The prevalence of gene mutations in homologous recombination repair pathways in Japanese patients with metastatic castration-resistant prostate cancer in real-world clinical practice: The multi-institutional observational ZENSHIN study

Hiroji Uemura; Mototsugu Oya; Toshiyuki Kamoto; Mikio Sugimoto; Kenta Shinozaki; Kiyomi Morita; Ryo Koto; Mai Takahashi; Masahiro Nii; Eisei Shin; Norio Nonomura

doi:10.1002/cam4.5333

The prevalence of gene mutations in homologous recombination repair pathways in Japanese patients with metastatic castration-resistant prostate cancer in real-world clinical practice: The multi-institutional observational ZENSHIN study

Cancer Med. 2023 Mar;12(5):5265-5274. doi: 10.1002/cam4.5333. Epub 2022 Nov 10.

Authors

Hiroji Uemura¹, Mototsugu Oya², Toshiyuki Kamoto³, Mikio Sugimoto⁴, Kenta Shinozaki⁵, Kiyomi Morita⁵, Ryo Koto⁵, Mai Takahashi⁵, Masahiro Nii⁵, Eisei Shin⁵, Norio Nonomura⁶

Affiliations

¹ Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama City, Japan.
² Department of Urology, Keio University School of Medicine, Tokyo, Japan.
³ Department of Urology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan.
⁴ Department of Urology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
⁵ AstraZeneca K.K, Osaka, Japan.
⁶ Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.

Abstract

Background: Metastatic castration-resistant prostate cancer (mCRPC) is a genetically heterogeneous disease with a poor prognosis. The prevalence of mutations in homologous recombination repair (HRR) pathway genes, including BRCA1/2, as well as treatment patterns and clinical outcomes, are not well characterized among Japanese men with mCRPC.

Methods: This multicenter, noninterventional cohort study enrolled Japanese men with mCRPC from 24 institutions between 2014 and 2018. Mutations in the 15 HRR-related genes were assessed using archival primary or metastatic tumor samples. Patterns of sequential therapies for mCRPC were investigated. Patients were followed up for survival evaluation including prostate-specific antigen progression-free survival (PSA-PFS) and overall survival (OS).

Results: Of the 143 patients analyzed, HRR-related mutations were detected in 51 patients (35.7%). The most frequently mutated genes were CDK12 (N = 19, 13.3%), followed by BRCA2 (N = 18, 12.6%), ATM (N = 8, 5.6%), and CHEK2 (N = 3, 2.1%). The most common type of first-line therapy for mCRPC was next-generation hormonal agents (NHA, 44.4%), followed by first-generation antiandrogens (FGA, 30.3%), and taxanes (22.5%). Commonly prescribed first-/second-line sequential regimens included FGA/NHA (17.6%), NHA/NHA (15.5%), and NHA/taxanes (14.1%). The median PSA-PFS and OS for the entire cohort were 5.6 and 26.1 months, respectively. Patients carrying BRCA1/2 mutations had numerically shorter PSA-PFS (median 3.3 vs. 5.9 months) and OS (median 20.7 vs. 27.3 months) than those without mutations.

Conclusions: In conclusion, approximately one-third of Japanese patients with mCRPC carried mutations in HRR-related genes in this study. The real-world outcomes of mCRPC are poor with conventional therapy, warranting an expansion of treatment options based on genetic abnormalities of the disease.

Keywords: BRCA; homologous recombination repair; metastatic castration-resistance prostate cancer; survival.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
East Asian People
Humans
Male
Mutation
Prevalence
Prostate-Specific Antigen*
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Prostatic Neoplasms, Castration-Resistant* / genetics
Prostatic Neoplasms, Castration-Resistant* / pathology
Recombinational DNA Repair
Retrospective Studies
Taxoids / therapeutic use
Treatment Outcome

Substances

Prostate-Specific Antigen
Taxoids