Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors

• DOI: 10.1016/j.ccell.2022.08.022
• Publication Date: 2022-09-29T14:50:12Z
• Authors: Amin H. Nassar; Elio Adib; Sarah Abou Alaiwi; Talal El Zarif; Stefan Groha; Elie W. Akl; Pier Vitale Nuzzo; Tarek H. Mouhieddine; Tomin Perea-Chamblee; Kodi Taraszka; Habib El-Khoury; Muhieddine Labban; Christopher Fong; Kanika S. Arora; Chris Labaki; Wenxin Xu; Guru Sonpavde; Robert I. Haddad; Kent W. Mouw; Marios Giannakis; F. Stephen Hodi; Noah Zaitlen; Adam J. Schoenfeld; Nikolaus Schultz; Michael F. Berger; Laura E. MacConaill; Guruprasad Ananda; David J. Kwiatkowski; Toni K. Choueiri; Deborah Schrag; Jian Carrot-Zhang; Alexander Gusev
• Keywords: Microsatellite Instability; Immune checkpoint

The immune checkpoint inhibitor (ICI) pembrolizumab is US FDA approved for treatment of solid tumors with high tumor mutational burden (TMB-high; ≥10 variants/Mb). However, the extent to which TMB-high generalizes as an accurate biomarker in diverse patient populations is largely unknown. Using two clinical cohorts, we investigated the interplay between genetic ancestry, TMB, and tumor-only versus tumor-normal paired sequencing in solid tumors. TMB estimates from tumor-only panels substantially overclassified individuals into the clinically important TMB-high group due to germline contamination, and this bias was particularly pronounced in patients with Asian/African ancestry. Among patients with non-small cell lung cancer treated with ICIs, those misclassified as TMB-high from tumor-only panels did not associate with improved outcomes. TMB-high was significantly associated with improved outcomes only in European ancestries and merits validation in non-European ancestry populations. Ancestry-aware tumor-only TMB calibration and ancestry-diverse biomarker studies are critical to ensure that existing disparities are not exacerbated in precision medicine.