Observational Study

. 2025 Feb;43(4):422-431.

doi: 10.1200/JCO.24.00176. Epub 2024 Oct 2.

Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2

Kelly-Anne Phillips^{1

2

3}, Joanne Kotsopoulos^{4

5}, Susan M Domchek^{6

7}, Mary Beth Terry^{8

9}, James A Chamberlain¹⁰, Julie K Bassett¹⁰, Amber M Aeilts¹¹, Irene L Andrulis^{12

13}, Saundra S Buys¹⁴, Wanda Cui^{1

2}, Mary B Daly¹⁵, Andrea F Eisen^{16

17}, William D Foulkes¹⁸, Michael L Friedlander^{19

20}, Jacek Gronwald²¹, John L Hopper³, Esther M John^{22

23

24}, Beth Y Karlan^{25

26}, Raymond H Kim^{27

28}, Allison W Kurian^{22

23

24}, Jan Lubinski²¹, Kelly Metcalfe^{4

29}, Katherine L Nathanson^{6

7

30}, Christian F Singer³¹, Melissa C Southey^{10

32

33}, Heather Symecko⁶, Nadine Tung³⁴, Steven A Narod^{4

5}, Roger L Milne^{3

10

33}; Kathleen Cuningham Foundation Consortium for Research Into Familial Breast Cancer, the Risk Factor Analysis of Hereditary Breast and Ovarian Cancer Study, the Basser Center University of Pennsylvania Registry, and the Breast Cancer Family Registry; Kathleen Cuningham Foundation Consortium for Research Into Familial Breast Cancer, the Risk Factor Analysis of Hereditary Breast and Ovarian Cancer Study, the Basser Center University of Pennsylvania Registry and the Breast Cancer Family Registry

Collaborators, Affiliations

Collaborators

David Amor, Lesley Andrews, Yoland Antill, Rosemary Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Simon Bodek, Leon Botes, Meagan Brennan, Melissa Brown, Michael Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Georgia Chenevix-Trench, Alice Christian, Paul Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret Cummings, Sarah-Jane Dawson, Anna DeFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Stacey Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James Flanagan, Peter Fong, Laura Forrest, Stephen Fox, Juliet French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Philip Harraka, Nick Hayward, John Hopper, Cass Hoskins, Clare Hunt, Paul James, Mark Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil Lakhani, Mitchell Lawrence, Jason Lee, Shuai Li, Geoff Lindeman, Jocelyn Lippey, Lara Lipton, Liz Lobb, Sherene Loi, Graham Mann, Deborah Marsh, Sue Anne McLachlan, Bettina Meiser, Roger Milne, Sophie Nightingale, Shona O'Connell, Sarah O'Sullivan, David Gallego Ortega, Nick Pachter, Jia-Min Pang, Gargi Pathak, Briony Patterson, Amy Pearn, Kelly Phillips, Ellen Pieper, Susan Ramus, Edwina Rickard, Abi Ragunathan, Bridget Robinson, Mona Saleh, Anita Skandarajah, Elizabeth Salisbury, Christobel Saunders, Jodi Saunus, Peter Savas, Rodney Scott, Clare Scott, Adrienne Sexton, Joanne Shaw, Andrew Shelling, Shweta Srinivasa, Peter Simpson, Melissa Southey, Amanda Spurdle, Jessica Taylor, Renea Taylor, Heather Thorne, Alison Trainer, Kathy Tucker, Jane Visvader, Logan Walker, Rachael Williams, Ingrid Winship, Mary Ann Young, Milita Zaheed

Affiliations

¹ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
² Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.
³ Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
⁴ Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, ON, Canada.
⁵ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
⁶ Basser Center for BRCA, University of Pennsylvania, Philadelphia, PA.
⁷ Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
⁸ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY.
⁹ Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY.
¹⁰ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
¹¹ Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
¹² Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
¹³ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁴ Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
¹⁵ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA.
¹⁶ Odette Cancer Centre, Sunnybrook Health Sciences, Toronto, ON, Canada.
¹⁷ Department of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁸ Department of Human Genetics, McGill University, Montreal, QC, Canada.
¹⁹ Department of Medical Oncology, Prince of Wales and Royal Hospital for Women, Sydney, NSW, Australia.
²⁰ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
²¹ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
²² Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California.
²³ Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
²⁴ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
²⁵ Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA.
²⁶ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
²⁷ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network and Sinai Health, Toronto, ON, Canada.
²⁸ Ontario Institute for Cancer Research, Toronto, ON, Canada.
²⁹ Bloomberg School of Nursing, University of Toronto, Toronto, ON, Canada.
³⁰ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
³¹ Department of Obstetrics and Gynecology and Center for Breast Health, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
³² Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia.
³³ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
³⁴ Beth Israel Deaconess Medical Center, Boston, MA.

PMID: 39356978
PMCID: PMC11771360
DOI: 10.1200/JCO.24.00176

Observational Study

Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2

Kelly-Anne Phillips et al. J Clin Oncol. 2025 Feb.

. 2025 Feb;43(4):422-431.

doi: 10.1200/JCO.24.00176. Epub 2024 Oct 2.

Authors

Collaborators

David Amor, Lesley Andrews, Yoland Antill, Rosemary Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Simon Bodek, Leon Botes, Meagan Brennan, Melissa Brown, Michael Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Georgia Chenevix-Trench, Alice Christian, Paul Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret Cummings, Sarah-Jane Dawson, Anna DeFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Stacey Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James Flanagan, Peter Fong, Laura Forrest, Stephen Fox, Juliet French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Philip Harraka, Nick Hayward, John Hopper, Cass Hoskins, Clare Hunt, Paul James, Mark Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil Lakhani, Mitchell Lawrence, Jason Lee, Shuai Li, Geoff Lindeman, Jocelyn Lippey, Lara Lipton, Liz Lobb, Sherene Loi, Graham Mann, Deborah Marsh, Sue Anne McLachlan, Bettina Meiser, Roger Milne, Sophie Nightingale, Shona O'Connell, Sarah O'Sullivan, David Gallego Ortega, Nick Pachter, Jia-Min Pang, Gargi Pathak, Briony Patterson, Amy Pearn, Kelly Phillips, Ellen Pieper, Susan Ramus, Edwina Rickard, Abi Ragunathan, Bridget Robinson, Mona Saleh, Anita Skandarajah, Elizabeth Salisbury, Christobel Saunders, Jodi Saunus, Peter Savas, Rodney Scott, Clare Scott, Adrienne Sexton, Joanne Shaw, Andrew Shelling, Shweta Srinivasa, Peter Simpson, Melissa Southey, Amanda Spurdle, Jessica Taylor, Renea Taylor, Heather Thorne, Alison Trainer, Kathy Tucker, Jane Visvader, Logan Walker, Rachael Williams, Ingrid Winship, Mary Ann Young, Milita Zaheed

Affiliations

¹ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
² Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.
³ Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
⁴ Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, ON, Canada.
⁵ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
⁶ Basser Center for BRCA, University of Pennsylvania, Philadelphia, PA.
⁷ Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
⁸ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY.
⁹ Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY.
¹⁰ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
¹¹ Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
¹² Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
¹³ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁴ Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
¹⁵ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA.
¹⁶ Odette Cancer Centre, Sunnybrook Health Sciences, Toronto, ON, Canada.
¹⁷ Department of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁸ Department of Human Genetics, McGill University, Montreal, QC, Canada.
¹⁹ Department of Medical Oncology, Prince of Wales and Royal Hospital for Women, Sydney, NSW, Australia.
²⁰ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
²¹ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
²² Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California.
²³ Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
²⁴ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
²⁵ Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA.
²⁶ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
²⁷ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network and Sinai Health, Toronto, ON, Canada.
²⁸ Ontario Institute for Cancer Research, Toronto, ON, Canada.
²⁹ Bloomberg School of Nursing, University of Toronto, Toronto, ON, Canada.
³⁰ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
³¹ Department of Obstetrics and Gynecology and Center for Breast Health, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
³² Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia.
³³ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
³⁴ Beth Israel Deaconess Medical Center, Boston, MA.

PMID: 39356978
PMCID: PMC11771360
DOI: 10.1200/JCO.24.00176

Abstract

Purpose: It is uncertain whether, and to what extent, hormonal contraceptives increase breast cancer (BC) risk for germline BRCA1 or BRCA2 mutation carriers.

Methods: Using pooled observational data from four prospective cohort studies, associations between hormonal contraceptive use and BC risk for unaffected female BRCA1 and BRCA2 mutation carriers were assessed using Cox regression.

Results: Of 3,882 BRCA1 and 1,509 BRCA2 mutation carriers, 53% and 71%, respectively, had ever used hormonal contraceptives for at least 1 year (median cumulative duration of use, 4.8 and 5.7 years, respectively). Overall, 488 BRCA1 and 191 BRCA2 mutation carriers developed BC during median follow-up of 5.9 and 5.6 years, respectively. Although for BRCA1 mutation carriers, neither current nor past use of hormonal contraceptives for at least 1 year was statistically significantly associated with BC risk (hazard ratio [HR], 1.40 [95% CI, 0.94 to 2.08], P = .10 for current use; 1.16 [0.80 to 1.69], P = .4, 1.40 [0.99 to 1.97], P = .05, and 1.27 [0.98 to 1.63], P = .07 for past use 1-5, 6-10, and >10 years before, respectively), ever use was associated with increased risk (HR, 1.29 [95% CI, 1.04 to 1.60], P = .02). Furthermore, BC risk increased with longer cumulative duration of use, with an estimated proportional increase in risk of 3% (1%-5%, P = .002) for each additional year of use. For BRCA2 mutation carriers, there was no evidence that current or ever use was associated with increased BC risk (HR, 0.70 [95% CI, 0.33 to 1.47], P = .3 and 1.07 [0.73 to 1.57], P = .7, respectively).

Conclusion: Hormonal contraceptives were associated with increased BC risk for BRCA1 mutation carriers, especially if used for longer durations. Decisions about their use in women with BRCA1 mutations should carefully weigh the risks and benefits for each individual.

PubMed Disclaimer

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Kelly-Anne Phillips

Research Funding: AstraZeneca (Inst)

Susan M. Domchek

Honoraria: AstraZeneca, GlaxoSmithKline

Research Funding: AstraZeneca (Inst), Clovis Oncology (Inst)

Open Payments Link: https://openpaymentsdata.cms.gov/physician/917904

James A. Chamberlain

Stock and Other Ownership Interests: ResMed, Sonic Healthcare Limited

Amber M. Aeilts

Employment: The Ohio State University

Wanda Cui

Honoraria: Eisai

Mary B. Daly

Consulting or Advisory Role: Caris Life Sciences

Travel, Accommodations, Expenses: Caris Life Sciences

Andrea F. Eisen

Other Relationship: Cancer Care Ontario

Michael L. Friedlander

Honoraria: AstraZeneca, MSD, Novartis, GlaxoSmithKline

Consulting or Advisory Role: AstraZeneca, MSD, AbbVie, Lilly, Takeda, Novartis, GlaxoSmithKline, Eisai, Incyclix Bio, Gilead Sciences

Speakers' Bureau: AstraZeneca, GlaxoSmithKline, MSD Oncology

Research Funding: BeiGene (Inst), AstraZeneca (Inst), Novartis (Inst)

Beth Y. Karlan

Consulting or Advisory Role: Foundation Medicine, Mercy Bioanalytics, InVitae, GCAR Global Coalition for Adaptive Research, OCRA Ovarian Cancer Research Alliance, Bio-Rad

Research Funding: NCI-NRG Oncology (Inst)

Patents, Royalties, Other Intellectual Property: US and EU patent on gene signature

Allison W. Kurian

Other Relationship: Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech, Myriad Genetics, Adela, Merck, Gilead Sciences

Kelly Metcalfe

Honoraria: AstraZeneca

Katherine L. Nathanson

Consulting or Advisory Role: Merck

Christian F. Singer

Honoraria: Novartis, AstraZeneca/MedImmune, Daiichi Sankyo Europe GmbH

Consulting or Advisory Role: AstraZeneca/MedImmune, Daiichi-Sankyo, Gilead Sciences, Sanofi/Aventis, Novartis

Speakers' Bureau: Novartis, AstraZeneca/MedImmune

Research Funding: Novartis, Sanofi, Myriad Genetics, Roche, AstraZeneca/MedImmune, Amgen

Travel, Accommodations, Expenses: Roche, Novartis, Gilead Sciences, Daiichi-Sankyo

Nadine Tung

Consulting or Advisory Role: AstraZeneca, GlaxoSmithKline

Research Funding: AstraZeneca (Inst)

No other potential conflicts of interest were reported.

Figures

**FIG 1.**
STROBE diagram of participant inclusion. BCFR, Breast Cancer Family Registry; RFS, Risk Factor Analysis of Hereditary Breast and Ovarian Cancer Study.

**FIG 2.**
Age at breast cancer diagnosis of 488 *BRCA1* and 191 *BRCA2* mutation carriers.

**FIG A1.**
Person-years of hormonal contraception by calendar year for 3882 *BRCA1* and 1509 *BRCA2* mutation carriers.

See this image and copyright information in PMC

References

1. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. : Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317:2402-2416, 2017 - PubMed
1. Iversen L, Sivasubramaniam S, Lee AJ, et al. : Lifetime cancer risk and combined oral contraceptives: The Royal College of General Practitioners’ oral contraception study. Am J Obstet Gynecol 216:580.e1-580.e9, 2017 - PubMed
1. Collaborative Group on Hormonal Factors in Breast Cancer : Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 347:1713-1727, 1996 - PubMed
1. Morch LS, Skovlund CW, Hannaford PC, et al. : Contemporary hormonal contraception and the risk of breast cancer. N Engl J Med 377:2228-2239, 2017 - PubMed
1. Burchardt NA, Eliassen AH, Shafrir AL, et al. : Oral contraceptive use by formulation and breast cancer risk by subtype in the Nurses’ Health study II: A prospective cohort study. Am J Obstet Gynecol 226:821.e1-821.e26, 2022 - PubMed

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Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2

Collaborators

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Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2

Authors

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Abstract

Conflict of interest statement

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