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Observational Study
. 2025 Jul;212(2):309-323.
doi: 10.1007/s10549-025-07726-2. Epub 2025 May 23.

Timely germline BRCA testing after invasive breast cancer promotes contralateral risk-reducing mastectomy and improves survival: an observational retrospective study

Aleksandar M Kostov  1 , Maj-Britt Jensen  2 , Bent Ejlertsen  2   3 , Mads Thomassen  4   5   6 , Maria Rossing  3   7 , Inge S Pedersen  8   9   10 , Annabeth H Petersen  11 , Lise Lotte Christensen  12 , Karin A W Wadt  3   13 , Luis C Berrocal-Almanza  14 , Miguel Miranda  14 , Anne-Vibeke Lænkholm  15   16
Affiliations
Observational Study

Timely germline BRCA testing after invasive breast cancer promotes contralateral risk-reducing mastectomy and improves survival: an observational retrospective study

Aleksandar M Kostov et al. Breast Cancer Res Treat. 2025 Jul.

Abstract

Purpose: To report the rates of risk-reducing surgery (RRS) following germline testing for BRCA1/2 (likely) pathogenic variants (BRCApv) and to assess the impact of RRS and BRCA status on survival after surgical treatment for unilateral breast cancer (BC).

Methods: We identified 7145 women with BC (2000-2017), a BRCA test and median follow-up of 10.8 years from the Danish Breast Cancer Cooperative Group's clinical database. Distant recurrence-free (DRFS) and overall survival (OS) according to BRCA status were evaluated using the Kaplan-Meier method. Hazard ratios (HR) for BRCApv vs. BRCA wild-type, contralateral risk-reducing mastectomy (CRRM), and risk-reducing bilateral salpingo-oophorectomy (RRBSO), including interaction tests, were estimated using multivariable Cox models.

Results: Among BRCA1pv carriers (n = 403), CRRM rates were higher than in BRCA2pv (n = 317) (66% vs. 52%, p < 0.001) and more likely to receive timely testing, i.e., within 6 months of BC diagnosis (75% vs. 52%, p = 0.004). Regarding RRBSO rates, no differences were observed. CRRM was associated with significantly improved DRFS (HR = 0.63, 95% CI 0.51-0.78) and OS (HR = 0.64, 95% CI 0.51-0.82), independently of BRCA status and age. RRBSO was associated with improved OS only in BRCApv carriers, specifically, those aged ≥ 50 years (HR = 0.44, 95% CI 0.26-0.75). BRCApv (irrespective of affected gene) was associated with worse DRFS (HR = 1.31, 95% CI 1.06-1.63); however, this was only evident after 2 years of follow-up (HR = 1.53, 95% CI 1.22-1.93). BRCApv was not significantly associated with worse OS (HR = 1.25, 95%CI 0.98-1.58).

Conclusion: Timely germline testing at BC diagnosis might increase CRRM rates in BRCApv carriers, thereby improving survival.

Keywords: Contralateral mastectomy; Danish breast cancer cooperative group; Genetic screening; Hereditary breast cancer; Risk-reducing surgery.

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Conflict of interest statement

Declarations. Conflict of interest: AK and AL: Institutional grants from AstraZeneca. Personal grants (presentation): AstraZeneca; AVL: Advisory board: MSD, congress attendance support: Daiichi Sankyo, AstraZeneca; MJ: Meeting expenses and advisory board, Novartis; BE: institutional grants from AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer, and Roche; grants for attending scientific meetings from MSD and Daiichi Sankyo; advisory board member organized by Eli Lilly and Medac. IP: Personal grant (presentation): AstraZeneca. KW: Personal grant (presentation), Seagen Denmark ApS. LCBA and MM are employees of AstraZeneca and hold shares; MT, CMR, and LL report no conflicts of interest. Ethical approval: The study was approved by the board of the Danish Breast Cancer Cooperative Group, the Capital Region’s Center for Health (R-21061634), and the Zealand University Hospital’s Administration Board (EMN-2021–09331). The study is registered at the Capital Region Research Overview – PACTIUS (J.nr. P-2021–0729) and adheres to the General Data Protection Regulations.

Figures

Fig. 1
Fig. 1
Trial profile. BC breast cancer, PBC primary breast cancer
Fig. 2
Fig. 2
Survival curves representing DRFS in a BRCApv vs. BRCAwt carriers; b BRCA1pv vs. BRCA2pv vs. BRCAwt carriers; DRFS-curves according to type and combination of risk-reducing surgery for c BRCApv carriers, d BRCAwt carriers. BRCAwt wild-type BRCA1 and BRCA2 genes, BRCApv pathogenic variants in the BRCA1 and BRCA2 genes, BC breast cancer, CI confidence interval, CRRM contralateral risk-reducing mastectomy, DRFS distant recurrence-free survival, RRBSO risk-reducing bilateral salpingo-oophorectomy
Fig. 3
Fig. 3
Survival curves representing OS in a BRCApv vs. BRCAwt carriers; b BRCA1pv vs. BRCA2pv vs. BRCAwt carriers; OS-curves according to type and combination of risk-reducing surgery for c BRCApv carriers, d BRCAwt carriers. BRCAwt wild-type BRCA1 and BRCA2 genes, BRCApv pathogenic variants in the BRCA1 and BRCA2 genes, BC breast cancer, CI confidence interval, CRRM contralateral risk-reducing mastectomy; OS overall survival; RRBSO risk-reducing bilateral salpingo-oophorectomy
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