Figure S7. Survival plots of patients stratified based on TMB levels of platinum-naïve or platinum-exposed tumors in the IMVigor210 dataset. (a) Kaplan Meier curves of patients stratified based on TMB levels in platinum-naïve tumors. (b) Kaplan Meier curves of patients stratified based on TMB levels in platinum-exposed tumors. All patients were treated with platinum, but the tumor samples were collected either before platinum treatment (platinum-naïve) or after platinum treatment (platinum-exposed). P-values of log-rank tests are shown in the bottom left for each panel.
Funding
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...DOD Peer Reviewed Cancer Research Program (PRCRP)
PA breast cancer coalition
Shear Family Foundation (Shear Family Foundation Inc)
Hillman Foundation
ARTICLE ABSTRACT
Immune checkpoint blockade (ICB) can induce durable cancer remission. However, only a small subset of patients gains benefits. While tumor mutation burden (TMB) differentiates responders from nonresponders in some cases, it is a weak predictor in tumor types with low mutation rates. Thus, there is an unmet need to discover a new class of genetic aberrations that predict ICB responses in these tumor types. Here, we report analyses of pan-cancer whole genomes which revealed that intragenic rearrangement (IGR) burden is significantly associated with immune infiltration in breast, ovarian, esophageal, and endometrial cancers, particularly with increased M1 macrophage and CD8+ T-cell signatures. Multivariate regression against spatially counted tumor-infiltrating lymphocytes in breast, endometrial, and ovarian cancers suggested that IGR burden is a more influential covariate than other genetic aberrations in these cancers. In the MEDI4736 trial evaluating durvalumab in esophageal adenocarcinoma, IGR burden correlated with patient benefits. In the IMVigor210 trial evaluating atezolizumab in urothelial carcinoma, IGR burden increased with platinum exposure and predicted patient benefit among TMB-low, platinum-exposed tumors. Altogether, we have demonstrated that IGR burden correlates with T-cell inflammation and predicts ICB benefit in TMB-low, IGR-dominant tumors, and in platinum-exposed tumors.
