Germline DNA damage repair variants and prognosis of patients with high-risk or metastatic prostate cancer Journal Article
| Authors: | Stopsack, K. H.; Vijai, J.; Conry, M.; Berchuck, J. E.; Kemel, Y.; Vasselman, S. E.; Freeman, D. A.; Lee, G. S. M.; Mandelker, D.; Solit, D. B.; Morris, M. J.; Penney, K. L.; Abida, W.; Offit, K.; Mucci, L. A.; Kantoff, P. W.; Pomerantz, M. M. |
| Article Title: | Germline DNA damage repair variants and prognosis of patients with high-risk or metastatic prostate cancer |
| Abstract: | Purpose: Deleterious germline variants in certain DNA repair genes are risk factors for developing aggressive prostate cancer. The objective was to quantify their prognostic impact after prostate cancer diagnosis. Experimental Design: Men with prostate cancer, predominantly of European ancestry, were included from four cohorts with long-term follow-up. Pathogenic or likely pathogenic germline variants in 26 DNA repair genes were assessed in relation to metastasis-free survival in high-risk localized prostate cancer and to overall survival in metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Results: Among 3,525 patients initially diagnosed with nonmetastatic prostate cancer, 2,594 had high-risk localized prostate cancer, 429 had mCSPC, and 502 had mCRPC at inclusion. BRCA2 variant carriers did not have worse metastasis-free survival in high-risk localized prostate cancer [hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.69–1.46] or overall survival in mCSPC (HR, 0.46; 95% CI, 0.14–1.45) or mCRPC (HR, 0.60; 95% CI, 0.31–1.17) compared with noncarriers of DNA repair variants. Among 868 additional patients with de novo metastatic (M1) prostate cancer, BRCA2 variant carriers tended to have worse overall survival (HR, 1.59; 95% CI, 1.01–2.51). BRCA2 prognostic associations were not explained by radiation, PARP inhibitor, or platinum therapy. Results for other genes were limited in precision because variants were less common. Conclusions: Among patients with high-risk or metastatic prostate cancer who were initially diagnosed with and treated for nonmetastatic tumors, germline DNA repair variants in BRCA2 do not confer a substantially worse prognosis. ©2024 American Association for Cancer Research. |
| Keywords: | adult; controlled study; treatment response; aged; gene mutation; major clinical study; overall survival; sequence analysis; single nucleotide polymorphism; chemotherapy; follow up; cancer incidence; prospective study; genetic analysis; rad50 protein; dna repair; radiotherapy; cohort analysis; genetic variability; brca1 protein; brca2 protein; protein p53; dna methylation; risk factor; cancer mortality; high risk patient; carcinogenesis; prostate cancer; gleason score; questionnaire; tumor suppressor gene; hospitalization; microarray analysis; mismatch repair; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; hazard ratio; drug therapy; dna extraction; protein msh6; mismatch repair protein pms2; caucasian; recurrence free survival; bloom syndrome helicase; germline mutation; fanconi anemia group a protein; local recurrence free survival; cancer prognosis; high throughput sequencing; xeroderma pigmentosum group d protein; germline micronucleus; metastatic prostate cancer; protein msh3; metastasis free survival; sanger sequencing; prognosis; human; male; article; metastatic castration resistant prostate cancer; whole exome sequencing; mutl protein homolog 1; dna mismatch repair protein msh2; metastatic castration sensitive prostate cancer; partner and localizer of brca2; germline dna damage repair variant |
| Journal Title: | Clinical Cancer Research |
| Volume: | 31 |
| Issue: | 1 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-01-01 |
| Start Page: | 122 |
| End Page: | 129 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-24-2483 |
| PUBMED: | 39450704 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Kenneth Offit -- Source: Scopus |
