Abstract
Introduction: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune–related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs.Methods: Using Cox proportional hazards model, we assessed the association between a polygenic risk score for autoimmune disease (PRSAD) and cessation of ICI therapy due to irAEs. All models were adjusted for age at diagnosis, sex, lung cancer histology, type of therapy, recruiting center, and the first 5 principal components. To further understand the differential effects of type of therapy and disease stage on the association between PRSAD and cessation of ICI due to irAEs, we conducted stratified logistic regression analysis by type of ICI therapy and disease stage.Results: We found an association between PRSAD and ICI cessation due to irAEs (HR per SD = 1.18, 95% CI = 1.02 – 1.37, P = 0.03). This association was particularly strong in patients who had ICI cessation due to irAEs within three months of therapy initiation (HR per SD = 1.38, 95% CI = 1.08 – 1.78, P = 0.01). Individuals in the top 20th percentile of PRSAD had 7.2% ICI discontinuation for irAEs by three months, compared to 3.9% discontinuation by three months among patients in the bottom 80th percentile (log–rank P = 0.02). In addition, among patients who received combination PD–1/PD–L1 and CTLA–4 inhibitor therapy, PRSAD had an OR per SD of 1.86 (95% CI = 1.08 – 3.51, P = 0.04). Conclusions: We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs, particularly among patients treated with combination ICI therapy. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision–making in solid tumor oncology.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
Funding This work was supported by the National Institutes of Health R01CA227466 to EZivCMLovly was supported in part by NIH NCI UG1CA233259 P01CA129243 and P30CA068485RThummalapalli was supported by T32CA009207The Lusi Wong Fund Posluns Fund Alan Brown Chair in Molecular Genomics Princess Margaret Cancer Foundation were awarded to G Liu for this workMC Aldrich was supported in part by R01CA227466 U01CA253560 R01CA251758 and the Vanderbilt Institute for Clinical and Translational Research UL1TR002243Z Quandt was supported NIDDK DiabDocs K12DK133995 and a Larry L Hillblom Foundation StartUp GrantAJSchoenfeld was supported by the Memorial Sloan Kettering Cancer Center Support Grant/Core P30CA008748 the Druckenmiller Center for Lung Cancer Research at Memorial Sloan Kettering Cancer CenterThe samples and/or datasets used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by numerous sources: institutional funding private agencies and federal grants These include the NIHfunded Shared Instrumentation Grant S10OD017985 and S10RR025141 and CTSA grants UL1TR002243 UL1TR000445 and UL1RR024975 Genomic data are also supported by investigatorled projects that include U01HG004798 R01NS032830 RC2GM092618 P50GM115305 U01HG006378 U19HL065962 R01HD074711 and additional funding sources listed at https://victrvumcorg/biovufunding/Princess Margaret Lung Group includes Natasha B Leighl Penelope A Bradbury Frances A Shepherd Adrian G Sacher & Lawson Eng
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Ethics committee/IRB of University of California San Francisco gave ethical approval for this workEthics committee/IRB of Vanderbilt University Medical Center gave ethical approval for this workEthics committee/IRB of Memorial Sloan Kettering Cancer Center gave ethical approval for this workEthics committee/IRB of Princess Margaret Cancer Center gave ethical approval for this work
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Data Availability
All data produced in the present study are available upon reasonable request to the authors
