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. 2025 Feb 20;43(6):651-661.
doi: 10.1200/JCO.24.01146. Epub 2024 Oct 29.

Second Primary Cancer Risks After Breast Cancer in BRCA1 and BRCA2 Pathogenic Variant Carriers

Affiliations

Second Primary Cancer Risks After Breast Cancer in BRCA1 and BRCA2 Pathogenic Variant Carriers

Isaac Allen et al. J Clin Oncol. .

Abstract

Purpose: Second primary cancer (SPC) risks after breast cancer (BC) in BRCA1/BRCA2 pathogenic variant (PV) carriers are uncertain. We estimated relative and absolute risks using a novel linkage of genetic testing data to population-scale National Disease Registration Service and Hospital Episode Statistics electronic health records.

Methods: We followed 25,811 females and 480 males diagnosed with BC and tested for germline BRCA1/BRCA2 PVs in NHS Clinical Genetics centers in England between 1995 and 2019 until SPC diagnosis, death, migration, contralateral breast/ovarian surgery plus 1 year, or the 31st of December 2020. We estimated standardized incidence ratios (SIRs) using English population incidences, hazard ratios (HRs) comparing carriers to noncarriers using Cox regression, and Kaplan-Meier 10-year cumulative risks.

Results: There were 1,840 BRCA1 and 1,750 BRCA2 female PV carriers. Compared with population incidences, BRCA1 carriers had elevated contralateral BC (CBC; SIR, 15.6 [95% CI, 11.8 to 20.2]), ovarian (SIR, 44.0 [95% CI, 31.4 to 59.9]), combined nonbreast/ovarian (SIR, 2.18 [95% CI, 1.59 to 2.92]), colorectal (SIR, 4.80 [95% CI, 2.62 to 8.05]), and endometrial (SIR, 2.92 [95% CI, 1.07 to 6.35]) SPC risks. BRCA2 carriers had elevated CBC (SIR, 7.70 [95% CI, 5.45 to 10.6]), ovarian (SIR, 16.8 [95% CI, 10.3 to 26.0]), pancreatic (SIR, 5.42 [95% CI, 2.09 to 12.5]), and combined nonbreast/ovarian (SIR, 1.68 [95% CI, 1.24 to 2.23]) SPC risks. Compared with females without BRCA1/BRCA2 PVs on testing, BRCA1 carriers had elevated CBC (HR, 3.60 [95% CI, 2.65 to 4.90]), ovarian (HR, 33.0 [95% CI, 19.1 to 57.1]), combined nonbreast/ovarian (HR, 1.45 [95% CI, 1.05 to 2.01]), and colorectal (HR, 2.93 [95% CI, 1.53 to 5.62]) SPC risks. BRCA2 carriers had elevated CBC (HR, 2.40 [95% CI, 1.70 to 3.40]), ovarian (HR, 12.0 [95% CI, 6.70 to 21.5]), and pancreatic (HR, 3.56 [95% CI, 1.34 to 9.48]) SPC risks. Ten-year cumulative CBC, ovarian, and combined nonbreast/ovarian cancer risks were 16%/6.3%/7.8% (BRCA1 carriers), 12%/3.0%/6.2% (BRCA2 carriers), and 3.6%/0.4%/4.9% (noncarriers). Male BRCA2 carriers had higher CBC (HR, 13.1 [95% CI, 1.19 to 146]) and prostate (HR, 5.61 [95% CI, 1.96 to 16.0]) SPC risks than noncarriers.

Conclusion: Survivors of BC carrying BRCA1 and BRCA2 PVs are at high SPC risk. They may benefit from enhanced surveillance and risk-reduction measures.

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Conflict of interest statement

Authors’ Disclosures of Potential Conflicts of Interest

Disclosures provided by the authors are available with this article at DOI https://doi.org/10.1200/JCO.24.01146.

Authors’ Disclosures of Potential Conflicts of Interest

Second Primary Cancer Risks After Breast Cancer in BRCA1 and BRCA2 Pathogenic Variant Carriers

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Tameera Rahman

Employment: Health Data Insight

Travel, Accommodations, Expenses: Health Data Insight

Bethany Torr Employment: Novartis

Stock and Other Ownership Interests: Novartis

Diana Eccles

Employment: University Hospitals Southampton NHS Foundation Trust

Research Funding: AstraZeneca

Clare Turnbull

Consulting or Advisory Role: Roche

Speakers’ Bureau: AstraZeneca

Paul Pharoah

Patents, Royalties, Other Intellectual Property: The PREDICT breast cancer prognostic model is licensed to OncoAssist by the University of Cambridge. I receive a share of the fees

Expert Testimony: Shook, Hardy, BCON

Antonis C. Antoniou

Patents, Royalties, Other Intellectual Property: Listed as creator of the BOADICEA model, which has been licensed by Cambridge Enterprise for commercial purposes

No other potential conflicts of interest were reported.

Figures

FIG 1
FIG 1
Cohort assembly. aThe other BRCA1/BRCA2 PV carrier status is defined in the Data Supplement (Table S1). BC, breast cancer; FU, follow-up; PV, pathogenic variant. respectively. Further descriptives are in the Data Supplement (Tables S5 and S6 and S13 and Figs S5-S8).
FIG 2
FIG 2
Ten-year cumulative second primary cancer risk curves, stratified by BRCA1 and BRCA2 PV carrier status: (A) CBC, (B) OC, and (C) nonbreast/ovarian cancer. CBC, contralateral breast cancer; CR, cumulative risk; FU, follow-up; OC, ovarian cancer; PV, pathogenic variant.

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