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

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

doi:10.1016/j.ccell.2022.08.022

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

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 GiannakisF. 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

Icahn School of Medicine at Mount Sinai

Research output: Contribution to journal › Article › peer-review

68 Scopus citations

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.

Original language	English
Pages (from-to)	1161-1172.e5
Journal	Cancer Cell
Volume	40
Issue number	10
DOIs	https://doi.org/10.1016/j.ccell.2022.08.022
State	Published - 10 Oct 2022

Keywords

biomarker
cancer disparities
genetic ancestry
genomics
immunotherapy
tumor mutational burden

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10.1016/j.ccell.2022.08.022

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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., ... Gusev, A. (2022). Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors. Cancer Cell, 40(10), 1161-1172.e5. https://doi.org/10.1016/j.ccell.2022.08.022

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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.",

keywords = "biomarker, cancer disparities, genetic ancestry, genomics, immunotherapy, tumor mutational burden",

author = "Nassar, {Amin H.} and Elio Adib and {Abou Alaiwi}, Sarah and {El Zarif}, Talal and Stefan Groha and Akl, {Elie W.} and Nuzzo, {Pier Vitale} and Mouhieddine, {Tarek H.} and Tomin Perea-Chamblee and Kodi Taraszka and Habib El-Khoury and Muhieddine Labban and Christopher Fong and Arora, {Kanika S.} and Chris Labaki and Wenxin Xu and Guru Sonpavde and Haddad, {Robert I.} and Mouw, {Kent W.} and Marios Giannakis and Hodi, {F. Stephen} and Noah Zaitlen and Schoenfeld, {Adam J.} and Nikolaus Schultz and Berger, {Michael F.} and MacConaill, {Laura E.} and Guruprasad Ananda and Kwiatkowski, {David J.} and Choueiri, {Toni K.} and Deborah Schrag and Jian Carrot-Zhang and Alexander Gusev",

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year = "2022",

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day = "10",

doi = "10.1016/j.ccell.2022.08.022",

language = "English",

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Nassar, AH, Adib, E, Abou Alaiwi, S, El Zarif, T, Groha, S, Akl, EW, Nuzzo, PV, Mouhieddine, TH, Perea-Chamblee, T, Taraszka, K, El-Khoury, H, Labban, M, Fong, C, Arora, KS, Labaki, C, Xu, W, Sonpavde, G, Haddad, RI, Mouw, KW, Giannakis, M, Hodi, FS, Zaitlen, N, Schoenfeld, AJ, Schultz, N, Berger, MF, MacConaill, LE, Ananda, G, Kwiatkowski, DJ, Choueiri, TK, Schrag, D, Carrot-Zhang, J & Gusev, A 2022, 'Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors', Cancer Cell, vol. 40, no. 10, pp. 1161-1172.e5. https://doi.org/10.1016/j.ccell.2022.08.022

TY - JOUR

T1 - Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors

AU - Nassar, Amin H.

AU - Adib, Elio

AU - Abou Alaiwi, Sarah

AU - El Zarif, Talal

AU - Groha, Stefan

AU - Akl, Elie W.

AU - Nuzzo, Pier Vitale

AU - Mouhieddine, Tarek H.

AU - Perea-Chamblee, Tomin

AU - Taraszka, Kodi

AU - El-Khoury, Habib

AU - Labban, Muhieddine

AU - Fong, Christopher

AU - Arora, Kanika S.

AU - Labaki, Chris

AU - Xu, Wenxin

AU - Sonpavde, Guru

AU - Haddad, Robert I.

AU - Mouw, Kent W.

AU - Giannakis, Marios

AU - Hodi, F. Stephen

AU - Zaitlen, Noah

AU - Schoenfeld, Adam J.

AU - Schultz, Nikolaus

AU - Berger, Michael F.

AU - MacConaill, Laura E.

AU - Ananda, Guruprasad

AU - Kwiatkowski, David J.

AU - Choueiri, Toni K.

AU - Schrag, Deborah

AU - Carrot-Zhang, Jian

AU - Gusev, Alexander

PY - 2022/10/10

Y1 - 2022/10/10

N2 - 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.

AB - 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.

KW - biomarker

KW - cancer disparities

KW - genetic ancestry

KW - genomics

KW - immunotherapy

KW - tumor mutational burden

UR - http://www.scopus.com/inward/record.url?scp=85139409894&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2022.08.022

DO - 10.1016/j.ccell.2022.08.022

M3 - Article

C2 - 36179682

AN - SCOPUS:85139409894

SN - 1535-6108

VL - 40

SP - 1161-1172.e5

JO - Cancer Cell

JF - Cancer Cell

IS - 10

ER -

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

Abstract

Keywords

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