICI) have shown clinical benefit in many types of metastatic cancers with only a few predictive biomarkers identified so far. <i>CDKN2A</i> is commonly altered in human cancers, but prior studies have provided conflicting evidence regarding the association between <i>CDKN2A</i> genomic alterations (GA) and response to ICIs. Herein, we examined the impact of loss-of-function <i>CDKN2A</i> alterations on response and survival in patients treated with ICIs. We studied the association between loss-of-function <i>CDKN2A</i> alterations and the response to ICIs in two independent cohorts of six different cancer types. Seven hundred and eighty-nine patients treated at Dana-Farber Cancer Institute (DFCI; Boston, MA) and 1,250 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY) were included in the final analysis. Patients' tumors were sequenced using Oncopanel or MSK-IMPACT. RNA sequencing data from The Cancer Genome Atlas and IMvigor210 were used to investigate differences in the tumor microenvironment. In the DFCI cohort, <i>CDKN2A</i> GAs were associated with poor response and survival in patients with urothelial carcinoma treated with ICIs, but not those treated with platinum-based therapy. Similarly, <i>CDKN2A</i> GAs were associated with worse outcomes in the MSKCC urothelial carcinoma cohort treated with ICIs. There was no association of <i>CDKN2A</i> status with ICI treatment outcome in five other cancers: esophagogastric, head and neck, non-small cell lung, renal cell carcinoma, and melanoma. Immuno-inflammatory pathways were significantly reduced in expression in <i>CDKN2A-</i>altered tumors. Our data show that <i>CDKN2A</i> GAs were associated with reduced benefit from ICI therapy in urothelial carcinoma as well as changes in the tumor-immune microenvironment.