Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE

Nasim Mavaddat, Susan Peock, Debra Frost, Steve Ellis, Radka Platte, Elena Fineberg, D Gareth Evans, Louise Izatt, Rosalind A Eeles, Julian Adlard, Rosemarie Davidson, Diana Eccles, Trevor Cole, Jackie Cook, Carole Brewer, Marc Tischkowitz, Fiona Douglas, Shirley Hodgson, Lisa Walker, Mary E PorteousPatrick J Morrison, Lucy E Side, M John Kennedy, Catherine Houghton, Alan Donaldson, Mark T Rogers, Huw Dorkins, Zosia Miedzybrodzka, Helen Gregory, Jacqueline Eason, Julian Barwell, Emma McCann, Alex Murray, Antonis C Antoniou, Douglas F Easton, on behalf of EMBRACE

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. METHODS: Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. RESULTS: The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02). CONCLUSIONS: Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.
Original languageEnglish
Pages (from-to)812-822
Number of pages11
JournalJournal of the National Cancer Institute
Volume105
Issue number11
Early online date29 Apr 2013
DOIs
Publication statusPublished - 5 Jun 2013

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Breast Neoplasms
Mutation
Neoplasms
Confidence Intervals
Ovarian Neoplasms
Alleles
Penetrance
Kaplan-Meier Estimate
Single Nucleotide Polymorphism
Breast
Retrospective Studies
Joints
Genotype

Cite this

Mavaddat, N., Peock, S., Frost, D., Ellis, S., Platte, R., Fineberg, E., ... on behalf of EMBRACE (2013). Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. Journal of the National Cancer Institute, 105(11), 812-822. https://doi.org/10.1093/jnci/djt095

Cancer risks for BRCA1 and BRCA2 mutation carriers : results from prospective analysis of EMBRACE. / Mavaddat, Nasim; Peock, Susan; Frost, Debra; Ellis, Steve; Platte, Radka; Fineberg, Elena; Evans, D Gareth; Izatt, Louise; Eeles, Rosalind A; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Tischkowitz, Marc; Douglas, Fiona; Hodgson, Shirley; Walker, Lisa; Porteous, Mary E; Morrison, Patrick J; Side, Lucy E; Kennedy, M John; Houghton, Catherine; Donaldson, Alan; Rogers, Mark T; Dorkins, Huw; Miedzybrodzka, Zosia; Gregory, Helen; Eason, Jacqueline; Barwell, Julian; McCann, Emma; Murray, Alex; Antoniou, Antonis C; Easton, Douglas F; on behalf of EMBRACE.

In: Journal of the National Cancer Institute, Vol. 105, No. 11, 05.06.2013, p. 812-822.

Research output: Contribution to journalArticle

Mavaddat, N, Peock, S, Frost, D, Ellis, S, Platte, R, Fineberg, E, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Brewer, C, Tischkowitz, M, Douglas, F, Hodgson, S, Walker, L, Porteous, ME, Morrison, PJ, Side, LE, Kennedy, MJ, Houghton, C, Donaldson, A, Rogers, MT, Dorkins, H, Miedzybrodzka, Z, Gregory, H, Eason, J, Barwell, J, McCann, E, Murray, A, Antoniou, AC, Easton, DF & on behalf of EMBRACE 2013, 'Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE', Journal of the National Cancer Institute, vol. 105, no. 11, pp. 812-822. https://doi.org/10.1093/jnci/djt095
Mavaddat, Nasim ; Peock, Susan ; Frost, Debra ; Ellis, Steve ; Platte, Radka ; Fineberg, Elena ; Evans, D Gareth ; Izatt, Louise ; Eeles, Rosalind A ; Adlard, Julian ; Davidson, Rosemarie ; Eccles, Diana ; Cole, Trevor ; Cook, Jackie ; Brewer, Carole ; Tischkowitz, Marc ; Douglas, Fiona ; Hodgson, Shirley ; Walker, Lisa ; Porteous, Mary E ; Morrison, Patrick J ; Side, Lucy E ; Kennedy, M John ; Houghton, Catherine ; Donaldson, Alan ; Rogers, Mark T ; Dorkins, Huw ; Miedzybrodzka, Zosia ; Gregory, Helen ; Eason, Jacqueline ; Barwell, Julian ; McCann, Emma ; Murray, Alex ; Antoniou, Antonis C ; Easton, Douglas F ; on behalf of EMBRACE. / Cancer risks for BRCA1 and BRCA2 mutation carriers : results from prospective analysis of EMBRACE. In: Journal of the National Cancer Institute. 2013 ; Vol. 105, No. 11. pp. 812-822.
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title = "Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE",
abstract = "BACKGROUND: Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. METHODS: Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. RESULTS: The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60{\%} (95{\%} confidence interval [CI] = 44{\%} to 75{\%}) for breast cancer, 59{\%} (95{\%} CI = 43{\%} to 76{\%}) for ovarian cancer, and 83{\%} (95{\%} CI = 69{\%} to 94{\%}) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55{\%} (95{\%} CI = 41{\%} to 70{\%}) for breast cancer, 16.5{\%} (95{\%} CI = 7.5{\%} to 34{\%}) for ovarian cancer, and 62{\%} (95{\%} CI = 44{\%} to 79.5{\%}) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95{\%} CI = 1.2 to 14.5; P = .02). CONCLUSIONS: Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.",
author = "Nasim Mavaddat and Susan Peock and Debra Frost and Steve Ellis and Radka Platte and Elena Fineberg and Evans, {D Gareth} and Louise Izatt and Eeles, {Rosalind A} and Julian Adlard and Rosemarie Davidson and Diana Eccles and Trevor Cole and Jackie Cook and Carole Brewer and Marc Tischkowitz and Fiona Douglas and Shirley Hodgson and Lisa Walker and Porteous, {Mary E} and Morrison, {Patrick J} and Side, {Lucy E} and Kennedy, {M John} and Catherine Houghton and Alan Donaldson and Rogers, {Mark T} and Huw Dorkins and Zosia Miedzybrodzka and Helen Gregory and Jacqueline Eason and Julian Barwell and Emma McCann and Alex Murray and Antoniou, {Antonis C} and Easton, {Douglas F} and {on behalf of EMBRACE}",
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pages = "812--822",
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TY - JOUR

T1 - Cancer risks for BRCA1 and BRCA2 mutation carriers

T2 - results from prospective analysis of EMBRACE

AU - Mavaddat, Nasim

AU - Peock, Susan

AU - Frost, Debra

AU - Ellis, Steve

AU - Platte, Radka

AU - Fineberg, Elena

AU - Evans, D Gareth

AU - Izatt, Louise

AU - Eeles, Rosalind A

AU - Adlard, Julian

AU - Davidson, Rosemarie

AU - Eccles, Diana

AU - Cole, Trevor

AU - Cook, Jackie

AU - Brewer, Carole

AU - Tischkowitz, Marc

AU - Douglas, Fiona

AU - Hodgson, Shirley

AU - Walker, Lisa

AU - Porteous, Mary E

AU - Morrison, Patrick J

AU - Side, Lucy E

AU - Kennedy, M John

AU - Houghton, Catherine

AU - Donaldson, Alan

AU - Rogers, Mark T

AU - Dorkins, Huw

AU - Miedzybrodzka, Zosia

AU - Gregory, Helen

AU - Eason, Jacqueline

AU - Barwell, Julian

AU - McCann, Emma

AU - Murray, Alex

AU - Antoniou, Antonis C

AU - Easton, Douglas F

AU - on behalf of EMBRACE

PY - 2013/6/5

Y1 - 2013/6/5

N2 - BACKGROUND: Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. METHODS: Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. RESULTS: The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02). CONCLUSIONS: Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.

AB - BACKGROUND: Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. METHODS: Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. RESULTS: The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02). CONCLUSIONS: Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.

U2 - 10.1093/jnci/djt095

DO - 10.1093/jnci/djt095

M3 - Article

C2 - 23628597

VL - 105

SP - 812

EP - 822

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 11

ER -