TY - JOUR
T1 - High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types
AU - McGrail, D. J.
AU - Pilié, P. G.
AU - Rashid, N. U.
AU - Voorwerk, L.
AU - Slagter, M.
AU - Kok, M.
AU - Jonasch, E.
AU - Khasraw, M.
AU - Heimberger, A. B.
AU - Lim, B.
AU - Ueno, N. T.
AU - Litton, J. K.
AU - Ferrarotto, R.
AU - Chang, J. T.
AU - Moulder, S. L.
AU - Lin, S. Y.
N1 - Funding Information:
This work was supported by the National Cancer Institute at the National Institutes of Health [grant number K99CA240689 ] and Susan G. Komen [grant number PDF17483544] to DJM and [grant number R01 CA218287 ] to S-YL; a George and Barbara Bush Endowment for Innovative Cancer Research to S-YL [no grant number]; and a Young Investigator Award from the Kidney Cancer Association [no grant number] and Prostate Cancer Foundation Young Investigator Award [no grant number] to PGP. Additional funding was provided by the MD Anderson Breast Cancer Moonshot program [no grant number] as well as CPRIT grants [grant number RP170668 ] to JTC and [grant number RP160710 ] to JTC and SLM.
Funding Information:
This work was supported by the National Cancer Institute at the National Institutes of Health [grant number K99CA240689] and Susan G. Komen [grant number PDF17483544] to DJM and [grant number R01 CA218287] to S-YL; a George and Barbara Bush Endowment for Innovative Cancer Research to S-YL [no grant number]; and a Young Investigator Award from the Kidney Cancer Association [no grant number] and Prostate Cancer Foundation Young Investigator Award [no grant number] to PGP. Additional funding was provided by the MD Anderson Breast Cancer Moonshot program [no grant number] as well as CPRIT grants [grant number RP170668] to JTC and [grant number RP160710] to JTC and SLM. DJM, PGP, EJ, and S-YL have a pending patent on a gene expression signature to predict response to immune checkpoint blockade. MK has served as a consultant or advisory roles for Janssen, AbbVie, Ipsen, Pfizer, Roche, and Jackson Laboratory for Genomic Medicine, received research funding from AbbVie, Bristol Myers Squibb (BMS), and Specialized Therapeutics, and has an advisory role for BMS, Roche, MSD, and Daiichi Sankyo, and the institute receives research funding from AstraZeneca, BMS, and Roche outside the submitted work. ABH has stock options, is an advisory board member of Caris Life Sciences, serves on the advisory board of WCG Oncology, has received licensing fees from Celldex Therapeutics and DNAtrix, and received research funding from Merck. The remaining authors have declared no conflicts of interest.
Publisher Copyright:
© 2021 The Authors
PY - 2021/5
Y1 - 2021/5
N2 - Background: High tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoint blockade (ICB), largely due to the potential for tumor mutations to generate immunogenic neoantigens. Despite recent pan-cancer approval of ICB treatment for any TMB-H tumor, as assessed by the targeted FoundationOne CDx assay in nine tumor types, the utility of this biomarker has not been fully demonstrated across all cancers. Patients and methods: Data from over 10 000 patient tumors included in The Cancer Genome Atlas were used to compare approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells. Association of TMB with ICB treatment outcomes was analyzed by both objective response rates (ORRs, N = 1551) and overall survival (OS, N = 1936). Results: In cancer types where CD8 T-cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors exhibited a 39.8% ORR to ICB [95% confidence interval (CI) 34.9-44.8], which was significantly higher than that observed in low TMB (TMB-L) tumors [odds ratio (OR) = 4.1, 95% CI 2.9-5.8, P < 2 × 10−16]. In cancer types that showed no relationship between CD8 T-cell levels and neoantigen load, such as breast cancer, prostate cancer, and glioma, TMB-H tumors failed to achieve a 20% ORR (ORR = 15.3%, 95% CI 9.2-23.4, P = 0.95), and exhibited a significantly lower ORR relative to TMB-L tumors (OR = 0.46, 95% CI 0.24-0.88, P = 0.02). Bulk ORRs were not significantly different between the two categories of tumors (P = 0.10) for patient cohorts assessed. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable. Conclusions: Our analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type-specific studies are warranted.
AB - Background: High tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoint blockade (ICB), largely due to the potential for tumor mutations to generate immunogenic neoantigens. Despite recent pan-cancer approval of ICB treatment for any TMB-H tumor, as assessed by the targeted FoundationOne CDx assay in nine tumor types, the utility of this biomarker has not been fully demonstrated across all cancers. Patients and methods: Data from over 10 000 patient tumors included in The Cancer Genome Atlas were used to compare approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells. Association of TMB with ICB treatment outcomes was analyzed by both objective response rates (ORRs, N = 1551) and overall survival (OS, N = 1936). Results: In cancer types where CD8 T-cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors exhibited a 39.8% ORR to ICB [95% confidence interval (CI) 34.9-44.8], which was significantly higher than that observed in low TMB (TMB-L) tumors [odds ratio (OR) = 4.1, 95% CI 2.9-5.8, P < 2 × 10−16]. In cancer types that showed no relationship between CD8 T-cell levels and neoantigen load, such as breast cancer, prostate cancer, and glioma, TMB-H tumors failed to achieve a 20% ORR (ORR = 15.3%, 95% CI 9.2-23.4, P = 0.95), and exhibited a significantly lower ORR relative to TMB-L tumors (OR = 0.46, 95% CI 0.24-0.88, P = 0.02). Bulk ORRs were not significantly different between the two categories of tumors (P = 0.10) for patient cohorts assessed. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable. Conclusions: Our analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type-specific studies are warranted.
KW - biomarker
KW - immune checkpoint blockade
KW - tumor mutation burden
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U2 - 10.1016/j.annonc.2021.02.006
DO - 10.1016/j.annonc.2021.02.006
M3 - Article
C2 - 33736924
AN - SCOPUS:85103112172
SN - 0923-7534
VL - 32
SP - 661
EP - 672
JO - Annals of Oncology
JF - Annals of Oncology
IS - 5
ER -
