TY - JOUR
T1 - Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers
AU - The BRCA1 and BRCA2 Cohort Consortium
AU - Kuchenbaecker, Kroline 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 - Simard, Jacques
N1 - Publisher Copyright:
© 2017 American Medical Association. All rights reserved.
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
UR - http://www.scopus.com/inward/record.url?scp=85021167654&partnerID=8YFLogxK
U2 - 10.1001/jama.2017.7112
DO - 10.1001/jama.2017.7112
M3 - Article
C2 - 28632866
AN - SCOPUS:85021167654
SN - 0098-7484
VL - 317
SP - 2402
EP - 2416
JO - JAMA
JF - JAMA
IS - 23
ER -