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; 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; Anne-Marie Gerdes; BRCA1 and BRCA2 Cohort Consortium

doi:10.1001/jama.2017.7112

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, Lesley McGuffog, D Gareth Evans, Daniel Barrowdale, Debra Frost, Julian AdlardKai-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, Anne-Marie Gerdes, BRCA1 and BRCA2 Cohort Consortium

Department of Clinical Medicine

785 Citations (Scopus)

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.

Original language	English
Journal	J A M A: The Journal of the American Medical Association
Volume	317
Issue number	23
Pages (from-to)	2402-2416
Number of pages	15
ISSN	0098-7484
DOIs	https://doi.org/10.1001/jama.2017.7112
Publication status	Published - 20 Jun 2017

Keywords

Adult
Age Distribution
Age Factors
Aged
Aged, 80 and over
Breast Neoplasms/epidemiology
Family
Female
Genes, BRCA1
Genes, BRCA2
Humans
Incidence
Middle Aged
Mutation
Neoplasms, Second Primary/epidemiology
Ovarian Neoplasms/epidemiology
Prospective Studies
Risk Assessment
Time Factors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kuchenbaecker, K. B., Hopper, J. L., Barnes, D. R., Phillips, K.-A., Mooij, T. M., Roos-Blom, M.-J., Jervis, S., van Leeuwen, F. E., Milne, R. L., Andrieu, N., Goldgar, D. E., Terry, M. B., Rookus, M. A., Easton, D. F., Antoniou, A. C., McGuffog, L., Evans, D. G., Barrowdale, D., Frost, D., ... BRCA1 and BRCA2 Cohort Consortium (2017). Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. J A M A: The Journal of the American Medical Association, 317(23), 2402-2416. https://doi.org/10.1001/jama.2017.7112

Kuchenbaecker, KB, Hopper, JL, Barnes, DR, Phillips, K-A, Mooij, TM, Roos-Blom, M-J, Jervis, S, van Leeuwen, FE, Milne, RL, Andrieu, N, Goldgar, DE, Terry, MB, Rookus, MA, Easton, DF, Antoniou, AC, McGuffog, L, Evans, DG, Barrowdale, D, Frost, D, Adlard, J, Ong, K-R, Izatt, L, Tischkowitz, M, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Nogues, C, Lasset, C, Stoppa-Lyonnet, D, Fricker, J-P, 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, Gerdes, A-M & BRCA1 and BRCA2 Cohort Consortium 2017, 'Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers', J A M A: The Journal of the American Medical Association, vol. 317, no. 23, pp. 2402-2416. https://doi.org/10.1001/jama.2017.7112

@article{cc332bdf918240b894edb49e5b125f33,

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

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.",

keywords = "Adult, Age Distribution, Age Factors, Aged, Aged, 80 and over, Breast Neoplasms/epidemiology, Family, Female, Genes, BRCA1, Genes, BRCA2, Humans, Incidence, Middle Aged, Mutation, Neoplasms, Second Primary/epidemiology, Ovarian Neoplasms/epidemiology, Prospective Studies, Risk Assessment, Time Factors",

author = "Kuchenbaecker, {Karoline B} and Hopper, {John L} and Barnes, {Daniel R} and Kelly-Anne Phillips and Mooij, {Thea M} and Marie-Jos{\'e} Roos-Blom and Sarah Jervis and {van Leeuwen}, {Flora E} and Milne, {Roger L} and Nadine Andrieu and Goldgar, {David E} and Terry, {Mary Beth} and Rookus, {Matti A} and Easton, {Douglas F} and Antoniou, {Antonis C} and Lesley McGuffog and Evans, {D Gareth} and Daniel Barrowdale and Debra Frost and Julian Adlard and Kai-Ren Ong and Louise Izatt and Marc Tischkowitz and Ros Eeles and Rosemarie Davidson and Shirley Hodgson and Steve Ellis and Catherine Nogues and Christine Lasset and Dominique Stoppa-Lyonnet and Jean-Pierre Fricker and Laurence Faivre and Pascaline Berthet and Hooning, {Maartje J} and {van der Kolk}, {Lizet E} and Kets, {Carolien M} and Adank, {Muriel A} and John, {Esther M} and Chung, {Wendy K} and Andrulis, {Irene L} and Melissa Southey and Daly, {Mary B} and Buys, {Saundra S} and Ana Osorio and Christoph Engel and Karin Kast and Schmutzler, {Rita K} and Trinidad Caldes and Anna Jakubowska and Anne-Marie Gerdes and {BRCA1 and BRCA2 Cohort Consortium}",

year = "2017",

month = jun,

day = "20",

doi = "10.1001/jama.2017.7112",

language = "English",

volume = "317",

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TY - JOUR

T1 - Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

AU - Kuchenbaecker, Karoline B

AU - Hopper, John L

AU - Barnes, Daniel R

AU - Phillips, Kelly-Anne

AU - Mooij, Thea M

AU - Roos-Blom, Marie-José

AU - Jervis, Sarah

AU - van Leeuwen, Flora E

AU - Milne, Roger L

AU - Andrieu, Nadine

AU - Goldgar, David E

AU - Terry, Mary Beth

AU - Rookus, Matti A

AU - Easton, Douglas F

AU - Antoniou, Antonis C

AU - McGuffog, Lesley

AU - Evans, D Gareth

AU - Barrowdale, Daniel

AU - Frost, Debra

AU - Adlard, Julian

AU - Ong, Kai-Ren

AU - Izatt, Louise

AU - Tischkowitz, Marc

AU - Eeles, Ros

AU - Davidson, Rosemarie

AU - Hodgson, Shirley

AU - Ellis, Steve

AU - Nogues, Catherine

AU - Lasset, Christine

AU - Stoppa-Lyonnet, Dominique

AU - Fricker, Jean-Pierre

AU - Faivre, Laurence

AU - Berthet, Pascaline

AU - Hooning, Maartje J

AU - van der Kolk, Lizet E

AU - Kets, Carolien M

AU - Adank, Muriel A

AU - John, Esther M

AU - Chung, Wendy K

AU - Andrulis, Irene L

AU - Southey, Melissa

AU - Daly, Mary B

AU - Buys, Saundra S

AU - Osorio, Ana

AU - Engel, Christoph

AU - Kast, Karin

AU - Schmutzler, Rita K

AU - Caldes, Trinidad

AU - Jakubowska, Anna

AU - Gerdes, Anne-Marie

AU - BRCA1 and BRCA2 Cohort Consortium

PY - 2017/6/20

Y1 - 2017/6/20

N2 - 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.

AB - 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.

KW - Adult

KW - Age Distribution

KW - Age Factors

KW - Aged

KW - Aged, 80 and over

KW - Breast Neoplasms/epidemiology

KW - Family

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Humans

KW - Incidence

KW - Middle Aged

KW - Mutation

KW - Neoplasms, Second Primary/epidemiology

KW - Ovarian Neoplasms/epidemiology

KW - Prospective Studies

KW - Risk Assessment

KW - Time Factors

U2 - 10.1001/jama.2017.7112

DO - 10.1001/jama.2017.7112

M3 - Journal article

C2 - 28632866

SN - 0098-7484

VL - 317

SP - 2402

EP - 2416

JO - J A M A: The Journal of the American Medical Association

JF - J A M A: The Journal of the American Medical Association

IS - 23

ER -

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

Abstract

Keywords

UN SDGs

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