Ancestry-Driven Recalibration of Tumor Mutational Burden as a Biomarker of Response to Immune Checkpoint Inhibitors - Expert Commentary

The immune checkpoint inhibitor (ICI) pembrolizumab is approved for the treatment of solid tumors with a high tumor mutational burden (TMB-high ≥ 10 variants/Mb). However, measurements of TMB as a biomarker for ICI response are mainly based on studies in European populations. A recent study by Nassar et al. investigated the interplay between genetic ancestry, TMB, and tumor-only versus tumor-normal paired sequencing of solid tumors.

The authors confirm the challenges of differentiating somatic from germline mutations with tumor-only sequencing resulting in higher TMB measurements. This was particularly pronounced in patients with Asian/African ancestry. In addition, this bias translated into a lack of clinical benefit in patients with non-small cell lung cancer treated with ICIs whose tumors were misclassified as TMB-high from tumor-only panels.

This important study highlights the importance of Ancestry-aware tumor-only TMB calibration. It also highlights the challenges of relying on tumor-only sequencing. The authors acknowledge that differences in biomarker performance by ancestry can be caused by various social and environmental confounding factors for which ancestry is merely a proxy. Higher inclusivity in biomarker and clinical studies is needed to ensure that existing disparities are not exacerbated in precision medicine strategies.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


  1. Nassar AH, Adib E, Abou Alaiwi S, et al. Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors. Cancer Cell. 2022 Sep 6:S1535-6108(22)00386-5. doi: 10.1016/j.ccell.2022.08.022.
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