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

   

Authors:	Nassar, A. H.; Adib, E.; Abou Alaiwi, S.; El Zarif, T.; Groha, S.; Akl, E. W.; Nuzzo, P. V.; Mouhieddine, T. H.; Perea-Chamblee, T.; Taraszka, K.; El-Khoury, H.; Labban, M.; Fong, C.; Arora, K. S.; Labaki, C.; Xu, W.; Sonpavde, G.; Haddad, R. I.; Mouw, K. W.; Giannakis, M.; Hodi, F. S.; Zaitlen, N.; Schoenfeld, A. J.; Schultz, N.; Berger, M. F.; MacConaill, L. E.; Ananda, G.; Kwiatkowski, D. J.; Choueiri, T. K.; Schrag, D.; Carrot-Zhang, J.; Gusev, A.
Article Title:	Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors
Abstract:	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. Copyright © 2022 Elsevier Inc. All rights reserved.
Keywords:	genetics; mutation; tumor volume; carcinoma, non-small-cell lung; lung neoplasms; pathology; tumor marker; lung tumor; immunotherapy; tumor burden; biomarker; genomics; pharmacology; non small cell lung cancer; humans; human; immune checkpoint inhibitors; cancer disparities; biomarkers, tumor; genetic ancestry; tumor mutational burden
Journal Title:	Cancer Cell
Volume:	40
Issue:	10
ISSN:	1535-6108
Publisher:	Cell Press
Date Published:	2022-10-10
Start Page:	1161
End Page:	1172
Language:	English
DOI:	10.1016/j.ccell.2022.08.022
PUBMED:	36179682
PROVIDER:	scopus
PMCID:	PMC9559771
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85139409894&doi=10.1016%2fj.ccell.2022.08.022&partnerID=40&md5=185a7259e9acc5585d082c26a4d90b2f
Notes:	Article -- Export Date: 1 November 2022 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/199075