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. 2025 Apr;116(4):1048-1058.
doi: 10.1111/cas.70002. Epub 2025 Feb 10.

Germline Pathogenic Variants and Clinical Outcomes in Asian Patients With Breast Cancer

Rui Kitadai  1   2 , Shu Yazaki  1   2   3 , Aya Kuchiba  4   5 , Takashi Yamanaka  6 , Sho Shiino  7 , Chisako Yamauchi  8 , Kenichi Harano  9   10 , Motonobu Saito  11 , Yosuke Hirotsu  12 , Hisaki Aiba  1   2 , Teruhiko Yoshida  13 , Ryuji Hamamoto  14   15 , Chikako Shimizu  16 , Akihiko Shimomura  16 , Yuki Kojima  2 , Tatsunori Shimoi  2 , Yukihide Momozawa  17 , Kazuki Sudo  2 , Masayuki Yoshida  18 , Kuniko Sunami  1 , Megumi Hori  19 , Kota Katanoda  20 , Yoko Shimada  1 , Yuji Yamashita  8 , Takahiro Kogawa  21 , Takeshi Murata  7 , Saori Fujiwara  6 , Yohei Miyagi  22   23 , Hiroshi Nakagomi  24 , Kazunoshin Tachibana  25 , Masao Omata  26   27 , Tohru Ohtake  25 , Akihiko Suto  7 , Tatsuya Onishi  8 , Yoichi Naito  9   10   28 , Toshinari Yamashita  6 , Kan Yonemori  2 , Takashi Kohno  1 , Kouya Shiraishi  1   29
Affiliations

Germline Pathogenic Variants and Clinical Outcomes in Asian Patients With Breast Cancer

Rui Kitadai et al. Cancer Sci. 2025 Apr.

Abstract

Despite the importance of genetic testing for risk assessment and treatment in breast cancer, the prognostic impact of germline pathogenic variants (PVs), especially in Asian populations, is unclear. We assessed the impact of germline PVs in patients with early-stage breast cancer. This study included 7278 Japanese multihospital registry patients. PVs of ATM, BRCA1, BRCA2, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, STK11, and TP53 were evaluated. PV and non-PV carriers were matched by age, histology, and stage. Associations between PVs and survival were assessed. The primary outcome was invasive disease-free survival (IDFS). Secondary outcomes included relapse-free survival (RFS), overall survival, and breast cancer-specific survival. We identified 320 (4.4%) patients with BRCA1/2 PVs and 79 (1.1%) with PVs other than BRCA1/2 (non-BRCA1/2). A total of 360 patients (BRCA1/2, n = 289; non-BRCA1/2, n = 71) were matched to 720 noncarriers. Patients with BRCA1/2 PVs had significantly shorter 10-year IDFS (adjusted hazard ratio (aHR) = 2.15; 95% confidence interval (CI), 1.61-2.86; p < 0.001); and RFS (aHR = 1.74; 95% CI, 1.25-2.44; p = 0.001) than noncarriers. Among patients with hormone receptor-positive HER2-negative breast cancer, BRCA1/2 PV carriers exhibited significantly shorter 10-year IDFS than noncarriers, even those with stage I/II disease (total, aHR = 2.23; 95% CI, 1.55-3.23; p < 0.001, Stage I/II, aHR = 2.22; 95% CI, 1.43-3.44; p < 0.001). There was no significant difference in 10-year IDFS between the non-BRCA1/2 PV carrier and noncarrier groups (aHR = 1.40; 95% CI, 0.67-2.93; p = 0.37). Asian patients with breast cancer carrying germline BRCA1/2 PV, even those with a low recurrence risk, have significantly shorter 10-year IDFS than noncarriers.

Keywords: Breast cancer; cancer predisposition genes; hormone receptor‐positive; pathogenic variants; prognosis.

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Conflict of interest statement

Tohru Ohtake reports personal fees from Chugai, Pfizer, Astra Zeneca, Eisai, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, Novartis, FUJIFILM Toyama Chemical, Johnson & Johnson, Asahi Kasei, Exact Sciences, Otsuka, and MSD, outside the submitted work. Akihiko Shimomura reports personal fees from Chugai Pharma, AstraZeneca, Pfizer, Eisai, Eli Lilly, Daiichi Sankyo/UCB Japan, Kyowa Kirin International, MSD K.K, Exact Sciences, and Nihon Medi‐Physics, outside the submitted work. Kazuki Sudo reports personal fees from AstraZeneca, Pfizer, Eisai, and Nihon Medi‐Physics, outside the submitted work. Toshinari Yamashita reports personal fees from Chugai Pharma, Eisai, Novartis, AstraZeneca, Kyowa Hakko Kirin, Pfizer, Taiho Pharmaceutical, Lilly, Nippon Kayaku, and Daiichi Sankyo, outside the submitted work. Kan Yonemori reports personal fees from Pfizer, AstraZeneca, EISAI, Takeda Pharmaceutical Company, Chugai, Ono Pharmaceutical Company, Novartis, and Daiichi Sankyo, outside the submitted work. All remaining authors declare no conflicts of interest. Teruhiko Yoshida, Ryuji Hamamoto, and Takashi Kohno are Editorial Board Members of Cancer Science.

Figures

FIGURE 1
FIGURE 1
CONSORT diagram. Fukushima, Fukushima Medical University Hospital; NCCE, National Cancer Center East; NCCH, National Cancer Center Hospital; Yamanashi, Yamanashi Prefectural Central Hospital.
FIGURE 2
FIGURE 2
Comparisons of 10‐year invasive disease‐free survival in patients with BRCA1/2 pathogenic variants and noncarriers (A) and patients with non‐BRCA1/2 pathogenic variants and noncarriers (B).
FIGURE 3
FIGURE 3
Comparisons of 10‐year relapse‐free survival in patients with BRCA1/2 pathogenic variants and noncarriers (A) and patients with non‐BRCA1/2 pathogenic variants and noncarriers (B).
FIGURE 4
FIGURE 4
Comparisons of 10‐year invasive disease‐free survival according to hormone status in patients with BRCA1/2 and non‐BRCA1/2 pathogenic variants; hormone‐positive (A), HER2‐positive (B), and triple‐negative (C).
See this image and copyright information in PMC

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