Prognostic implications of tissue-based homologous recombination deficiency in metastatic gastric cancer treated with immune checkpoint inhibitor plus chemotherapy

Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398:27–40. https://doi.org/10.1016/s0140-6736(21)00797-2.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang X, Dai X, Liu A, Sun M, Cong L, Liang J, et al. Efficacy, safety, and biomarker analysis of first-line immune checkpoint inhibitors with chemotherapy versus chemotherapy for advanced gastric cancer: a multicenter, retrospective cohort study. BMC Med. 2024;22:585. https://doi.org/10.1186/s12916-024-03801-5.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Stewart MD, Merino Vega D, Arend RC, Baden JF, Barbash O, Beaubier N, et al. Homologous recombination deficiency: concepts, definitions, and assays. Oncologist. 2022;27:167–74. https://doi.org/10.1093/oncolo/oyab053.

Article  PubMed  PubMed Central  Google Scholar 

DiSilvestro P, Banerjee S, Colombo N, Scambia G, Kim BG, Oaknin A, et al. Overall survival with maintenance Olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 trial. J Clin Oncol. 2023;41:609–17. https://doi.org/10.1200/jco.22.01549.

Article  CAS  PubMed  Google Scholar 

Mateo J, de Bono JS, Fizazi K, Saad F, Shore N, Sandhu S, et al. Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations in BRCA1 and/or BRCA2 in the PROfound trial. J Clin Oncol. 2024;42:571–83. https://doi.org/10.1200/jco.23.00339.

Article  CAS  PubMed  Google Scholar 

Robson ME, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Eur J Cancer. 2023;184:39–47. https://doi.org/10.1016/j.ejca.2023.01.031.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhou P, Wu X, Chen H, Hu Y, Zhang H, Wu L, et al. The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses. Aging (Albany NY). 2020;13:2365–78. https://doi.org/10.18632/aging.202267.

Article  PubMed  PubMed Central  Google Scholar 

Wang HY, Deng L, Li YQ, Zhang X, Long YK, Zhang X, et al. Pan-cancer analysis of tumor mutational burden and homologous recombination DNA damage repair using targeted next-generation sequencing. Cancer Res Treat. 2021;53:973–82. https://doi.org/10.4143/crt.2020.798.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Silva SB, Wanderley CWS, Colli LM. Immune checkpoint inhibitors in tumors harboring homologous recombination deficiency: Challenges in attaining efficacy. Front Immunol. 2022;13:826577. https://doi.org/10.3389/fimmu.2022.826577.

Article  CAS  PubMed  PubMed Central  Google Scholar 

van Wilpe S, Tolmeijer SH, Koornstra RHT, de Vries IJM, Gerritsen WR, Ligtenberg M, et al. Homologous recombination repair deficiency and implications for tumor immunogenicity. Cancers (Basel). 2021. https://doi.org/10.3390/cancers13092249.

Article  PubMed  PubMed Central  Google Scholar 

Heeke AL, Pishvaian MJ, Lynce F, Xiu J, Brody JR, Chen WJ, et al. Prevalence of homologous recombination-related gene mutations across multiple cancer types. JCO Precis Oncol. 2018. https://doi.org/10.1200/po.17.00286.

Article  PubMed  PubMed Central  Google Scholar 

Kim H, Ahn S, Kim H, Hong JY, Lee J, Park SH, et al. The prevalence of homologous recombination deficiency (HRD) in various solid tumors and the role of HRD as a single biomarker to immune checkpoint inhibitors. J Cancer Res Clin Oncol. 2022;148:2427–35. https://doi.org/10.1007/s00432-021-03781-6.

Article  CAS  PubMed  Google Scholar 

Tébar-Martínez R, Martín-Arana J, Gimeno-Valiente F, Tarazona N, Rentero-Garrido P, Cervantes A. Strategies for improving detection of circulating tumor DNA using next generation sequencing. Cancer Treat Rev. 2023;119:102595. https://doi.org/10.1016/j.ctrv.2023.102595.

Article  CAS  PubMed  Google Scholar 

Hahn AW, Gill DM, Maughan B, Agarwal A, Arjyal L, Gupta S, et al. Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications. Oncotarget. 2017;8:33614–20. https://doi.org/10.18632/oncotarget.16833.

Article  PubMed  PubMed Central  Google Scholar 

Labiano I, Huerta AE, Arrazubi V, Hernandez-Garcia I, Mata E, Gomez D, et al. State of the art: ctDNA in upper gastrointestinal malignancies. Cancers (Basel). 2023. https://doi.org/10.3390/cancers15051379.

Article  PubMed  PubMed Central  Google Scholar 

Budczies J, Kluck K, Beck S, Ourailidis I, Allgäuer M, Menzel M, et al. Homologous recombination deficiency is inversely correlated with microsatellite instability and identifies immunologically cold tumors in most cancer types. J Pathol: Clin Res. 2022;8:371–82. https://doi.org/10.1002/cjp2.271.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Shin JE, Kwon M, Lim SH, Hong JY, Kim ST. The impact of DDR gene mutations on the efficacy of Etoposide plus Cisplatin in grade 3 metastatic gastroenteropancreatic (GEP)-neuroendocrine carcinoma (NEC). Cancers (Basel). 2025. https://doi.org/10.3390/cancers17152436.

Article  PubMed  PubMed Central  Google Scholar 

Mouw KW, Goldberg MS, Konstantinopoulos PA, D’Andrea AD. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov. 2017;7:675–93. https://doi.org/10.1158/2159-8290.Cd-17-0226.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Knijnenburg TA, Wang L, Zimmermann MT, Chambwe N, Gao GF, Cherniack AD, et al. Genomic and molecular landscape of DNA damage repair deficiency across The Cancer Genome Atlas. Cell Rep. 2018;23:239-54.e6. https://doi.org/10.1016/j.celrep.2018.03.076.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Germano G, Lamba S, Rospo G, Barault L, Magrì A, Maione F, et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature. 2017;552:116–20. https://doi.org/10.1038/nature24673.

Article  CAS  PubMed  Google Scholar 

Sha D, Jin Z, Budczies J, Kluck K, Stenzinger A, Sinicrope FA. Tumor mutational burden as a predictive biomarker in solid tumors. Cancer Discov. 2020;10:1808–25. https://doi.org/10.1158/2159-8290.Cd-20-0522.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sun F, Gao X, Wang W, Zhao X, Zhang J, Zhu Y. Predictive biomarkers in the era of immunotherapy for gastric cancer: current achievements and future perspectives. Front Immunol. 2025;16:1599908. https://doi.org/10.3389/fimmu.2025.1599908.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fan Y, Ying H, Wu X, Chen H, Hu Y, Zhang H, et al. The mutational pattern of homologous recombination (HR)-associated genes and its relevance to the immunotherapeutic response in gastric cancer. Cancer Biol Med. 2020;17:1002–13. https://doi.org/10.20892/j.issn.2095-3941.2020.0089.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gandara DR, Agarwal N, Gupta S, Klempner SJ, Andrews MC, Mahipal A, et al. Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types. J Immunother Cancer. 2025. https://doi.org/10.1136/jitc-2024-010311.

Article  PubMed  PubMed Central  Google Scholar 

Yamaguchi K, Kusaba H, Makiyama A, Mitsugi K, Uchino K, Tamura S, et al. The risk factors for oxaliplatin-induced peripheral sensory neuropathy and thrombocytopenia in advanced gastric cancer. Cancer Chemother Pharmacol. 2018;82:625–33. https://doi.org/10.1007/s00280-018-3652-2.

Article  CAS  PubMed 

Comments (0)

No login
gif