Prevalence of Homologous Recombination Repair Mutations and Association with Clinical Outcomes in Patients with Solid Tumors: A Study Using the AACR Project GENIE Dataset

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2025 Feb 26

PMID 40002171

Authors

Changxia Shao

Heng Zhou

Cai Chen

Elisha J Dettman

Yixin Ren

Razvan Cristescu

Alexander Gozman

Fan Jin

Affiliations

Soon will be listed here.

Abstract

Background/objectives: Mutations in and/or (BRCAm) and other homologous recombination repair genes (HRRm) are associated with several cancers. We evaluated the prevalence and association with overall survival (OS) of somatic BRCAm and HRRm among patients with advanced solid tumors.

Methods: We used deidentified data from the AACR GENIE Biopharma Collaborative dataset derived from patients with tumors genotyped using next-generation sequencing between 1 January 2014 and 31 December 2017. Eligible patients were aged ≥18 years diagnosed with non-small-cell lung, colorectal, breast, bladder, prostate, or pancreatic cancer, with documented BRCA/HRR somatic mutation status. The primary analysis was OS (censored at the start of poly[ADP ribose] polymerase inhibitors [PARPi]/immunotherapy) after initiation of second-line therapy since most patients had sequencing after first-line therapy.

Results: Among eligible patients, 242/7022 (3.4%) had BRCAm and 477/5474 (8.7%) had HRRm. Adjusted OS HRs (95% CI) for the primary analysis (using the initiation of second-line therapy as index date) were 0.79 (0.61-1.03) with/without BRCAm (n = 116/n = 3394) and 0.83 (0.69-0.99) with/without HRRm (n = 247/n = 2656); in sensitivity analysis of patients with stage IV disease, HRs were 0.97 (0.68-1.38) with/without BRCAm (n = 58/n = 1847) and 0.92 (0.73-1.18) with/without HRRm (n = 132/n = 1488).

Conclusions: Overall, BRCAm and HRRm did not show a strong association with OS, with a trend toward longer OS among patients receiving standard second-line therapies excluding PARPi/immunotherapy.

References

Leibowitz B, Dougherty B, Bell J, Kapilivsky J, Michuda J, Sedgewick A . Validation of genomic and transcriptomic models of homologous recombination deficiency in a real-world pan-cancer cohort. BMC Cancer. 2022; 22(1):587. PMC: 9148513. DOI: 10.1186/s12885-022-09669-z. View

San Filippo J, Sung P, Klein H . Mechanism of eukaryotic homologous recombination. Annu Rev Biochem. 2008; 77:229-57. DOI: 10.1146/annurev.biochem.77.061306.125255. View

. AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov. 2017; 7(8):818-831. PMC: 5611790. DOI: 10.1158/2159-8290.CD-17-0151. View

Prakash R, Zhang Y, Feng W, Jasin M . Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb Perspect Biol. 2015; 7(4):a016600. PMC: 4382744. DOI: 10.1101/cshperspect.a016600. View

Wu Z, Tao H, Zhang S, Wang X, Ma J, Li R . Efficacy and safety of anti-PD-1-based therapy in combination with PARP inhibitors for patients with advanced solid tumors in a real-world setting. Cancer Immunol Immunother. 2021; 70(10):2971-2980. PMC: 8423634. DOI: 10.1007/s00262-021-02852-4. View

Fizazi K, Retz M, Petrylak D, Goh J, Perez-Gracia J, Lacombe L . Nivolumab plus rucaparib for metastatic castration-resistant prostate cancer: results from the phase 2 CheckMate 9KD trial. J Immunother Cancer. 2022; 10(8). PMC: 9389086. DOI: 10.1136/jitc-2022-004761. View

Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall M . Maintenance Olaparib for Germline -Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019; 381(4):317-327. PMC: 6810605. DOI: 10.1056/NEJMoa1903387. View

Moore K, Colombo N, Scambia G, Kim B, Oaknin A, Friedlander M . Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2018; 379(26):2495-2505. DOI: 10.1056/NEJMoa1810858. View

Robson M, Im S, Senkus E, Xu B, Domchek S, Masuda N . Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017; 377(6):523-533. DOI: 10.1056/NEJMoa1706450. View

10.

Abida W, Patnaik A, Campbell D, Shapiro J, Bryce A, McDermott R . Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a or Gene Alteration. J Clin Oncol. 2020; 38(32):3763-3772. PMC: 7655021. DOI: 10.1200/JCO.20.01035. View

11.

Litton J, Rugo H, Ettl J, Hurvitz S, Goncalves A, Lee K . Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018; 379(8):753-763. PMC: 10600918. DOI: 10.1056/NEJMoa1802905. View

12.

Brown S, Lavery J, Shen R, Martin A, Kehl K, Sweeney S . Implications of Selection Bias Due to Delayed Study Entry in Clinical Genomic Studies. JAMA Oncol. 2021; 8(2):287-291. PMC: 9190030. DOI: 10.1001/jamaoncol.2021.5153. View

13.

Fumet J, Limagne E, Thibaudin M, Truntzer C, Bertaut A, Rederstorff E . Precision medicine phase II study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or.... BMC Cancer. 2020; 20(1):748. PMC: 7418426. DOI: 10.1186/s12885-020-07253-x. View

14.

Heeke A, Pishvaian M, Lynce F, Xiu J, Brody J, Chen W . Prevalence of Homologous Recombination-Related Gene Mutations Across Multiple Cancer Types. JCO Precis Oncol. 2018; 2018. PMC: 6139373. DOI: 10.1200/PO.17.00286. View

15.

Karzai F, VanderWeele D, Madan R, Owens H, Cordes L, Hankin A . Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J Immunother Cancer. 2018; 6(1):141. PMC: 6280368. DOI: 10.1186/s40425-018-0463-2. View

16.

Tutt A, Tovey H, Chon U Cheang M, Kernaghan S, Kilburn L, Gazinska P . Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med. 2018; 24(5):628-637. PMC: 6372067. DOI: 10.1038/s41591-018-0009-7. View

17.

Gallagher D, Konner J, Bell-McGuinn K, Bhatia J, Sabbatini P, Aghajanian C . Survival in epithelial ovarian cancer: a multivariate analysis incorporating BRCA mutation status and platinum sensitivity. Ann Oncol. 2010; 22(5):1127-1132. PMC: 6267858. DOI: 10.1093/annonc/mdq577. View

18.

Shao C, Chang M, Lam F, Marley A, Tang H, Song Y . A Systematic Review and Meta-Analysis on the Prognostic Value of BRCA Mutations, Homologous Recombination Gene Mutations, and Homologous Recombination Deficiencies in Cancer. J Oncol. 2022; 2022:5830475. PMC: 9328957. DOI: 10.1155/2022/5830475. View

19.

Shui I, Burcu M, Shao C, Chen C, Liao C, Jiang S . Real-world prevalence of homologous recombination repair mutations in advanced prostate cancer: an analysis of two clinico-genomic databases. Prostate Cancer Prostatic Dis. 2023; 27(4):728-735. PMC: 11543596. DOI: 10.1038/s41391-023-00764-1. View

20.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View