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

References:

  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.
Read the Abstract
email news signup