Landscape of tumor mutational burden-high (TMB-high) and its correlation with immune checkpoint inhibitor biomarkers in gynecologic tumors

Objectives: Recently, TMB ≥10 tumor mutational burden-high (TMB-high)mutations/megabase (mut/Mb) was approved as a companion diagnostic for pembrolizumab in patients with unresectable or metastatic solid tumor based on the KEYNOTE-158 trial. This approval offers patients with gynecologic tumors another pathway to pursue eligibility for immune checkpoint inhibitors (ICPI). Here, we present the real-world prevalence of TMB-High in a large cohort of gynecologic tumors and examine its correlation to other ICPI biomarkers. Methods: We retrospectively reviewed 17,304 gynecologic tumors tested with comprehensive genomic profiling (CGP). TMB was determined on 0.79 Mb of sequenced DNA, microsatellite instability (MSI) was assessed across 95 loci, and CD274 amplification was defined copy number ≥ ploidy + 4. For a subset of cases, PD-L1 immunohistochemistry was performed concurrently on the samples with DAKO 22C3 assay and scored with a combined positive score (CPS) or a tumor proportion score (TPS). For cervical carcinoma, a CPS ≥ 1 was considered positive and for non-cervical carcinoma, a TPS ≥ 1 was considered positive. Results: TMB-High frequencies varied amongst the different types of gynecologic tumors, with TMB-High occurring more frequently in vaginal carcinoma, uterine carcinoma, and cervical carcinoma (27.5%, 22.1%, and 21.4%, respectively) and less frequently in vulvar carcinoma, ovarian carcinoma, fallopian tube carcinoma, and peritoneum carcinoma (10.0%, 4.0%, 3.5%, 2.0%, respectively). MSI-High was highly correlated with TMB-High, although a small subset of MSI-High was present in the cervical carcinoma and uterine carcinoma TMB Download : Download high-res image (190KB) Download : Download full-size image Conclusions: TMB-High is common in many types of gynecologic tumors and can identify additional patients that may be eligible for ICPI that are not identified by MSI, PD-L1, and CD274 amplification ICPI biomarkers. In addition, potential resistance and hyper-progression biomarkers were present in most gynecologic tumor TMB disease subsets. These results highlight that CGP should be considered for all gynecologic tumors in order to evaluate TMB, identify POLE-hypermutated carcinomas, and to determine eligibility for ICPI.