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High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naive Patients with Diverse Cancers.

ABSTRACT: Higher tumor mutational burden (TMB) has been correlated with response to checkpoint blockade immunotherapy. However, it is unclear whether TMB independently serves as a prognostic biomarker for outcomes in immunotherapy-naïve patients. Here, we evaluated the relationship between TMB and overall survival in 1,415 immunotherapy-naïve patients with diverse advanced malignancies. TMB was studied both as a tiered variable (low ≤5 mutations/Mb, intermediate >5 and <20, high ≥20 and <50, and very high ≥50) and as a continuous variable. Interestingly, we observed a parabolic correlation between TMB and overall survival, in which intermediate-range TMB correlated with decreased survival, whereas low and very high TMB correlated with improved outcomes (median survival: 238, 174, 195, and 350 weeks for low, intermediate, high, and very high TMB, respectively; multivariate P < 0.01). This corresponded to an HR of 1.29 (95% confidence interval, 1.07-1.54; P < 0.01) for intermediate-range TMB on multivariable survival analysis correcting for known confounders, including primary tumor of origin. These results demonstrate that TMB may have utility as a prognostic biomarker in immunotherapy-naïve patients, with a protective effect at higher TMBs, and that studies of survival in immunotherapy-treated patients may need to stratify or randomize by TMB in a nonlinear fashion to account for this confounding.

SUBMITTER: Riviere P

PROVIDER: S-EPMC7541603 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: Panel-based sequencing is widely used to measure tumor mutational burden (TMB) in clinical trials and is ready to enter routine diagnostics. However, cut-off points to distinguish "TMB-high" from "TMB-low" tumors are not consistent and the clinical implications of TMB in predicting responses to immune checkpoint blockade (ICB) in gastric cancer are not clearly defined. We aimed to assess whether TMB is associated with the response to immunotherapy and to examine its relation with other biomarkers of immunotherapy response in advanced gastric cancer. Design: In total, 63 patients with advanced gastric cancer treated with ICB were included in the study. Panel-based TMB in gastric tumor samples, treatment responses to ICB, clinicopathological data, and time to progression were retrospectively analyzed. Microsatellite instability (MSI) status, Epstein-Barr virus (EBV) positivity, and programmed death-ligand 1 (PD-L1) combined positive score (CPS) were also analyzed. Results: TMB ranged from 0 to 446 mutations/megabase (mt/mb) and was significantly associated with MSI (P < 0.001), PD-L1 CPS (P = 0.022), response to ICB (P = 0.04), chemotherapy (P = 0.02) and older patient age (?65 years; P = 0.0014). The cut-off point of 14.31 mt/mb determined by log-rank statistics for progression-free survival divided the tumors into eight (12.7%) TMB-high and 55 (87.3%) TMB-low tumors. The median TMB of the chemo-refractory group was significantly higher (8.43 mt/mb) compared to that of chemo-naïve group (3.42 mt/mb) (P = 0.02). Patients with TMB-high tumors showed prolonged progression-free survival in univariate [HR, 0.32; 95% confidence interval (CI), 0.12-0.90] and multivariate (HR, 0.21; 95% CI, 0.07-0.69) analyses. In area under the receiver operating curve (AUC) analysis of TMB, PD-L1, EBV, MSI, and their combination, the AUC value was the highest for EBV (0.97), followed by MSI (0.96), PD-L1 (0.81), the combination (0.78), and TMB (0.56). Conclusion: In addition to EBV, MSI, and PD-L1 CPS, TMB could be used as a predictive biomarker in patients with advanced gastric cancer treated with ICB and may aid clinical decision making.

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High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naive Patients with Diverse Cancers.

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