TY - JOUR
T1 - Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma
AU - Labriola, Matthew Kyle
AU - Zhu, Jason
AU - Gupta, Rajan
AU - McCall, Shannon
AU - Jackson, Jennifer
AU - Kong, Eric F.
AU - White, James R.
AU - Cerqueira, Gustavo
AU - Gerding, Kelly
AU - Simmons, John K.
AU - George, Daniel
AU - Zhang, Tian
N1 - Funding Information:
Personal Genome Diagnostics Inc. Duke Cancer Institute
Funding Information:
TZ: research funding from Acerta, Novartis, Merrimack, AbbVie, Merck, Regeneron, Mirati Therapeutics, Janssen, AstraZeneca, Pfizer, OmniSeq and PGDx. Speakers bureau for Genentech Roche, Exelixis, Sanofi-Aventis and Genomic Health. Advisory board/consultant for Genentech/Roche, Merck, Exelixis, Sanofi-Aventis, Janssen, AstraZeneca, Pfizer, Amgen, BMS, Pharmacyclics, Bayer, Foundation Medicine and Seattle Genetics. Employee/stockholder of Capio Biosciences (spouse) JZ: consulting: Bayer, NGM Biopharmaceuticals.Travel assistance: UroTodayRG: consulting: Bayer, Philips, Bard. Speakers bureau: Bayer. DG: research funding: Acerta, Astellas, Bayer, BMS, Calithera. Exelixis, Janssen, Novartis, Pfizer, Sanofi, Seattle Genetics. Speakers bureau: Bayer, Exelixis. Advisory board/consultant: Astellas, AztraZeneca. Bayer, BMS, Exelixis, Flatiron. Janssen, Merck, Michael J Hennessey Associates, Modra, Myovant Sciences, Nektar, Physician Education Resource LLC, Pfizer, Sanofi, Vizuri Health, NCI. Editor: American Association for Cancer Research. Millennium Medical Publishing, Clinical Advances in Hematology and Oncology. Independent contractor: Axess Oncology, Honorarium: Bayer, EMD Serono, Exilixis, Ipsen, Michael J Hennessey Associates, Pfizer, Sanofi, UroGPO, UroToday. The remaining authors have no competing interests.
Publisher Copyright:
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2020/3/26
Y1 - 2020/3/26
N2 - Background Immune checkpoint inhibitors (ICIs) have expanded treatment options for metastatic renal cell carcinoma (mRCC); however, there are limited predictive biomarkers for response to ICIs in this indication, with programmed death-ligand 1 (PD-L1) status demonstrating little predictive utility in mRCC. While predictive of ICI response in other tumor types, the utility of tumor mutation burden (TMB) in mRCC is unclear. Here, we assess TMB, loss of antigen presentation genes and PD-L1 status correlated with outcomes to ICI treatment in mRCC. Methods Tumor samples from 34 patients with mRCC treated with ICI therapy at Duke Cancer Institute were retrospectively evaluated using Personal Genome Diagnostics elio tissue complete (RUO version), a tumor genomic profiling assay for somatic variants, TMB, microsatellite status and genomic status of antigen presentation genes. Tumor samples were also analyzed with the Dako 28-8 PD-L1 immunohistochemistry assay. Deidentified clinical information was extracted from the medical record, and tumor response was evaluated based on the Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1 criteria. Results Patients were stratified by overall response following ICI therapy and designated as progressive disease (PD; n=18) or disease control groups (DC; n=16). TMB scores ranged from 0.36 to 12.24 mutations/Mb (mean 2.83 mutations/Mb) with no significant difference between the PD and DC groups (3.01 vs 2.63 mutations/Mb, respectively; p=0.7682). Interestingly, 33% of PD patients displayed loss of heterozygosity of major histocompatibility complex class I genes (LOH-MHC) vs 6% of DC patients. Nine of 34 samples were PD-L1-positive (4 in the PD group; 5 in the DC group), suggesting no correlation between PD-L1 expression and response to ICI therapy. Notably, the DC group displayed an enrichment of mutations in DNA repair genes (p=0.04), with 68.8% exhibiting at least one mutated homologous recombination repair (HRR)-related gene compared with only 38.9% of the PD group (p=0.03). Conclusions Overall, neither TMB nor PD-L1 correlated with ICI response and TMB was not significantly associated with PD-L1 expression. The higher incidence of LOH-MHC in PD group suggests that loss of antigen presentation may restrict response to ICIs. Separately, enrichment of HRR gene mutations in the DC group suggests potential utility in predicting ICI response and a potential therapeutic target, warranting future studies.
AB - Background Immune checkpoint inhibitors (ICIs) have expanded treatment options for metastatic renal cell carcinoma (mRCC); however, there are limited predictive biomarkers for response to ICIs in this indication, with programmed death-ligand 1 (PD-L1) status demonstrating little predictive utility in mRCC. While predictive of ICI response in other tumor types, the utility of tumor mutation burden (TMB) in mRCC is unclear. Here, we assess TMB, loss of antigen presentation genes and PD-L1 status correlated with outcomes to ICI treatment in mRCC. Methods Tumor samples from 34 patients with mRCC treated with ICI therapy at Duke Cancer Institute were retrospectively evaluated using Personal Genome Diagnostics elio tissue complete (RUO version), a tumor genomic profiling assay for somatic variants, TMB, microsatellite status and genomic status of antigen presentation genes. Tumor samples were also analyzed with the Dako 28-8 PD-L1 immunohistochemistry assay. Deidentified clinical information was extracted from the medical record, and tumor response was evaluated based on the Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1 criteria. Results Patients were stratified by overall response following ICI therapy and designated as progressive disease (PD; n=18) or disease control groups (DC; n=16). TMB scores ranged from 0.36 to 12.24 mutations/Mb (mean 2.83 mutations/Mb) with no significant difference between the PD and DC groups (3.01 vs 2.63 mutations/Mb, respectively; p=0.7682). Interestingly, 33% of PD patients displayed loss of heterozygosity of major histocompatibility complex class I genes (LOH-MHC) vs 6% of DC patients. Nine of 34 samples were PD-L1-positive (4 in the PD group; 5 in the DC group), suggesting no correlation between PD-L1 expression and response to ICI therapy. Notably, the DC group displayed an enrichment of mutations in DNA repair genes (p=0.04), with 68.8% exhibiting at least one mutated homologous recombination repair (HRR)-related gene compared with only 38.9% of the PD group (p=0.03). Conclusions Overall, neither TMB nor PD-L1 correlated with ICI response and TMB was not significantly associated with PD-L1 expression. The higher incidence of LOH-MHC in PD group suggests that loss of antigen presentation may restrict response to ICIs. Separately, enrichment of HRR gene mutations in the DC group suggests potential utility in predicting ICI response and a potential therapeutic target, warranting future studies.
KW - Genitourinary medicine
KW - Immunology
KW - Molecular immunogene
KW - Oncology
KW - Tumors
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U2 - 10.1136/jitc-2019-000319
DO - 10.1136/jitc-2019-000319
M3 - Article
C2 - 32221016
AN - SCOPUS:85082516829
SN - 2051-1426
VL - 8
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 1
M1 - e000319
ER -