Breast and Ovarian Cancer Among Individuals Undergoing BRCA1 and BRCA2 Testing

Fahima Dossa; Kelly Metcalfe; Zharmaine Ante; Ning Liu; Jordan Lerner-Ellis; Andrea Eisen; Nancy N Baxter

doi:10.1001/jamanetworkopen.2026.26334

. 2026 Jul 30;9(7):e2626334. doi: 10.1001/jamanetworkopen.2026.26334

Breast and Ovarian Cancer Among Individuals Undergoing BRCA1 and BRCA2 Testing

Fahima Dossa ^1,^✉, Kelly Metcalfe ^2,³, Zharmaine Ante ⁴, Ning Liu ^4,⁵, Jordan Lerner-Ellis ^6,^7,⁸, Andrea Eisen ^9,¹⁰, Nancy N Baxter ^4,^5,^11,^12,¹³

¹Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California

²Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, Canada

³Women’s College Research Institute, Toronto, Ontario, Canada

⁴ICES, Toronto, Ontario, Canada

⁵Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada

⁶Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

⁷Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada

⁸Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada

⁹Division of Medical Oncology, Juravinski Cancer Centre, Hamilton, Ontario, Canada

¹⁰McMaster University, Hamilton, Ontario, Canada

¹¹Li Ka Shing Knowledge Institute, Unity Health, Toronto, Ontario, Canada

¹²Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

¹³Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia

Accepted for Publication: June 9, 2026

Published: July 30, 2026. doi:10.1001/jamanetworkopen.2026.26334

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2026 Dossa F et al. JAMA Network Open.

^✉

Corresponding Author: Fahima Dossa, MD, PhD, Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, South Tower, Ste 5532, Los Angeles, CA 90048 (fahima.dossa@cshs.org).

Author Contributions: Dr Dossa and Ms Ante had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Dossa, Metcalfe, Lerner-Ellis, Eisen, Baxter.

Acquisition, analysis, or interpretation of data: Dossa, Metcalfe, Ante, Liu, Lerner-Ellis, Baxter.

Drafting of the manuscript: Dossa, Metcalfe.

Critical review of the manuscript for important intellectual content: Metcalfe, Ante, Liu, Lerner-Ellis, Eisen, Baxter.

Statistical analysis: Dossa, Ante, Liu.

Obtained funding: Lerner-Ellis, Eisen, Baxter.

Administrative, technical, or material support: Dossa, Lerner-Ellis, Baxter.

Supervision: Metcalfe, Baxter.

Conflict of Interest Disclosures: Dr Eisen reported receiving personal fees from Ontario Health and grants from Canadian Cancer Society and Hamilton Health Sciences Foundation outside the submitted work. Dr Baxter reported receiving grants from Canadian Breast Cancer Foundation and Canadian Institutes of Health Research (CIHR) during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. This study received funding from the Canadian Cancer Society (grant No. 315358). This work was supported by the CIHR (grant No. 148470).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred.

Data Sharing Statement: See Supplement 2.

^✉

Corresponding author.

PMCID: PMC13425191 PMID: 42530926

Key Points

Question

What are the lifetime risks of breast and ovarian cancer among females undergoing BRCA1 or BRCA2 testing across different result categories, and how does family history modify risk?

Findings

In this cohort study of 41 786 females eligible for breast cancer incidence evaluation and 79 656 females eligible for ovarian cancer incidence evaluation, pathogenic or likely pathogenic variant carriers had high lifetime risks of breast and ovarian cancer, and risks were further increased among individuals with positive family history. Individuals with variants of uncertain significance or negative results also had elevated breast cancer risk, while predictive (ie, true) negatives had risks similar to the general population.

Meaning

These findings suggest that cancer risk after BRCA1 or BRCA2 testing varies by test result and family history, supporting individualized risk assessment and management beyond test results alone.

This cohort study estimates lifetime incidence of breast and ovarian cancer among females undergoing BRCA1 or BRCA2 testing across all result categories and evaluates the modifying association of family history.

Abstract

Importance

Pathogenic variants in BRCA1 and BRCA2 confer substantial risks of breast and ovarian cancer; however, risk for female individuals undergoing testing, particularly those with variants of uncertain significance (VUS) or negative results, remain poorly defined.

Objective

To estimate lifetime incidence of breast and ovarian cancer among female individuals undergoing BRCA1 or BRCA2 testing across all result categories and evaluate the modifying association of family history.

Design, Setting, and Participants

This retrospective cohort study was conducted as part of the What Comes Next Cohort Study, a near–population-based cohort in Ontario, Canada, established through linkage with administrative databases. Female participants who underwent BRCA1 or BRCA2 testing from 2007 to 2016 were matched 1:5 to females from the general population. Participants were followed up to September 2024. Data were analyzed from May to December 2025.

Main Outcomes and Measures

The outcome of interest was the cumulative incidence of breast and ovarian cancer to age 80 years, stratified by genetic test result and family history.

Results

Of 15 986 individuals in the What Comes Next Cohort Study cohort, 6966 individuals eligible for breast cancer analyses (median [IQR] age, 49 [38-60] years) were matched to 34 830 individuals from the general population and 13 276 individuals eligible for ovarian cancer analyses (median [IQR] age, 51 [41-61] years) were matched to 66 380 individuals from the general population. Cumulative breast cancer incidence to age 80 years was 62.1% (95% CI, 52.2%-69.9%) for BRCA1 pathogenic variant carriers and 66.1% (95% CI, 57.5%-72.9%) for BRCA2 pathogenic variant carriers, compared with 12.0% (95% CI, 11.2%-12.8%) in the general population; corresponding ovarian cancer incidence was 56.0% (95% CI, 40.0%-67.7%) for BRCA1 pathogenic variant carriers and 29.3% (95% CI, 14.2%-41.7%) for BRCA2 pathogenic variant carriers, compared with 1.5% (95% CI, 1.3%-1.7%) in the general population. Family history modified breast cancer risk, reaching a cumulative incidence of 86.3% (95% CI, 70.9%-93.5%) in carriers with at least 2 affected first-degree relatives vs 55.8% (95% CI, 45.4%-64.2%) in carriers without a family history of breast cancer. Among individuals with test results positive for pathogenic variants, lifetime risk of ovarian cancer was similarly modified by family history, reaching 64.2% (95% CI, 37.0%-79.7%) in those with vs 38.2% (95% CI, 25.8%-48.4%) in those without a family history of ovarian cancer. Individuals with VUS and negative test results also had increased lifetime breast cancer risks (31.2% [95% CI, 19.2%-41.4%] and 26.3% [95% CI, 23.0%-29.4%], respectively) but no increase in ovarian cancer risk. Individuals with test results negative for a known familial variant had risks similar to the general population.

Conclusions and Relevance

In this cohort study of females who underwent BRCA1 or BRCA2 testing, the lifetime cancer risk varied substantially across BRCA test result groups and was further modified by family history. Elevated breast cancer risk among individuals with VUS or negative results highlights the need for individualized risk assessment and management beyond genetic test results alone.

Introduction

Approximately 5% to 10% of breast cancers are attributable to germline pathogenic variants in the BRCA1 and BRCA2 genes.¹ The estimated cumulative risk of breast cancer to age 80 years is estimated at 72% among carriers of pathogenic or likely pathogenic (P/LP) variants in BRCA1 and 69% among carriers of P/LP variants in BRCA2, and the risk of ovarian cancer estimated at 44% and 17% among carriers of P/LP variants in BRCA1 or BRCA2, respectively.² These risks far exceed those in the general population and form the foundation for current recommendations for enhanced surveillance and risk-reducing surgery in this group.

Since 2001, publicly funded testing for germline BRCA1 and BRCA2 variants has been available to individuals in Ontario, Canada, who meet specific high-risk criteria.³ Those with test results positive for P/LP variants are counseled to consider enhanced surveillance or risk-reducing surgery.⁴ However, penetrance is variable, and the determinants and clinical indicators of variability are not fully understood. For example, Metcalfe et al⁵ found that among female carriers of P/LP variants, each first-degree relative diagnosed with breast cancer before age 50 years increased breast cancer risk in the proband by 1.2- to 1.7-fold. Estimates of the impact of such familial modifiers on absolute lifetime cancer risk remain imprecise, in part due to limited follow-up. Additionally, selection of participants from cancer genetics clinics may bias samples toward those with higher-risk family histories.

Importantly, most female individuals who undergo BRCA1 or BRCA2 testing are not found to carry P/LP variants. Individuals with test results negative for a known familial risk-increasing variant (ie, predictive negative or true negative) are generally considered to have risks comparable to the general population. In contrast, most individuals receive inconclusive results, either as variants of uncertain significance (VUS) or noninformative negative results, where no risk-increasing variant is identified in the BRCA1 or BRCA2 genes but clinical suspicion for increased risk remains high based on personal and family cancer history. These inconclusive results present a major counseling challenge: although such individuals likely have higher cancer risks than the general population, reliable estimates of absolute lifetime risk are lacking.

These gaps in risk estimation complicate clinical counseling and decision-making. The aim of this study is to estimate the lifetime incidence of breast and ovarian cancer among females who meet criteria for BRCA1 or BRCA2 testing in Ontario, Canada, stratified by test result, and to assess how family history modifies risk among P/LP variant carriers.

Methods

This cohort study received ethics approval from the research ethics boards at Mount Sinai Hospital, Toronto; North York General Hospital; Sunnybrook Health Sciences Centre; and the University of Toronto. Aggregate deidentified data for this study were obtained from ICES. Under Ontario law (Personal Health Information Protection Act, Ontario Regulation 329/04), ICES is named as a prescribed entity and can receive and use health information without consent for the purpose of compiling and analyzing statistical information about the health care system in Ontario. This study is reported in accordance with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.

Study Design and Setting

We conducted a retrospective cohort study using data from the What Comes Next Cohort.^3,6 Briefly, this cohort includes adult female participants who underwent germline BRCA1 or BRCA2 testing at 1 of 2 regional genetic testing laboratories in Ontario, Canada, from January 1, 2007, to April 30, 2016. Over the study period, the 2 included sites performed approximately 70% of cancer genetic testing in Ontario. The What Comes Next Cohort combines family history and genetic testing information, obtained through health record review, with demographics and cancer history data, acquired through linkage with administrative health databases at ICES, an independent, nonprofit research institute. Further details are available in the eMethods and eTable 2 in Supplement 1. A detailed description of this cohort has been published elsewhere.⁶

Data Sources

Detailed information on data sources is available in the eMethods in Supplement 1. Over the study period, variants were classified using the American College of Medical Genetics and Genomics 2007 guidelines.⁷ Based on the results of testing, individuals who underwent familial testing (for a known cancer risk–increasing variant previously found in a relative) were classified as having positive or predictive negative results. Those who underwent full sequencing were classified as having positive (P/LP variant identified), VUS, or negative (benign or likely benign variant identified) results. Of note, in Ontario, there is no systematic updating or reclassification of VUS results once reported. Individuals who underwent founder testing (for 3 specific variants common to individuals of Ashkenazi Jewish descent) were classified as having positive or negative results.

Participants and Matching

Participants from the What Comes Next Cohort were matched to females from the general population who had not undergone genetic testing. For evaluation of breast cancer incidence, we first identified individuals from the What Comes Next Cohort who did not have a history of invasive breast cancer or ductal carcinoma in situ (DCIS) prior to their most recent genetic test. We additionally excluded individuals who had undergone bilateral mastectomy prior to genetic testing. The date of the most recent genetic test was then assigned as the index date for matching the remaining individuals. From the general population, we identified potential matches based on sex, birth year (±1 year), median household income quintile, and urban or rural residence status. We then ensured that the selected woman from the general population did not have a history of invasive breast cancer, DCIS, or bilateral mastectomy prior to the index date of their potential match. We used fixed-ratio matching without replacement, with 5 individuals from the general population matched to each participant from the What Comes Next Cohort.

For evaluation of ovarian cancer incidence, we used a separate subset of the What Comes Next Cohort: individuals who did not have a history of ovarian cancer or who had not undergone bilateral salpingo-oophorectomy prior to genetic testing. We used a similar process for identifying matches, ensuring that participants from the general population did not have a history of ovarian cancer or bilateral salpingo-oophorectomy prior to the index date of their potential match.

Statistical Analysis

Baseline characteristics of all included individuals (at the index date), stratified by genetic test result, were described using median and IQR or proportion and compared using the Kruskal-Wallis test for continuous variables and χ² test for proportions. There were no missing data for variables included in analyses. For each test result group, we estimated the crude rate of breast and ovarian cancer per 1000 person-years (PYs) in 10-year age intervals.

To estimate breast cancer incidence, we generated cumulative incidence curves using attained age as the time scale. Observation began at the time of the last of the following events: date of the most recent test, age 18 years, or Ontario Health Insurance Plan eligibility start date. Individuals were followed for the occurrence of invasive breast cancer or DCIS and censored at date of bilateral mastectomy, death, last contact, or end of study period (September 30, 2024). We performed a sensitivity analysis that did not censor at date of bilateral mastectomy. We used a similar process to estimate the incidence of ovarian cancer, with censoring at the time of bilateral salpingo-oophorectomy, death, last contact, or end of study period. Cumulative incidence was compared between groups using Gray test, taking death prior to the cancer of interest as a competing event.

For each test result group, we generated cumulative incidence curves of breast cancer, stratified by the number of first-degree relatives with a history of breast cancer prior to the participant undergoing genetic testing. We used a similar process to evaluate whether family history modified the incidence of ovarian cancer, with individuals in each test result group stratified by the number of first-degree relatives with ovarian cancer and the number of first-degree relatives with breast cancer.

Datasets were linked using unique encoded identifiers and analyzed at ICES. Statistical analyses were 2-sided, with P < .05 considered statistically significant. Analyses were performed using SAS Enterprise Guide version 8.3 (SAS Institute) from May to December 2025.

Results

Patient Characteristics

Of 15 986 individuals in the What Comes Next Cohort Study cohort, 6966 individuals eligible for breast cancer analyses (median [IQR] age, 49 [38-60] years) were matched to 34 830 individuals from the general population (Figure 1). This included 1248 individuals (17.9%) with a positive test result, 362 individuals (5.2%) with a VUS, 1271 individuals (18.2%) with a predictive negative result, and 4085 individuals (58.6%) with a negative result. After matching to the general population, a total of 41 796 individuals were available for analyses of breast cancer incidence (eTable 1 in Supplement 1). For analysis of ovarian cancer incidence, we identified 13 276 individuals (median [IQR] age, 51 [41-61] years) within the What Comes Next Cohort who did not have a history of ovarian cancer or bilateral salpingo-oophorectomy prior to genetic testing who were matched to 66 380 individuals from the general population (Figure 1), including 1628 individuals (12.3%) with a positive test result, 943 individuals (7.1%) with a VUS, 1257 individuals (9.5%) with a predictive negative result, and 9448 individuals (71.2%) with a negative result. After matching, 79 656 individuals were evaluable for ovarian cancer incidence (eTable 1 in Supplement 1).

Flowchart of cohort selection for breast and ovarian cancer incidence analyses. Light blue rectangular nodes connected by gray arrows. Top center node: 15986 Participants included in the What Comes Next cohort. A rightward arrow from the top node points to an upper right node: 154 Excluded at linkage. A vertical connector from the top node leads to a large central blank rectangle, from which two horizontal arrows extend left and right to exclusion boxes. Left exclusion box: 8866 Excluded; 8841 History of invasive or in situ breast cancer prior to test date; 25 History of bilateral mastectomy prior to test date. Right exclusion box: 2566 Excluded; 1530 History of ovarian cancer prior to test date; 1026 History of bilateral salpingo-oophorectomy prior to test date. From the central area, two downward arrows lead to midlevel cohort nodes: left node 6966 Breast cancer incidence cohort; right node 13276 Ovarian cancer incidence cohort. Between these two midlevel nodes, a small central node reads 1:5 Match to general population, with opposing horizontal arrows pointing toward both cohorts. From each midlevel cohort node, a downward arrow leads to a bottom node listing included totals and subgroup counts. Bottom left node: 41796 Included in breast cancer incidence cohort; 34830 General population; 1248 Positive; 362 V U S; 4085 Negative; 1271 Predictive negative. Bottom right node: 79656 Included in ovarian cancer incidence cohort; 66380 General population; 1628 Positive; 943 V U S; 9448 Negative; 1257 Predictive negative. — VUS indicates variant of uncertain significance.

Breast Cancer Incidence

A total of 1462 breast cancer events were observed over the follow-up period (median [IQR] follow-up, 11 [0-18] years), including 969 events among the general population, 87 events among individuals with P/LP BRCA1 variants, 99 events among individuals with P/LP BRCA2 variants, 25 events among individuals with VUS results, 242 events among individuals with negative results, and 40 events among individuals with predictive negative results (Table 1). In the general population, breast cancer incidence increased across successive decades of age, with total incidence across all individuals estimated at 2.5 per 1000 PYs. Among individuals who underwent BRCA1 or BRCA2 testing, in each decade, the group with positive test results exhibited the highest incidence of breast cancer, reaching a peak of 24.0 events per 1000 PYs among BRCA1 P/LP variant carriers aged 30 to 39 years and a peak of 22.7 events per 1000 PYs among BRCA2 P/LP variant carriers aged 50 to 59 years. Individuals with a VUS or negative result also demonstrated elevated breast cancer incidence, peaking among individuals with VUS aged 40 to 49 years (10.1 events per 1000 PYs). For individuals with a negative result, breast cancer risk increased steadily with age, reaching an overall rate of 6.2 events per 1000 PYs and remained higher than in their matched controls. In contrast, individuals who received a negative result after testing exhibited a breast cancer incidence rate of 2.7 events per 1000 PYs, similar to the general population.

Table 1. Breast Cancer Incidence Rates per 1000 Person-Years and Cumulative Incidence by Age Group by Genetic Test Result.

Age group, y	No.			Rate per 1000 person-years (95%CI)	Cumulative risk, % (95% CI)^a
Age group, y	Individuals	Events	Person-years	Rate per 1000 person-years (95%CI)	Cumulative risk, % (95% CI)^a
General population
18-29	3223	14	36 984	0.4 (0.2-0.6)	NA
30-39	6400	95	73 253	1.3 (1.1-1.6)	0.08 (0-1.8)
40-49	8213	204	95 126	2.1 (1.9-2.5)	0.5 (0.3-0.7)
50-59	8200	303	94 431	3.2 (2.9-3.6)	2.1 (1.7-2.4)
60-69	5768	263	63 502	4.1 (3.7-4.7)	4.3 (3.9-4.8)
70-79	2260	74	21 902	3.4 (2.7-4.2)	7.9 (7.4-8.5)
≥80	766	16	5367	3.0 (1.8-4.9)	12.0 (11.2-12.8)
Total	34 830	969	390 565	2.5 (2.3-2.6)	NA
Positive: BRCA1
18-29	130	16	1343	11.9 (7.3-19.4)	NA
30-39	160	29	1210	24.0 (16.7-34.5)	5.2 (6.4-9.6)
40-49	141	17	1086	15.6 (9.7-25.2)	23.4 (15.9-30.2)
50-59	119	18	900	20.0 (12.6-31.8)	40.0 (31.3-47.3)
60-69	55	6	399	15.0 (6.7-33.4)	48.5 (39.8-55.9)
70-79	Suppressed^b	Suppressed^b	Suppressed^b	9.7 (1.4-69.1)	56.3 (47.6-63.6)
≥80	Suppressed^b	Suppressed^b	Suppressed^b	0	62.1 (52.2-69.9)
Total	623	87	5094	17.1 (13.8-21.1)	NA
Positive: BRCA2
18-29	86	Suppressed^b	Suppressed^b	5.8 (2.4-14.0)	NA
30-39	141	24	1149	20.9 (14.0-31.2)	NA
40-49	138	23	1081	21.3 (14.1-32.0)	13.2 (6.5-19.5)
50-59	126	23	1012	22.7 (15.1-34.2)	31.4 (22.8-39.0)
60-69	97	20	898	22.3 (14.4-34.5)	48.3 (39.4-55.9)
70-79	Suppressed^b	Suppressed^b	Suppressed^b	12.6 (4.1-39.1)	56.5 (47.9-63.6)
≥80	Suppressed^b	Suppressed^b	Suppressed^b	21.0 (3.0-149.1)	66.1 (57.5-72.9)
Total	620	99	5285	18.7 (15.4-22.8)	NA
VUS
18-29	14	Suppressed^b	Suppressed^b	5.7 (0.8-40.3)	NA
30-39	49	Suppressed^b	Suppressed^b	6.3 (2.0-19.4)	NA
40-49	101	10	993	10.1 (5.4-18.7)	6.2 (0-14.4)
50-59	91	Suppressed^b	Suppressed^b	4.4 (1.6-11.7)	18.3 (7.1-28.1)
60-69	66	Suppressed^b	Suppressed^b	9.2 (3.8-22.0)	23.4 (12.0-33.3)
70-79	30	Suppressed^b	Suppressed^b	9.4 (2.3-37.4)	29.8 (18.0-39.9)
≥80	11	0	43.7	0	31.2 (19.2-41.4)
Total	362	25	3362	7.4 (5.0-11.0)	NA
Negative
18-29	200	Suppressed^b	Suppressed^b	1.9 (0.7-4.9)	NA
30-39	664	29	7190	4.0 (2.8-5.8)	0.6 (0-1.8)
40-49	969	75	10 309	7.3 (5.8-9.1)	4.7 (2.4-6.9)
50-59	1033	71	10 099	7.0 (5.6-8.9)	11.0 (8.3-13.6)
60-69	786	42	6827	6.2 (4.5-8.3)	17.1 (14.2-19.9)
70-79	333	18	2047	8.8 (5.5-14.0)	22.4 (19.4-25.3)
≥80	100	Suppressed^b	Suppressed^b	5.8 (1.9-18.1)	26.3 (23.0-29.4)
Total	4085	242	39 144	6.2 (5.5-7.0)	NA
Predictive negative
18-29	214	Suppressed^b	Suppressed^b	0.4 (0.1-2.9)	NA
30-39	263	Suppressed^b	Suppressed^b	0.6 (0.2-2.6)	NA
40-49	301	Suppressed^b	Suppressed^b	1.4 (0.6-3.3)	0.3 (0-1.1)
50-59	259	13	3077	4.2 (2.5-7.3)	1.6 (0.2-3.0)
60-69	155	14	1722	8.1 (4.8-13.7)	4.2 (2.0-6.4)
70-79	43	Suppressed^b	Suppressed^b	4.2 (1.1-17.0)	9.8 (6.3-13.2)
≥80	36	Suppressed^b	Suppressed^b	8.9 (2.9-27.5)	13.1 (8.8-17.2)
Total	1271	40	14 756	2.7 (2.0-3.7)	NA

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Abbreviations: NA, not applicable; VUS, variant of uncertain significance.

^{^a}

Cumulative risk estimated from cumulative incidence curve for individuals at the lowest age in the interval.

^{^b}

Cells with counts fewer than 6 are suppressed; corresponding cells are suppressed where back-calculation would be possible.

The lifetime breast cancer incidence differed significantly between groups (Figure 2A). Among the general population, the cumulative incidence of breast cancer up to age 80 years was 12.0% (95% CI, 11.2%-12.8%). Carriers of P/LP variants in BRCA1 or BRCA2 demonstrated significantly elevated risks. For BRCA1 carriers, the cumulative risk of breast cancer to age 80 years was 62.1% (95% CI, 52.2%-69.9%), compared with 66.1% (95% CI, 57.5%-72.9%) for BRCA2 carriers. Individuals with a VUS or negative result also demonstrated higher cumulative risks than the general population, with estimates of 31.2% (95% CI, 19.2%-41.4%) and 26.3% (95% CI, 23.0%-29.4%), respectively, while individuals in the predictive negative group were estimated to have a cumulative risk of 13.1% (95% CI, 8.8%-17.2%). The analysis in which individuals were not censored at bilateral mastectomy demonstrated similar results (eFigure 1 in Supplement 1).

Two-panel line charts of cancer incidence by age for breast and ovarian cancer. Two panels arranged left to right, labeled A and B in boxed letters at the upper left of each panel. Panel A title at top left: Breast cancer. Vertical axis labeled Incidence of breast cancer, ranging from 0 to 1 point 0. Horizontal axis labeled Age, y, ranging from 18 to 80. A legend box in the upper left lists six line categories with matching colors: B R C A 1 in dark teal, B R C A 2 in orange, General population in bright blue, Negative in gray, Predictive negative in magenta, and V U S in light green; each category has a step-like cumulative curve with a semi-transparent shaded band around it. Near the upper right of panel A, text P less than dot 001. Curves begin near zero in the late 20s to 30s and rise with age; the dark teal and orange curves reach roughly 0 point 6 to 0 point 7 by age 80, the light green curve about 0 point 3 to 0 point 4, the gray curve about 0 point 25, and the bright blue and magenta curves about 0 point 1 to 0 point 15. Beneath panel A, a No. at risk table lists rows B R C A 1, B R C A 2, General population, Negative, Predictive negative, and V U S with counts aligned under age ticks; several early cells display less than or equal to 5. Panel B title at top left: Ovarian cancer. Vertical axis labeled Incidence of ovarian cancer, ranging from 0 to 1 point 0. Horizontal axis labeled Age, y, ranging from 18 to 80. Text P less than dot 001 near the upper right. Step curves with shaded bands use the same color scheme as panel A; the dark teal curve rises steeply after about age 40 to approximately 0 point 55 to 0 point 6 by age 80, the orange curve rises later to about 0 point 25 to 0 point 3 by age 80, and the remaining curves stay near zero with small increases under about 0 point 05. A matching No. at risk table appears beneath panel B with the same row labels and age-aligned counts, including multiple less than or equal to 5 entries.

Breast Cancer Risk by Family History

In the breast cancer cohort, among 1248 P/LP variant carriers who had a known family history, breast cancer was identified in no, 1, and at least 2 first-degree relatives in 638 individuals (51.1%), 492 individuals (39.4%), and 118 individuals (9.5%), respectively, and breast cancer incidence was found to vary by family history (Figure 3A). Carriers of P/LP variants with at least 2 first-degree relatives with breast cancer had a cumulative lifetime risk of 86.3% (95% CI, 70.9%-93.5%). Risk was attenuated but remained elevated among P/LP variant carriers with 1 affected first-degree relative, as well as those with no affected first-degree relatives with breast cancer (67.8% [95% CI, 57.3%-75.7%] and 55.8% [95% CI, 45.4%-64.2%], respectively). An elevated cumulative lifetime incidence of breast cancer was also observed among individuals with negative test results who had at least 2 first-degree relatives with a history of breast cancer, compared with those with 1 or no first-degree relative with a history of breast cancer (42.6% [95% CI, 29.1-53.6%] vs 28.2% [95% CI, 23.2%-32.9%] and 21.1% [95% CI, 16.3%-25.6%], respectively; P < .001). No statistically significant differences were observed based on the number of first-degree relatives with ovarian cancer (Figure 3B) or among family history groups for those with VUS or predictive negative test results; however, event rates were low for both groups (25 and 40 events per 1000 PYs, respectively) (eFigure 2 in Supplement 1).

Four-panel cumulative incidence plots by age and family history for breast and ovarian cancer. Four Kaplan Meier–style step plots arranged in a two by two grid, panels A to D. All panels use a horizontal axis labeled Age, y, ranging from 18 to 80, and a vertical axis labeled Incidence of breast cancer or Incidence of ovarian cancer, ranging from 0 to 1 point 0. Shaded bands surround each step line. Panel A, title Breast cancer by family history of breast cancer, includes a legend with three line colors: dark gray labeled 0 F D R, orange labeled 1 F D R, and bright blue labeled greater than or equal to 2 F D R. The bright blue curve rises earliest and highest, reaching about 0 point 85 by age 80; the orange curve reaches about 0 point 68 by age 80; the dark gray curve reaches about 0 point 55 by age 80. Text P less than .001 appears near the lower right. A No. at risk table beneath lists rows 0 F D R, 1 F D R, and greater than or equal to 2 F D R with values at successive ages: 0 F D R, less than or equal to 5, 114, 112, 92, 87, 60, 20; 1 F D R, 6, 78, 91, 84, 65, 42, 13; greater than or equal to 2 F D R, 0, less than or equal to 5, 20, 17, 21, 20, less than or equal to 5. Panel B, title Breast cancer by family history of ovarian cancer, contains three similarly colored curves with substantial overlap; text P equals .42 appears near the upper left. The bright blue line has large step increases after about age 50 and wide shading. The No. at risk table reads: 0 F D R, 10, 169, 183, 147, 125, 87, 20; 1 F D R, less than or equal to 5, 27, 40, 38, 42, 33, 15; greater than or equal to 2 F D R, 0, 0, 0, 8, 6, less than or equal to 5, less than or equal to 5. Panel C, title Ovarian cancer by family history of ovarian cancer, has two curves: dark gray labeled 0 F D R and orange labeled greater than or equal to 1 F D R, with the orange curve higher, reaching about 0 point 65 by age 80, while dark gray reaches about 0 point 38; text P equals .01 appears near the upper left. The No. at risk table reads: 0 F D R, 10, 200, 167, 66, 45, 47, 32; greater than or equal to 1 F D R, less than or equal to 5, 34, 30, 11, 14, 15, 8. Panel D, title Ovarian cancer by family history of breast cancer, includes three curves with legend colors matching panel A; text P equals .20 appears near the upper left. By age 80, the orange and dark gray curves are near about 0 point 50, and the bright blue curve is lower near about 0 point 30, with wide shading. The No. at risk table reads: 0 F D R, less than or equal to 5, 137, 93, 33, 28, 26, 15; 1 F D R, 6, 93, 83, 34, 23, 24, 14; greater than or equal to 2 F D R, 0, less than or equal to 5, 21, 10, 8, 12, 11. — FDR indicates first-degree relative.

Ovarian Cancer Incidence

A total of 335 ovarian cancer events were observed over the follow-up period, including 238 events in the general population, 30 events among individuals with P/LP BRCA1 variants, 13 events among individuals with P/LP BRCA2 variants, 7 events among individuals with VUS results, 41 events among individuals with negative results, and 6 events among individuals with predictive negative results (Table 2). Among the general population, the incidence of ovarian cancer varied by decade, with the highest incidence observed in the individuals aged 60 to 69 years and 70 to 79 years (0.5 events per 1000 PYs) and total incidence of 0.3 events per 1000 PYs. Total incidence was similarly low among individuals with VUS, negative, and predictive negative results (0.8, 0.4, and 0.4 events per 1000 PYs, respectively). Individuals with positive results had significantly increased ovarian cancer incidence in each decade, peaking at 33.7 events per 1000 PYs among individuals aged 50 to 59 years with test results positive for P/LP in BRCA1 (8.1 events per 1000 PYs overall) and 18.2 events per 1000 PYs among individuals aged 70 to 79 years with test results positive for P/LP in BRCA2. Overall, there were 3.6 events per 1000 PYs.

Table 2. Ovarian Cancer Incidence Rates per 1000 Person-Years and Cumulative Incidence by Age Group by Genetic Test Result.

Age group, y	No.			Rate per 1000 person-years (95%CI)	Cumulative risk, % (95% CI)^a
Age group, y	Individuals	Events	Person-years	Rate per 1000 person-years (95%CI)	Cumulative risk, % (95% CI)^a
General population
18-29	3851	0	43 777	0	NA
30-39	10 852	Suppressed^b	Suppressed^b	0.1 (0.1-0.2)	NA
40-49	16 485	57	185 374	0.3 (0.2-0.4)	0.05 (0-0.09)
50-59	16 912	77	190 462	0.4 (0.3-0.5)	0.2 (0.1-0.3)
60-69	11 808	62	127 114	0.5 (0.4-0.6)	0.5 (0.4-0.7)
70-79	4892	23	47 389	0.5 (0.3-0.7)	1.0 (0.8-1.1)
≥80	1580	Suppressed^b	Suppressed^b	0.4 (0.1-1.0)	1.5 (1.3-1.7)
Total	66 380	238	727 592	0.3 (0.3-0.4)	NA
Positive: BRCA1
18-29	144	Suppressed^b	Suppressed^b	1.4 (0.4-5.6)	NA
30-39	233	Suppressed^b	Suppressed^b	2.8 (0.9-8.6)	NA
40-49	183	7	385	18.2 (8.7-38.2)	7.1 (0-20.8)
50-59	142	12	356	33.7 (19.2-59.4)	18.8 (7.1-29.1)
60-69	66	Suppressed^b	Suppressed^b	11.2 (3.6-34.7)	41.2 (25.7-53.4)
70-79	22	Suppressed^b	Suppressed^b	12.4 (3.1-49.6)	51.7 (36.0-63.6)
≥80	6	Suppressed^b	Suppressed^b	19.7 (2.8-140.0)	56.0 (40.0-67.7)
Total	796	30	3724	8.1 (5.6-11.5)	-
Positive: BRCA2
18-29	93	0	898	0	NA
30-39	193	Suppressed^b	Suppressed^b	0.9 (0.1-6.2)	NA
40-49	217	Suppressed^b	Suppressed^b	2.1 (0.3-15.0)	NA
50-59	158	Suppressed^b	Suppressed^b	8.0 (2.6-24.9)	2.7 (0-6.4)
60-69	116	Suppressed^b	Suppressed^b	10.4 (4.3-25.0)	5.3 (0-11.2)
70-79	32	Suppressed^b	Suppressed^b	18.2 (5.9-56.4)	20.4 (7.1-31.7)
≥80	16	0	124	0	29.3 (14.2-41.7)
Total	825	13	3655	3.6 (2.1-6.1)	NA
VUS
18-29	26	0	272	0	NA
30-39	133	Suppressed^b	Suppressed^b	0.8 (0.1-5.4)	NA
40-49	287	Suppressed^b	Suppressed^b	0.8 (0.2-3.1)	1.0 (0-3.0)
50-59	212	Suppressed^b	Suppressed^b	0.5 (0.1-3.5)	1.5 (0-3.6)
60-69	188	Suppressed^b	Suppressed^b	1.0 (0.3-4.1)	2.3 (0-4.7)
70-79	75	Suppressed^b	Suppressed^b	1.3 (0.2-9.2)	2.3 (0-4.7)
≥80	22	0	92	0	3.7 (5.4-6.7)
Total	943	7	8966	0.8 (0.4-1.6)	-
Negative
18-29	284	0	2911	0	NA
30-39	1354	Suppressed^b	Suppressed^b	0.2 (0-0.6)	NA
40-49	2334	8	22 069	0.4 (0.2-0.7)	0.2 (0-0.5)
50-59	2588	11	26 396	0.4 (0.2-0.8)	0.4 (0.01-0.8)
60-69	1879	18	18 685	1.0 (0.6-1.5)	0.8 (0.3-1.3)
70-79	782	Suppressed^b	Suppressed^b	0.3 (0.1-1.1)	1.3 (0.8-1.9)
≥80	227	0	1524	0	2.0 (1.3-2.7)
Total	9448	41	91 936	0.4 (0.3-0.6)	NA
Predictive negative
18-29	214	0	2432	0	NA
30-39	261	0	2953	0	NA
40-49	290	Suppressed^b	Suppressed^b	0.6 (0.1-2.4)	NA
50-59	259	Suppressed^b	Suppressed^b	0.3 (0-2.4)	NA
60-69	146	Suppressed^b	Suppressed^b	0.6 (0.1-4.4)	0.9 (0-2.0)
70-79	45	Suppressed^b	Suppressed^b	4.3 (1.1-17.2)	0.9 (0-2.0)
≥80	42	0	374	0	3.0 (0-6.3)
Total	1257	6	14 113	0.4 (0.2-0.9)	NA

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Abbreviations: NA, not applicable; VUS, variant of uncertain significance.

^{^a}

Cumulative risk estimated from cumulative incidence curve for individuals at the lowest age in the interval.

^{^b}

Cells with counts fewer than 6 are suppressed; corresponding cells are suppressed where back-calculation would be possible.

Lifetime ovarian cancer incidence is presented in Figure 2B. The cumulative risk to age 80 years ranged from 1.5% (95% CI, 1.3%-1.7%) to 3.7% (95% CI, 0.5%-6.7%) among individuals in the general population and those with VUS, negative, and predictive negative results. In contrast, BRCA1 carriers exhibited 56.0% (95% CI, 40.0%-67.7%) cumulative risk to age 80 years and BRCA2 carriers exhibited 29.3% (95% CI, 14.2%-41.7%) cumulative risk. In sensitivity analysis in which individuals were not censored at bilateral salpingo-oophorectomy, cumulative risk was reduced among BRCA1 and BRCA2 carriers (21.0% [95% CI, 13.0%-28.3%] and 14.9% [95% CI, 5.8-23.1%], respectively) (eFigure 3 in Supplement 1).

Ovarian Cancer Risk by Family History

In the ovarian cancer cohort, among 1628 individuals with positive test results, breast cancer was present in no, 1, and at least 2 first-degree relatives in 800 individuals (49.1%), 668 individuals (41.0%), and 160 individuals (9.8%), respectively. Among P/LP variant carriers, ovarian cancer incidence did not vary significantly based on number of first-degree relatives with breast cancer. Similarly, ovarian cancer incidence did not vary significantly by family history of breast cancer among any other test result groups (eFigure 4 in Supplement 1).

Among 1628 individuals with positive test results, a family history of ovarian cancer was present in no and at least 1 first-degree relative in 1312 individuals (80.6%) and 316 individuals (19.4%), respectively. Ovarian cancer incidence was significantly increased among those with a family history of ovarian cancer, where those testing positive and who had at least 1 first-degree relative with ovarian cancer demonstrated a 64.2% (95% CI, 37.0%-79.7%) cumulative incidence of ovarian cancer, compared with 38.2% (95% CI, 25.8%-48.4%) observed in those with positive test results but without a family history (P = .02) (Figure 3C). Results could not be stratified by BRCA1 vs BRCA2 variants due to low event rates. Statistically significant differences in the incidence of ovarian cancer were not observed based on family history of breast cancer (Figure 3D) or in any other test result groups when stratified by family history of ovarian cancer; however, event rates for each analysis were low (eFigure 5 in Supplement 1).

Discussion

In this cohort study of nearly 16 000 females who underwent germline BRCA1 or BRCA2 testing, we estimated cumulative incidences of breast cancer to age 80 years of 62% and 66% for carriers of P/LP BRCA1 and BRCA2 variants, respectively. Breast cancer risk was modified by family history, such that lifetime risk among carriers of P/LP variants was greater than 80% in those with 2 or more first-degree relatives with a history of breast cancer. Ovarian cancer risks were estimated at 56% for BRCA1 P/LP variant carriers and 29% for BRCA2 P/LP variant carriers, with risk accumulating steadily over time. Uniquely, we additionally estimated lifetime risks of breast cancer of 31% and 26% among individuals with VUS or negative test results, respectively; we did not observe an increased risk of ovarian cancer in these groups.

Our estimates are broadly concordant with prior studies, including an analysis of more than 9000 BRCA1 and BRCA2 variant carriers, which reported cumulative breast cancer risks to age 80 years of 72% and 69%, respectively, and ovarian cancer risks of 44% and 17%, respectively.² The lower BRCA1-associated breast cancer risk and higher ovarian cancer risks observed in our cohort may reflect differences in variant spectrum and penetrance or uptake of prophylactic interventions. Importantly, we identified family history as a modifier of breast cancer risk, with cumulative incidences of 55.8%, 67.8%, and 86.3% among P/LP variant carriers with no, 1, or 2 or more first-degree relatives with breast cancer, respectively. This pattern aligns with prior findings: in a multinational study of more than 3000 P/LP variant carriers with limited follow-up, Metcalfe et al⁵ reported increases in breast cancer risk among BRCA1 or BRCA2 variant carriers with each additional first-degree relative with breast cancer before age 50 years. However, conflicting data have also been reported. In a 2025 study of breast cancer risk among variant carriers of various genes, including 948 participants with P/LP variants in BRCA1 or BRCA2, the cumulative risk of breast cancer was elevated among those with BRCA2 variants and a family history of breast cancer but not among those with BRCA1 variants.⁸ However, this study estimated cumulative risk to age 80 years among individuals who were cancer-free at age 50 years, a time point after which the greatest number of breast cancers develop, thereby possibly missing important associations between risk and family history. Notably, our data, as well as these previous studies, underscore that, although risk increases with family history, it remains substantial even among individuals without affected relatives. Accordingly, a negative family history should not preclude consideration of risk-reducing strategies among carriers of P/LP variants in BRCA1 and BRCA2.

However, most individuals who undergo testing do not receive a positive test result. Among individuals with negative test results for a known familial P/LP variant (predictive negative), cancer risks were comparable to those in the general population, corroborating earlier studies with few events and limited follow-up.^9,10 While a small study has reported conflicting results,¹¹ our cohort, including more than 1200 individuals with predictive negative results, provides precise estimates confirming previous findings and further supports current recommendations that these individuals follow general population-based screening guidelines.

In contrast, individuals with VUS or uninformative negative results demonstrated elevated lifetime risks of breast cancer, at 31% and 26%, respectively, which were approximately double those of the general population. This excess risk likely reflects underlying familial and clinical risk factors rather than undetected pathogenicity of the tested variants, as most VUS are ultimately reclassified as benign.¹² Of note, our cohort included individuals who met high-risk testing criteria, and most individuals who were cancer-free at the time of testing qualified based on family history. For example, testing criteria for individuals without a personal cancer history included being a relative of an individual with a known BRCA1 or BRCA2 variant, being of Ashkenazi Jewish descent and having a family history of early breast cancer (age <50 years) or ovarian cancer (any age), or having a more than 10% estimated risk of a P/LP variant based on family history. Therefore, at baseline, individuals selected for tested represented a group at higher risk for breast or ovarian cancer than the general population. Prior work has shown a 4-fold increase in breast cancer risk among individuals with negative genetic test results and strong family histories.¹³ Although a small proportion of these risks may be attributable to moderate risk-increasing variants in genes beyond BRCA1 and BRCA2, such variants are detected in only 3% to 6% of individuals who undergo multigene panel testing after a negative BRCA1 or BRCA2 test result.^14,15 Therefore, our findings highlight that individuals who meet clinical high-risk criteria, such as the genetic testing criteria suggested by the National Comprehensive Cancer Network guidelines, may have elevated lifetime risks of breast cancer even if germline testing does not identify a P/LP variant in a known risk-increasing gene. In contrast, we did not observe an increased risk of ovarian cancer in individuals with VUS or negative results, consistent with previous studies,¹⁶ indicating that BRCA1 and BRCA2 account for most inherited ovarian cancer risk. Taken together, these findings have important implications for clinical management of individuals who receive VUS or negative results after BRCA1 or BRCA2 testing. Specifically, the substantially elevated lifetime risk of breast cancer observed in this study supports current recommendations that management should not be based on the genetic test alone but should incorporate family history and other clinical risk factors. Specifically, individuals whose overall risk exceeds accepted thresholds for high-risk screening may benefit from intensified breast cancer surveillance, including consideration of annual breast magnetic resonance imaging, despite the absence of an identified P/LP variant. At this time, however, we cannot make recommendations for the utility of other breast cancer risk-reducing strategies (eg, surgery) in this population, given the overall low cancer event rates observed. In contrast, the absence of increased ovarian cancer risk among individuals with VUS or negative results suggest that ovarian cancer risk-reducing strategies should generally be reserved for individuals with confirmed P/LP variants or other established indications.

Limitations

Despite the near–population-based capture of BRCA1 and BRCA2 testing in Ontario, extended follow-up, and large representation of individuals without P/LP variants in BRCA1/BRCA2 allowing robust estimation of cancer risks across result categories, this study has notable limitations. We did not capture multigene panel testing; therefore, we cannot ascertain the component of cancer risk attributable to variants in alternate genes. However, these genes likely contribute minimally to risk. Our analysis of risk modification by family history does not account for size of families and only captures family history at genetic testing. Nonetheless, our findings confirm that baseline family history provides clinically meaningful risk discrimination. We also did not assess contralateral breast cancer risk, previously estimated at 40% and 26% for BRCA1 and BRCA2 P/LP variant carriers, respectively, 20 years after initial diagnosis.² Furthermore, known clinical risk factors for breast cancer were not captured in this study; therefore, their associations with cancer risk within each group could not be ascertained.

Conclusions

Our findings from this cohort study of 15 986 individuals who underwent BRCA1 or BRCA2 testing refine lifetime estimates of breast and ovarian cancer risk across test result categories, including individuals who did not have positive test results. Cancer risk among carriers of P/LP variants in BRCA1 and BRCA2 was substantially modified by family history yet remained high even in its absence. Elevated breast cancer risks among individuals with VUS and noninformative negative results highlight the need for individualized risk assessment beyond genetic testing results. Together, these data reinforce the importance of tailored risk-reduction and surveillance strategies across the full spectrum of BRCA1 and BRCA2 testing results.

Supplement 1.

eMethods.

eTable 1. Baseline characteristics at the time of genetic testing for women included in analyses of breast and ovarian cancer incidence

eTable 2. Diagnostic codes used to identify occurrences of invasive and in situ breast and ovarian cancer

eFigure 1. Sensitivity analysis of breast cancer incidence where women were not censored at the time of bilateral mastectomy

eFigure 2. Cumulative incidence of breast cancer stratified by family history of breast cancer among women with negative, predictive negative, and VUS test results

eFigure 3. Sensitivity analysis of ovarian cancer incidence where women were not censored at the time of bilateral salpingo-oophorectomy

eFigure 4. Cumulative incidence of ovarian cancer stratified by family history of breast cancer among women with positive, negative, predictive negative, and VUS test results

eFigure 5. Cumulative incidence of ovarian cancer stratified by family history of ovarian cancer among women with negative, predictive negative, and VUS test results

jamanetwopen-e2626334-s001.pdf^{(986.2KB, pdf)}

Supplement 2.

Data Sharing Statement

jamanetwopen-e2626334-s002.pdf^{(15.7KB, pdf)}

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eMethods.

eTable 1. Baseline characteristics at the time of genetic testing for women included in analyses of breast and ovarian cancer incidence

eTable 2. Diagnostic codes used to identify occurrences of invasive and in situ breast and ovarian cancer

eFigure 1. Sensitivity analysis of breast cancer incidence where women were not censored at the time of bilateral mastectomy

eFigure 2. Cumulative incidence of breast cancer stratified by family history of breast cancer among women with negative, predictive negative, and VUS test results

eFigure 3. Sensitivity analysis of ovarian cancer incidence where women were not censored at the time of bilateral salpingo-oophorectomy

eFigure 4. Cumulative incidence of ovarian cancer stratified by family history of breast cancer among women with positive, negative, predictive negative, and VUS test results

eFigure 5. Cumulative incidence of ovarian cancer stratified by family history of ovarian cancer among women with negative, predictive negative, and VUS test results

jamanetwopen-e2626334-s001.pdf^{(986.2KB, pdf)}

Supplement 2.

Data Sharing Statement

jamanetwopen-e2626334-s002.pdf^{(15.7KB, pdf)}

[zoi260724r1] 1.Owens DK, Davidson KW, Krist AH, et al. ; US Preventive Services Task Force . Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement. JAMA. 2019;322(7):652-665. doi: 10.1001/jama.2019.10987 [DOI] [PubMed] [Google Scholar]

[zoi260724r2] 2.Kuchenbaecker KB, Hopper JL, Barnes DR, et al. ; BRCA1 and BRCA2 Cohort Consortium . Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-2416. doi: 10.1001/jama.2017.7112 [DOI] [PubMed] [Google Scholar]

[zoi260724r3] 3.Dossa F, Cusimano MC, Sutradhar R, et al. Real-world health services utilisation and outcomes after BRCA1 and BRCA2 testing in Ontario, Canada: the What Comes Next Cohort Study protocol. BMJ Open. 2018;8(9):e025317. doi: 10.1136/bmjopen-2018-025317 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260724r4] 4.Daly MB, Pal T, AlHilli Z, et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. Version 1.2026. National Comprehensive Cancer Network; 2025. [DOI] [PubMed] [Google Scholar]

[zoi260724r5] 5.Metcalfe K, Lubinski J, Lynch HT, et al. ; Hereditary Breast Cancer Clinical Study Group . Family history of cancer and cancer risks in women with BRCA1 or BRCA2 mutations. J Natl Cancer Inst. 2010;102(24):1874-1878. doi: 10.1093/jnci/djq443 [DOI] [PubMed] [Google Scholar]

[zoi260724r6] 6.Dossa F, Metcalfe K, Sutradhar R, et al. Building the What Comes Next Cohort for BRCA1 and BRCA2 testing: a descriptive analysis. CMAJ Open. 2021;9(3):E874-E885. doi: 10.9778/cmajo.20200228 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Breast and Ovarian Cancer Among Individuals Undergoing BRCA1 and BRCA2 Testing

Fahima Dossa, MD, PhD

Kelly Metcalfe, RN, PhD

Zharmaine Ante, MSc

Ning Liu, PhD

Jordan Lerner-Ellis, PhD

Andrea Eisen, MD

Nancy N Baxter, MD, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Study Design and Setting

Data Sources

Participants and Matching

Statistical Analysis

Results

Patient Characteristics

Figure 1. Flowchart of Cohort Creation .

Breast Cancer Incidence

Table 1. Breast Cancer Incidence Rates per 1000 Person-Years and Cumulative Incidence by Age Group by Genetic Test Result.

Figure 2. Cumulative Incidence of Breast Cancer and Ovarian Cancer Stratified by Genetic Test Result.

Breast Cancer Risk by Family History

Figure 3. Cumulative Incidence Breast and Ovarian Cancer Stratified by Family History of Breast or Ovarian Cancer in Individuals With Test Results Positive for Pathogenic or Likely Pathogenic Variants in BRCA1 or BRCA2.

Ovarian Cancer Incidence

Table 2. Ovarian Cancer Incidence Rates per 1000 Person-Years and Cumulative Incidence by Age Group by Genetic Test Result.

Ovarian Cancer Risk by Family History

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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