Highlights
- •Mutations in seven DNA repair genes (ATM, ATR, POLE, ERCC4, NBN, RAD50, PARP1) were significantly associated with improved overall survival (OS) in patients treated with immune checkpoint blockade (ICB) (p < 0.05 for all) and had significant interaction with treatment (pinteraction < 0.05 for all).
- •Mutations in DNA damage sensing genes were associated with improved OS in ICB-treated patients (adjusted HR: 0.7, p = 0.004) and worse OS in patients not treated with ICB (adjusted HR: 1.31 (p = 0.003), pinteraction = 7E-6).
- •Mutations in other subclasses including nucleotide excision repair (NER), homologous repair (HR), and Fanconi anemia (FA) were similarly predictive of ICB response (pinteraction = 3E-5, 0.005, 0.007, respectively).
- •Using the AACR GENIE project (23,435 samples across 31 cancer types), we found that skin (melanoma and non-melanoma), small bowel, endometrial, lung (small cell and NSCLC), and colorectal cancers were enriched (>10%) with NER and/or DNAsense mutations.
- •We observed that primary tumors of unknown origin were also enriched with NER and DNAsense mutations, suggesting these mutations have potential to serve as a biomarker independent of cancer type.
Abstract
Immune checkpoint blockade (ICB) has shown immense promise for treating patients with
various cancer types, but its effectiveness relies on our ability to identify likely
responders. Here, we examined the association between mutations in 25 core DNA repair
genes and ICB outcomes in 6619 patients across 9 cancer types with advanced disease
and MSK-IMPACT tumor sequencing. Notably, we observed that mutations in 7 of the DNA
repair genes (ATM, ATR, POLE, ERCC4, NBN, RAD50, PARP1) were significantly associated with improved overall survival in ICB-treated patients
(p < 0.05 for all) and had significant interaction with treatment (pinteraction <0.05 for all). Similarly, DNA repair mutations were enriched in other cancer types
not previously assessed and primary tumors of unknown origins, suggesting that mutations
could serve as a biomarker independent of cancer type. Although our cohort was enriched
in certain cancer types, such as melanoma and non-small cell lung cancer, and clinically
matched samples were not assessed, our study provides a robust approach in characterizing
clinically-adoptable biomarkers that can select for potential ICB responders.
Keywords
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Article Info
Publication History
Published online: February 23, 2022
Accepted:
February 17,
2022
Received in revised form:
January 18,
2022
Received:
August 17,
2021
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
