DNA Repair Gene Mutations as Predictors of Immune Checkpoint Inhibitor Response beyond Tumor Mutation Burden

Area of Science:

• Oncology
• Genetics
• Immunotherapy

Background:

• Immune checkpoint inhibitors (ICIs) have transformed cancer treatment.
• Predicting patient response to ICIs remains a significant clinical challenge.
• Neoantigens from DNA repair defects may enhance ICI efficacy.

Purpose of the Study:

• To identify genetic biomarkers that predict response to immune checkpoint inhibitors.
• To investigate the role of DNA repair pathway mutations in ICI therapy outcomes.
• To assess the prevalence of these mutations in a large cancer patient cohort.

Main Methods:

• Analysis of genomic data from 1,661 patients treated with ICIs.
• Examination of mutations in nucleotide excision repair (NER) and homologous repair (HR) pathways.
• Correlation of NER and HR mutations with objective response rates and ICI benefit.

Main Results:

• Deletions and mutations in NER and HR pathways predict ICI benefit, independent of tumor mutational burden and cancer type.
• NER and HR mutations are associated with improved objective response rates in esophagogastric and non-small-cell lung cancers.
• NER and HR mutations are found in 3.4% and 13.9% of cancers, respectively, across 40,181 patients.

Conclusions:

• NER and HR gene mutations identify a specific subpopulation of cancer patients.
• These mutations can aid in selecting patients for immune checkpoint inhibitor therapy.
• Combining NER/HR mutation assessment with other biomarkers may optimize ICI treatment selection.