Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes with PD-1 Blockade in Non–Small Cell Lung Cancer

Purpose: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of immune-related thyroid dysfunction (thyroid irAEs). Experimental Design: In patients with NSCLC treated with CPIs at MSK and VUMC, we evaluated thyroid irAEs. We typed germline DNA using genome-wide single nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent DFCI cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in non-cancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in NSCLC patients at MSK, VUMC, and DFCI. Results: Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes (PFS aHR=0.68, 95%CI: 0.52-0.88). The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in non-cancer patients (OR per standard deviation [SD]=1.33, 95%CI: 1.29-1.37; AUROC= 0.6). The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD=1.34, 95%CI: 1.08-1.66; AUROC 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit. Conclusions: Thyroid irAEs were associated with response to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine if other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.