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

Jia Luo1, Victoria L Martucci2, Zoe Quandt3,4

  • 1Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 10, 2021
PubMed
Abstract

Insights

Genetic predisposition to hypothyroidism is linked to developing thyroid immune-related adverse events (irAEs) during immune checkpoint inhibitor (CPI) therapy. This genetic risk, however, did not predict treatment response in non-small cell lung cancer patients.

Area of Science:

  • Genetics
  • Immunology
  • Oncology

Background:

  • Immune checkpoint inhibitors (CPIs) improve cancer outcomes but can cause immune-related adverse events (irAEs).
  • Genetic factors influencing irAEs, particularly thyroid irAEs, are not well understood.
  • Understanding these genetic links can inform patient selection and management during CPI therapy.

Purpose of the Study:

  • To investigate the genetic basis of thyroid immune-related adverse events (irAEs) in patients undergoing CPI therapy.
  • To determine if genetic predisposition to hypothyroidism is associated with the development of thyroid irAEs.
  • To explore the relationship between genetic risk scores and CPI treatment outcomes.

Main Methods:

  • Genome-wide single-nucleotide polymorphism (SNP) arrays were used to analyze germline DNA in patients with non-small cell lung cancer (NSCLC) treated with CPIs.
  • Polygenic risk scores (PRS) for hypothyroidism were developed in noncancerous biobanks and validated.
  • The developed PRS were applied to cohorts of NSCLC patients to assess prediction of thyroid irAEs and CPI response.

Main Results:

  • Thyroid irAEs occurred in 13% of patients and were associated with improved progression-free survival.
  • A PRS for hypothyroidism successfully predicted hypothyroidism in noncancer patients and predicted the development of thyroid irAEs in CPI-treated NSCLC patients.
  • The PRS for hypothyroidism did not predict clinical benefit from CPI therapy.

Conclusions:

  • Thyroid irAEs are associated with anti-PD-1 therapy response.
  • Genetic predisposition to hypothyroidism is a risk factor for developing thyroid irAEs.
  • Further research is needed to explore shared genetic risks for other irAEs and their impact on treatment response.

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