Accurate TMB Biomarker Analysis Requires Ancestry-Specific Correction

High tumor mutational burden (TMB) is currently used as a predictive biomarker for immune checkpoint inhibitor (ICI) response regardless of PD-L1 expression, tumor type, or microsatellite instability status. TMB is currently being used in clinical decision-making, but whether this biomarker is accurate and generalizable in diverse patient cohorts remains to be determined. To investigate the interplay between genetic ancestry and TMB, Nassar, Adib, Alaiwi, and colleagues analyzed the genetic ancestry of more than 2,000 patients with common solid tumor types treated with ICIs and found that current methods for TMB quantification are inadequate for accurate analysis of patients with non-European ancestry. Initial comparisons of TMB calculated from tumor–normal pairs (TMB-paired) to TMB calculated from the same tumors without matched normal tissue (TMB tumor-only) using the standard computational approach indicated that, across all ancestries, TMB tumor-only was higher than TMB-paired. Notably, the inflation of TMB tumor-only was found to be significantly higher in non-Europeans than in Europeans. To control for ancestry-based differences in TMB, calibration coefficients for European, African, and Asian ancestries were computed and subsequently applied to the DFCI/PROFILE dataset and showed that recalibration of the TMB was able to improve these observed ancestral biases. Furthermore, investigation into whether the greater inflation of TMB in non-Europeans would lead to higher rates of TMB-high misclassification indicated that individuals with non-European ancestry were much more likely to be falsely classified as TMB-high. Moreover, methods to categorize individuals as true TMB-high, false TMB-high, and true TMB-low revealed that true TMB-high patients had significantly superior outcomes following ICI treatment, but further stratification based on ancestry demonstrated that true TMB-high was predictive of ICI response only in European patients. Altogether, this work reveals a lack of generalizability of TMB-high as a biomarker for ICI response and underscores the need to increase representation of patients with non-European ancestry in public datasets.

Nassar AH, Adib E, Alaiwi SA, El Zarif T, Groha S, Akl EW, et al. Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors. Cancer Cell 2022;40:1161–72.e5.

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