Endokrine Interventionen bei Trägerinnen einer pathogenen Variante in den Genen BRCA1 oder BRCA2

In diesem Artikel stellt die Arbeitsgruppe „Hormone“ des „Deutschen Konsortiums für Familiären Brust- und Eierstockkrebs“ relevante Fragestellungen, Statements und Empfehlungen zu oraler Kontrazeption, ovarieller Stimulation im Rahmen einer Kinderwunschbehandlung, Hormonsubstitution nach risikoreduzierender Salpingoophorektomie (RRSO) und Behandlung von Symptomen in der Peri- und Postmenopause vor.

Kernaussagen

• Orale Kontrazeptiva sollen bei Trägerinnen einer pV in den Genen BRCA1 oder BRCA2 nicht zur Reduktion des Ovarialkarzinomrisikos eingesetzt werden.

• Aufgrund der möglichen Erhöhung des Mammakarzinomrisikos nach Anwendung oraler Kontrazeptiva sollen diese bei Trägerinnen einer pV in den Genen BRCA1 oder BRCA2 unter Berücksichtigung des Alters und nur nach sorgfältiger Abwägung eingesetzt werden.

• Eine ovarielle Stimulationstherapie im Rahmen einer Fertilitätsbehandlung bei Trägerinnen einer pV in den Genen BRCA1 oder BRCA2 kann durchgeführt werden. Über die eingeschränkte Datenlage zur onkologischen Sicherheit soll aufgeklärt werden.

• Prämenopausalen Trägerinnen einer pV in den Genen BRCA1 oder BRCA2 sollte nach RRSO eine Substitution von Östrogenen ggf. in Kombination mit Gestagenen zur Prävention negativer Folgen des Östrogenmangels bis zum Erreichen des natürlichen Menopausealters angeboten werden.

• Bei Trägerinnen einer pV in den Genen BRCA1 oder BRCA2 ohne RRSO kann bei ausgeprägten klimakterischen Beschwerden nach Versagen nicht-hormoneller Therapiemöglichkeiten eine HRT erwogen werden. Eine adäquate Aufklärung über die schwache Evidenz und mögliche Erhöhung des Karzinomrisikos muss erfolgen.

Schlüsselwörter

BRCA - orale Kontrazeption - Hormone - Mammakarzinom - Ovarialkarzinom

Publication History

Article published online:
02 October 2025

• Literatur

• 1 Ortmann O, Schüler-Toprak S, Kast K. The risk of endocrine interventions in carriers of a genetic predisposition for breast and gynecologic cancers: recommendations of the German Consortium for Hereditary Breast and Ovarian Cancer. J Cancer Res Clin Oncol 2024; 150: 417
• 2 AWMF. S3-Guideline Diagnosis, Treatment and Follow-up of malignant Ovarian Tumors: AWMF-Registrynumber: 032–035OL; Version 6.0. 2024 Accessed March 16, 2025 at: https://www.leitlinienprogramm-onkologie.de/fileadmin/user_upload/Downloads/Leitlinien/Ovarialkarzinom/Version_6/LL_Ovarialkarzinom_Langversion_6.0.pdf
• 3 Beral V, Doll R, Hermon C. et al. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 2008; 371: 303-314
• 4 Soini T, Hurskainen R, Grénman S. et al. Impact of levonorgestrel-releasing intrauterine system use on the cancer risk of the ovary and fallopian tube. Acta Oncol 2016; 55: 1281-1284
• 5 van den Brandt PA, Goldbohm RA. 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 1996; 347: 1713-1727
• 6 Cibula D, Gompel A, Mueck AO. et al. Hormonal contraception and risk of cancer. Hum Reprod Update 2010; 16: 631-650
• 7 Fitzpatrick D, Pirie K, Reeves G. et al. Combined and progestagen-only hormonal contraceptives and breast cancer risk: A UK nested case-control study and meta-analysis. PLoS Med 2023; 20: e1004188
• 8 Mørch LS, Skovlund CW, Hannaford PC. et al. Contemporary Hormonal Contraception and the Risk of Breast Cancer. N Engl J Med 2017; 377: 2228-2239
• 9 Huber D, Seitz S, Kast K. et al. Use of oral contraceptives in BRCA mutation carriers and risk for ovarian and breast cancer: a systematic review. Arch Gynecol Obstet 2020; 301: 875-884
• 10 Schrijver LH, Antoniou AC, Olsson H. et al. Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study. Am J Obstet Gynecol 2021; 225: 51.e1-51.e17
• 11 Phillips K-A, Kotsopoulos J, Domchek SM. et al. Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2. J Clin Oncol 2025; 43: 422-431
• 12 Schrijver LH, Mooij TM, Pijpe A. et al. Oral Contraceptive Use in BRCA1 and BRCA2 Mutation Carriers: Absolute Cancer Risks and Benefits. J Natl Cancer Inst 2022; 114: 540-552
• 13 Jensen A, Sharif H, Frederiksen K, Kjaer SK. Use of fertility drugs and risk of ovarian cancer: Danish Population Based Cohort Study. BMJ 2009; 338: b249
• 14 Siristatidis C, Sergentanis TN, Kanavidis P. et al. Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer–a systematic review and meta-analysis. Hum Reprod Update 2013; 19: 105-123
• 15 Kessous R, Davidson E, Meirovitz M. et al. The risk of female malignancies after fertility treatments: a cohort study with 25-year follow-up. J Cancer Res Clin Oncol 2016; 142: 287-293
• 16 Sergentanis TN, Diamantaras A-A, Perlepe C. et al. IVF and breast cancer: a systematic review and meta-analysis. Hum Reprod Update 2014; 20: 106-123
• 17 van den Belt-Dusebout AW, Spaan M, Lambalk CB. et al. Ovarian Stimulation for In Vitro Fertilization and Long-term Risk of Breast Cancer. JAMA 2016; 316: 300-312
• 18 Barcroft JF, Galazis N, Jones BP. et al. Fertility treatment and cancers-the eternal conundrum: a systematic review and meta-analysis. Hum Reprod 2021; 36: 1093-1107
• 19 Huber D, Seitz S, Kast K. et al. Use of fertility treatments in BRCA1/2 mutation carriers and risk for ovarian and breast cancer: a systematic review. Arch Gynecol Obstet 2020; 302: 715-720
• 20 Perri T, Lifshitz D, Sadetzki S. et al. Fertility treatments and invasive epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers. Fertil Steril 2015; 103: 1305-1312
• 21 Gronwald J, Glass K, Rosen B. et al. Treatment of infertility does not increase the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation. Fertil Steril 2016; 105: 781-785
• 22 Kotsopoulos J, Librach CL, Lubinski J. et al. Infertility, treatment of infertility, and the risk of breast cancer among women with BRCA1 and BRCA2 mutations: a case-control study. Cancer Causes Control 2008; 19: 1111-1119
• 23 Perri T, Naor-Revel S, Eliassi-Revivo P. et al. Fertility treatments and breast cancer risk in Jewish Israeli BRCA mutation carriers. Fertil Steril 2021; 116: 538-545
• 24 Liu X, Yue J, Pervaiz R. et al. Association between fertility treatments and breast cancer risk in women with a family history or BRCA mutations: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2022; 13: 986477
• 25 Faubion SS, Kuhle CL, Shuster LT, Rocca WA. Long-term health consequences of premature or early menopause and considerations for management. Climacteric 2015; 18: 483-491
• 26 Georgakis MK, Beskou-Kontou T, Theodoridis I. et al. Surgical menopause in association with cognitive function and risk of dementia: A systematic review and meta-analysis. Psychoneuroendocrinology 2019; 106: 9-19
• 27 Parker WH, Broder MS, Chang E. et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study. Obstet Gynecol 2009; 113: 1027-1037
• 28 Rocca WA, Grossardt BR, de Andrade M. et al. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol 2006; 7: 821-828
• 29 Parker WH, Feskanich D, Broder MS. et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the nurses’ health study. Obstet Gynecol 2013; 121: 709-716
• 30 Liu J, Jin X, Liu W. et al. The risk of long-term cardiometabolic disease in women with premature or early menopause: A systematic review and meta-analysis. Front Cardiovasc Med 2023; 10: 1131251
• 31 van der Klift M, de Laet CEDH, McCloskey EV. et al. Risk factors for incident vertebral fractures in men and women: the Rotterdam Study. J Bone Miner Res 2004; 19: 1172-1180
• 32 Vega EM, Egea MA, Mautalen CA. Influence of the menopausal age on the severity of osteoporosis in women with vertebral fractures. Maturitas 1994; 19: 117-124
• 33 Vermeulen RFM, van Beurden M, Korse CM. et al. Impact of risk-reducing salpingo-oophorectomy in premenopausal women. Climacteric 2017; 20: 212-221
• 34 Gaba F, Manchanda R. Systematic review of acceptability, cardiovascular, neurological, bone health and HRT outcomes following risk reducing surgery in BRCA carriers. Best Pract Res Clin Obstet Gynaecol 2020; 65: 46-65
• 35 Challberg J, Ashcroft L, Lalloo F. et al. Menopausal symptoms and bone health in women undertaking risk reducing bilateral salpingo-oophorectomy: significant bone health issues in those not taking HRT. Br J Cancer 2011; 105: 22-27
• 36 AWMF. S3-Guideline Peri- and Postmenopause – Diagnosis and Interventions: Guideline of the German Society of Gynecology and Obstetrics (S-3 Level, AWMF Registry No. 015–062). 2018 Accessed November 27, 2021 at: https://www.awmf.org/leitlinien/detail/ll/015-062.html
• 37 Huber D, Seitz S, Kast K. et al. Hormone replacement therapy in BRCA mutation carriers and risk of ovarian, endometrial, and breast cancer: a systematic review. J Cancer Res Clin Oncol 2021; 147: 2035-2045
• 38 Rebbeck TR, Friebel T, Wagner T. et al. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2005; 23: 7804-7810
• 39 Michaelson-Cohen R, Gabizon-Peretz S, Armon S. et al. Breast cancer risk and hormone replacement therapy among BRCA carriers after risk-reducing salpingo-oophorectomy. Eur J Cancer 2021; 148: 95-102
• 40 Dominguez-Valentin M, Sampson JR, Seppälä TT. et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 2020; 22: 15-25
• 41 Prentice RL, Manson JE, Langer RD. et al. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 2009; 170: 12-23
• 42 Manson JE, Chlebowski RT, Stefanick ML. et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013; 310: 1353-1368
• 43 Prentice RL, Aragaki AK, Chlebowski RT. et al. Randomized Trial Evaluation of the Benefits and Risks of Menopausal Hormone Therapy Among Women 50–59 Years of Age. Am J Epidemiol 2021; 190: 365-375
• 44 Chlebowski RT, Anderson GL, Aragaki AK. et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials. JAMA 2020; 324: 369-380
• 45 Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019; 394: 1159-1168
• 46 Anderson GL, Limacher M, Assaf AR. et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291: 1701-1712
• 47 Cherry N, Gilmour K, Hannaford P. et al. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 2002; 360: 2001-2008
• 48 Hodis HN, Mack WJ, Lobo RA. et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001; 135: 939-953
• 49 Viscoli CM, Brass LM, Kernan WN. et al. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345: 1243-1249
• 50 Beral V, Gaitskell K, Hermon C. et al. Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. Lancet 2015; 385: 1835-1842
• 51 Tempfer CB, Hilal Z, Kern P. et al. Menopausal Hormone Therapy and Risk of Endometrial Cancer: A Systematic Review. Cancers (Basel) 2020; 12: 2195
• 52 Kotsopoulos J, Huzarski T, Gronwald J. et al. Hormone replacement therapy after menopause and risk of breast cancer in BRCA1 mutation carriers: a case-control study. Breast Cancer Res Treat 2016; 155: 365-373
• 53 Kotsopoulos J, Lubinski J, Neuhausen SL. et al. Hormone replacement therapy and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Gynecol Oncol 2006; 100: 83-88
• 54 Dominick S, Hickey M, Chin J, Su HI. Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen. Cochrane Database Syst Rev 2015; (12) CD007245
• 55 AWMF. S3-Guideline Hormonal Contraception: AWMF-Registrynumber 015/015, Version 1.2. 2020 Accessed May 03, 2025 at: https://register.awmf.org/assets/guidelines/015-015l_S3_Hormonelle_Empfaengnisverhuetung_2020-09.pdf
• 56 AWMF. S3-Guideline Screening, Diagnosis, Treatment and Follow-up of Breast Cancer: AWMF-Registrynumber: 032-045, long version, Version 4.4. 2021 Accessed March 26, 2025 at: https://register.awmf.org/assets/guidelines/032-045OLl_S3_Mammakarzinom_2021-07.pdf
• 57 Kim J, Turan V, Oktay K. Long-Term Safety of Letrozole and Gonadotropin Stimulation for Fertility Preservation in Women With Breast Cancer. J Clin Endocrinol Metab 2016; 101: 1364-1371
• 58 AWMF. S3-Guideline Endometrial Cancer: AWMF-Registrynumber 032/034-OL, long version 2.0. 2022 Accessed May 03, 2025 at: https://www.leitlinienprogramm-onkologie.de/fileadmin/user_upload/Downloads/Leitlinien/Endometriumkarzinom/Version_2/LL_Endometriumkarzinom_Langversion_2.0.pdf