Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

Karoline B Kuchenbaecker; John L Hopper; Daniel R Barnes; Kelly-Anne Phillips; Thea M Mooij; Marie-José Roos-Blom; Sarah Jervis; Flora E van Leeuwen; Roger L Milne; Nadine Andrieu; David E Goldgar; Mary Beth Terry; Matti A Rookus; Douglas F Easton; Antonis C Antoniou; BRCA1 and BRCA2 Cohort Consortium; Lesley McGuffog; D Gareth Evans; Daniel Barrowdale; Debra Frost; Julian Adlard; Kai-Ren Ong; Louise Izatt; Marc Tischkowitz; Ros Eeles; Rosemarie Davidson; Shirley Hodgson; Steve Ellis; Catherine Nogues; Christine Lasset; Dominique Stoppa-Lyonnet; Jean-Pierre Fricker; Laurence Faivre; Pascaline Berthet; Maartje J Hooning; Lizet E van der Kolk; Carolien M Kets; Muriel A Adank; Esther M John; Wendy K Chung; Irene L Andrulis; Melissa Southey; Mary B Daly; Saundra S Buys; Ana Osorio; Christoph Engel; Karin Kast; Rita K Schmutzler; Trinidad Caldes; Anna Jakubowska; Jacques Simard; Michael L Friedlander; Sue-Anne McLachlan; Eva Machackova; Lenka Foretova; Yen Y Tan; Christian F Singer; Edith Olah; Anne-Marie Gerdes; Brita Arver; Håkan Olsson

doi:10.1001/jama.2017.7112

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, Jervis S, van Leeuwen FE, Milne RL, Andrieu N, Goldgar DE, Terry MB, Rookus MA, Easton DF, Antoniou AC, BRCA1 and BRCA2 Cohort Consortium, McGuffog L, Evans DG, Barrowdale D, Frost D, Adlard J, Ong KR, Izatt L, Tischkowitz M, Eeles R, Davidson R, Hodgson S, Ellis S, Nogues C, Lasset C, Stoppa-Lyonnet D, Fricker JP, Faivre L, Berthet P, Hooning MJ, van der Kolk LE, Kets CM, Adank MA, John EM, Chung WK, Andrulis IL, Southey M, Daly MB, Buys SS, Osorio A, Engel C, Kast K, Schmutzler RK, Caldes T, Jakubowska A, Simard J, Friedlander ML, McLachlan SA, Machackova E, Foretova L, Tan YY, Singer CF, Olah E, Gerdes AM, Arver B, Olsson H

Published June 20, 2017 JAMA

DOI 10.1001/jama.2017.7112 PMID 28632866

RRM Academy Synopsis

BRCA1 and BRCA2 carriers had 72% and 69% breast cancer risk by age 80

Among 6036 BRCA1 and 3820 BRCA2 female carriers in a 2017 prospective cohort, the estimated cumulative breast cancer risk by age 80 years was 72% for BRCA1 and 69% for BRCA2. Ovarian cancer risk by that age was estimated at 44% for BRCA1 and 17% for BRCA2.

Key Findings

Over the follow-up, researchers identified 426 breast cancers among 3886 eligible women, 109 ovarian cancers among 5066 women, and 245 contralateral breast cancers among 2213 women.
The estimated cumulative breast cancer risk by age 80 years was 69% for BRCA2 carriers (95% confidence interval [CI], 61%-77%) and 72% for BRCA1 carriers (95% CI, 65%-79%).
The estimated cumulative ovarian cancer risk by age 80 years was 17% for BRCA2 carriers (95% CI, 11%-25%) and 44% for BRCA1 carriers (95% CI, 36%-53%).
Twenty years after a first breast cancer, the estimated cumulative risk in the opposite breast was 26% for BRCA2 carriers (95% CI, 20%-33%) and 40% for BRCA1 carriers (95% CI, 35%-45%).
Hazard ratios for breast cancer were 1.99 for BRCA1 carriers and 1.91 for BRCA2 carriers who had 2 or more affected relatives, compared with none.

Interpretation

The record rests on the published abstract alone, so the synopsis describes what that abstract reports. The authors followed a prospective cohort for a median of 5 years, and most women joined through family clinics (94%). They conclude that the estimates come from prospective data and that family history and mutation location may matter in risk assessment.

RRM Context

Restorative reproductive medicine considers a woman's health across her whole lifespan. Carrier status and family history belong in that picture beside cycle charting and hormonal health. Risk estimates add firm detail to it.

Our editorial summary of this paper, not the article's abstract.

Abstract

Importance

The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates.

Objectives

To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location.

Design, Setting, and Participants

Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years.

Exposures

BRCA1/2 mutations, family cancer history, and mutation location.

Main Outcomes and Measures

Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer.

Results

Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001).

Conclusions and Relevance

These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

Topics

General Gynecology

Breast Health Breast Cancer Risk

General Gynecology › Breast Health › Breast Cancer Risk

Karoline B Kuchenbaecker, John L Hopper, Daniel R Barnes, Kelly-Anne Phillips, Thea M Mooij, Marie-José Roos-Blom, Sarah Jervis, Flora E van Leeuwen, Roger L Milne, Nadine Andrieu, David E Goldgar, Mary Beth Terry, Matti A Rookus, Douglas F Easton, Antonis C Antoniou, Lesley McGuffog, D Gareth Evans, Daniel Barrowdale, Debra Frost, Julian Adlard, Kai-Ren Ong, Louise Izatt, Marc Tischkowitz, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Steve Ellis, Catherine Nogues, Christine Lasset, Dominique Stoppa-Lyonnet, Jean-Pierre Fricker, Laurence Faivre, Pascaline Berthet, Maartje J Hooning, Lizet E van der Kolk, Carolien M Kets, Muriel A Adank, Esther M John, Wendy K Chung, Irene L Andrulis, Melissa Southey, Mary B Daly, Saundra S Buys, Ana Osorio, Christoph Engel, Karin Kast, Rita K Schmutzler, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Michael L Friedlander, Sue-Anne McLachlan, Eva Machackova, Lenka Foretova, Yen Y Tan, Christian F Singer, Edith Olah, Anne-Marie Gerdes, Brita Arver, Håkan Olsson

K Kuchenbaecker, Jack Hopper, J Hopper, Dan Barnes, Danny Barnes, D Barnes, K Phillips, T Mooij, M Roos-Blom, S Jervis, F Leeuwen, R Milne, N Andrieu, Dave Goldgar, D Goldgar, M Terry, M Rookus, Doug Easton, D Easton, A Antoniou, L McGuffog, Dan Barrowdale, Danny Barrowdale, D Barrowdale, D Frost, J Adlard, K Ong, L Izatt, M Tischkowitz, R Eeles, R Davidson, S Hodgson, Stephen Ellis, Steven Ellis, S Ellis, Cathy Nogues, Kate Nogues, C Nogues, Chris Lasset, C Lasset, D Stoppa-Lyonnet, J Fricker, Larry Faivre, L Faivre, P Berthet, M Hooning, L Kolk, C Kets, M Adank, E John, W Chung, I Andrulis, M Southey, M Daly, S Buys, A Osorio, C Engel, K Kast, R Schmutzler, T Caldes, A Jakubowska, J Simard, Mike Friedlander, M Friedlander, S McLachlan, E Machackova, L Foretova, Y Tan, C Singer, E Olah, A Gerdes, B Arver, H Olsson

PMID 28632866 28632866 DOI 10.1001/jama.2017.7112 10.1001/jama.2017.7112 Kuchenbaecker et al. 2017, Kuchenbaecker 2017

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

BRCA1 and BRCA2 carriers had 72% and 69% breast cancer risk by age 80

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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