Advertisement

DNA repair and immune checkpoint blockade response

      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

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cancer Genetics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hargadon KM
        • Johnson CE
        • Williams CJ.
        Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors.
        Int Immunopharmacol. 2018; 62: 29-39
        • Bonneville R
        • Krook MA
        • Kautto EA
        • et al.
        Landscape of microsatellite instability across 39 cancer types.
        JCO Precis Oncol. 2017; : 1-15
        • Knijnenburg TA
        • Wang L
        • Zimmermann MT
        • et al.
        Genomic and molecular Landscape of DNA damage repair deficiency across the cancer genome atlas.
        Cell Rep [Internet]. 2018; 23 ([cited 2022 Jan 10]e6. Available from): 239-254
        • Sweeney SM
        • Cerami E
        • Baras A
        • et al.
        AACR Project GENIE: powering precision medicine through an international consortium.
        Cancer Discov [Internet]. 2017; 7 ([cited 2021 Nov 20]Available from): 818-831
        • Wang F
        • Zhao Q
        • Wang YN
        • et al.
        Evaluation of POLE and POLD1 mutations as biomarkers for immunotherapy outcomes across multiple cancer types.
        JAMA Oncol [Internet]. 2019; 5 ([cited 2022 Jan 10]Available from): 1504-1506
        • Lee JS
        • Ruppin E.
        Multiomics prediction of response rates to therapies to inhibit programmed cell death 1 and programmed Cell Death 1 Ligand 1.
        JAMA Oncol [Internet]. 2019; 5 ([cited 2022 Jan 10]Available from:): 1614-1618
        • Hsiehchen D
        • Hsieh A
        • Samstein RM
        • et al.
        DNA repair gene mutations as predictors of immune checkpoint inhibitor response beyond tumor mutation burden.
        Cell Reports Med. 2020; 1100034
        • Samstein, RM, Lee, CH, Shoushtari, AN, Hellmann, MD, Shen, R, Janjigian, YY, Barron, DA, Zehir, A, Jordan, EJ, Omuro, A, Kaley, TJ, Kendall, SM, Motzer, RJ, Hakimi, AA, Voss, MH, Russo, P, Rosenberg, J, Iyer, G, Bochner, BH, Bajorin, DF, ... Morris, L
        Tumor mutational load predicts survival after immunotherapy across multiple cancer types.
        Nat. Genet. 2019; 51: 202-206https://doi.org/10.1038/s41588-018-0312-8
        • Zehir, A, Benayed, R, Shah, RH, Syed, A, Middha, S, Kim, HR, Srinivasan, P, Gao, J, Chakravarty, D, Devlin, SM, Hellmann, MD, Barron, DA, Schram, AM, Hameed, M, Dogan, S, Ross, DS, Hechtman, JF, DeLair, DF, Yao, J, Mandelker, DL, ... Berger, MF
        Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.
        Nat Medic. 2017; 23: 703-713https://doi.org/10.1038/nm.4333