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Hormonal Management in Hereditary Breast and Ovarian Cancer Patients

Yael Simons, MD�Clinical Assistant Professor, Breast Medical Oncology

High Risk Cancer Genetics Program

NYU Grossman School of Medicine

Perlmutter Cancer Center

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Disclosures

  • I have no conflicts of interest to disclose

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28-year-old female with a germline BRCA2 pathogenic variant presents for consultation. She has a history of menorrhagia and painful periods for which she has been taking oral birth control pills for the past three years.

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She asks you whether it is safe to continue or if there are any other options that may be better suited for her.

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How do you counsel her?

Case #1

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Hormonal Contraception and Breast Cancer Risk in the General Population

What is hormonal contraception?

    • Pills, Patch, Ring, Progestin IUD, Implant, Injection

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On average, people who use hormonal birth control for five years have a slightly higher risk of breast cancer—about 20% higher than people who don’t use it.

    • No large differences between types
    • Higher risk if on for longer
    • Risk decreases after 5–10 years
    • Unclear if young age of onset increases risk

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    • Large systematic review in 2020 (10 studies)
    • Meta-analysis of observational studies in 2022 (12 studies)
    • Systematic review and meta-analysis in 2022 (11 studies)

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Results are mixed:

    • Trend toward increased risk; similar to general population increase of 20%
    • Risk most associated with early age of diagnosis
    • Many excluded patients with history of risk-reducing mastectomy
    • May be impacted by starting at younger age
    • No distinction between BRCA1 and BRCA2
    • Formulations of hormonal contraception have changed over time

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Hormonal Contraception and Breast Cancer Risk in the BRCA1 and BRCA2 Population

Huber D, et al. Arch Gynecol Obstet. 2020 Apr;301(4):875-884.

Park J, et al. Carcinogenesis. 2022 Apr 25;43(3):231-242.

Van Bommel MHD, et al. Hum Reprod Update. 2023 Mar 1;29(2):197-217.

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Observational study using pooled prospective cohort data:

    • Women from Australia, New Zealand, Europe, Canada, and the United States
    • Enrolled in cohort between December 1991 and August 2019
    • No personal history of breast cancer or risk-reducing mastectomy

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BRCA1:

    • Elevated risk for both current and past hormonal contraception use compared to never use (HR 1.29), but not statistically significant
    • Younger age at first use not associated with breast cancer risk
    • Cumulative duration of use was associated with breast cancer risk

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BRCA2:

    • Current and past use was not associated with increased breast cancer risk

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Results from this study suggest hormonal contraception increases risk of breast cancer for BRCA1 mutation carriers but not BRCA2 mutation carriers

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Hormonal Contraception and Breast Cancer Risk in the BRCA1 and BRCA2 Population

Phillips KA, et al. J Clin Oncol. 2025 Feb;43(4):422-431.

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    • Combined hormonal birth control pills lowers risk for ovarian cancer (about 33%)
    • With >10 years of use, can see 50% risk reduction
    • Effect lasts nearly 30 years
    • Unclear benefit for non-OCP and progestin-only options (closer to 25–30% for implant, injection, IUD)
    • Thought to be due to ovulation suppression

Hormonal Contraception and Ovarian Cancer Risk in the General Population

Beral V, et al. Lancet. 2008 Jan 26;371(9609):303-14.

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Meta-analysis in 2023 that includes:

    • 10 studies, including approximately 21,000 carriers
    • Showed 48% reduction in ovarian cancer risk
    • Longer duration of use associated with greater benefit
    • Risk-reduction effect lessens over time
    • Data only included OCPs; less known about implant, injection, progestin-based IUD

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Hormonal Contraception and Ovarian Cancer Risk in the BRCA1 and BRCA2 Population

Van Bommel MHD, et al. Hum Reprod Update. 2023 Mar 1;29(2):197-217.

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35-year-old female with a germline BRCA1 pathogenic variant is interested in pursuing a risk-reducing bilateral salpingo-oophorectomy (RR BSO) and wants to understand her options for post-operative hormone replacement therapy.

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How do you counsel her?

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Case #2

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No effective ovarian cancer screening method that has been shown to reduce mortality or detect early-stage disease. Oophorectomy reduces risk of death in BRCA carriers by 64%.

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BRCA1:

      • RR BSO between ages 35-40

BRCA2:

      • RR BSO between ages 40-45

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Need to mitigate short- and long-term adverse effects of early menopause and improve quality of life

      • WISP and SOROCk studies investigating role of delayed oophorectomy

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Ovarian Cancer Risk Management in the BRCA1 and BRCA2 Patient Population

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    • Premenopausal RR BSO is associated with increased mortality risk
    • Risks of early menopause:
        • Nurses Health Study: risk of cardiovascular disease
        • Women’s Health Initiative: increased risk all-cause mortality
        • Increased risk of osteoporosis
        • Possible increased risk of cognitive dysfunction
    • Hormone replacement therapy decreases mortality, osteoporosis, cardiovascular disease
    • Not associated with increased breast cancer risk

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Premenopausal Hormone Replacement Therapy in the General Population

Hassan H, et al. Am J Obstet Gynecol. 2024;230(1):44–57.

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Premenopausal Hormone Replacement Therapy in BRCA1 and BRCA2 Population

Kotsopoulos J, et al. J Natl Cancer Inst. 2025 Dec 17.

Presented at San Antonio Breast Cancer Symposium in 2025

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Premenopausal Hormone Replacement Therapy in BRCA1 and BRCA2 Population

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Kotsopoulos J, et al. J Natl Cancer Inst. 2025 Dec 17.

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Premenopausal Hormone Replacement Therapy in BRCA1 and BRCA2 Population

Kotsopoulos J, et al. J Natl Cancer Inst. 2025 Dec 17.

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Premenopausal Hormone Replacement Therapy in BRCA1 and BRCA2 Population

Kotsopoulos J, et al. J Natl Cancer Inst. 2025 Dec 17.

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What should she start?

    • Around two weeks after surgery: medium to higher dose of estrogen
    • Can consider hysterectomy, if not micronized progestin or progestin IUD

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When should she stop?

    • Consider tapering at age 45

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Back to Our Patient in Case #2

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50-year-old female with a germline BRCA2 pathogenic variant presents to discuss her menopausal hormone therapy (MHT) regimen. She had a RR BSO at age 40 and has been on MHT since then. She is feeling great and wonders about risks associated with continued use.

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How do you counsel her?

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Case #3

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Postmenopausal Hormone Replacement Therapy and Breast Cancer Risk in the General Population

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Women’s Health Initiative:

    • 27,347 women age 50-79 randomized to E+P (16,608) vs. placebo OR E only (10,739) vs. placebo
    • Only oral conjugated equine estrogen and medroxyprogesterone studied (no transdermal or bioidentical)
    • Average age was 63
    • Risk based on timing of initiation, duration of therapy
    • E+P use for five years associated with increased breast cancer risk (20%)
    • No risk for estrogen alone
    • Effect may not be shown for micronized progesterone
    • Lower risk for IUD
    • Primarily a short-acting effect

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Postmenopausal Hormone Replacement Therapy and Breast Cancer Risk in the General Population

Manson JE, et al. JAMA. 2024;331(20):1748–1760.

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    • Minimal data
    • Possibly an increased risk similar to the general population (20%)
    • Must consider progestin type
    • Must consider estrogen dose

Postmenopausal Hormone Replacement Therapy and Breast Cancer Risk in the BRCA1 and BRCA2 Population

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Localized Hormone Replacement Therapy: Vaginal Estrogen

Genitourinary Syndrome of Menopause:

    • In two prospective cohort studies, meta-analyses, and systematic review, low dose vaginal estrogen was not associated with increased risk of breast cancer
    • Systemically absorbed in dose-dependent manner, with serum estrogen levels within postmenopausal range
    • Users had a significant reduction in all-cause mortality

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Santos GML, et al. Rev Bras Ginecol Obstet. 2025 Jul 15;47.

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The 50-year-old female with a BRCA2 pathogenic variant has tapered off her menopausal hormone therapy and is curious if there is anything else she can take that will help reduce her breast cancer risk.

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How do you counsel her?

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Case #3 Continued

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    • Can be used in women considered high risk based on breast lesions or risk models
    • Approximately 50% breast cancer risk reduction
    • Tamoxifen: NSABP-P1, IBIS-I
        • Uterine cancer risk, hot flashes, venous thromboembolism
    • Raloxifene: STAR
        • Venous thromboembolism
        • Slightly less efficacious (33% risk reduction)
    • Aromatase inhibitors: MAP.3, IBIS-II
        • No risk for uterine cancer or venous thromboembolism
        • Arthralgias, osteoporosis

Endocrine Therapy and Breast Cancer Risk in the General Population

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    • NSABP-P1 Tamoxifen for prevention study: 8 BRCA1 patients, 11 BRCA2 patients
        • A 62% risk reduction in BRCA2 carriers, but no benefit in BRCA1 carriers

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    • Meta-analysis in 2025 including 9 studies and approximately 13,000 women
        • Tamoxifen and Raloxifene decreased breast cancer risk compared to controls
        • Efficacy was similar for both BRCA1 and BRCA2 carriers

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    • Prospective cohort study in 2023 of approximately 4,500 women
        • After mean follow up of 6.8 years, Tamoxifen and Raloxifene associated with trend toward reduced breast cancer incidence
        • Effect was not statistically significant

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Endocrine Therapy and Breast Cancer Risk in the BRCA1 and BRCA2 Population

King MC, et al. JAMA. 2001 Nov 14;286(18):2251-6.

Alwashmi ASS, et al. Sci Rep. 2025 Feb 25;15(1):6796.

Kotsopoulos J, et al. Breast Cancer Res Treat. 2023 Sep;201(2):257-264.

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Duavee (conjugated estrogen/bazedoxifene):

    • Conjugated estrogen acts as an agonist in the hypothalamus and bone
    • Bazedoxifene is a selective estrogen receptor modulator (SERM) that acts as estrogen antagonist in endometrium and breast tissue
    • FDA approved in postmenopausal women for vasomotor symptoms and prevention of osteoporosis
    • Progestin free formulation may offer theoretical advantages for BRCA carriers
    • Preclinical studies have shown reduction in proliferation of cells in the milk ducts and increased expression of markers in surrounding breast tissue that may be protective against cancer

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Endocrine Therapy and Breast Cancer Risk in the BRCA1 and BRCA2 Population

Fabian CJ, et al. Cancer Prev Res. 2019 Oct;12(10):711–720.

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    • 117 patients enrolled:
        • 59 received Duavee
        • 58 received Placebo
    • Duavee significantly reduced Ki-67 (marker of cell growth/proliferation)
    • Quality of life scores did not differ, but was reduction in hot flashes
    • No serious treatment related side effects

The Promise Study: a presurgical randomized clinical trial of Duavee vs placebo in postmenopausal women with DCIS

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Kotsopoulos J, et al. J Natl Cancer Inst. 2025 Dec 17.

Presented at San Antonio Breast Cancer Symposium in 2025

Endocrine Therapy and Breast Cancer Risk in the BRCA1 and BRCA2 Population

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THANK YOU