What is the most suitable hormone replacement therapy (HRT) for a 47-year-old perimenopausal woman with a family history of breast cancer, including a mother with negative BRCA (Breast Cancer Gene) and a history of breast cancer, as well as an affected aunt?

From the Guidelines

For a 47-year-old perimenopausal woman with a family history of breast cancer, the best HRT approach is to use the lowest effective dose of transdermal estradiol, such as a 0.025 mg patch, combined with micronized progesterone (100 mg daily) if she still has her uterus, while closely monitoring for any increased risk of breast cancer and cardiovascular events, as suggested by 1. Given the family history of breast cancer, including a mother with BRCA-negative breast cancer, it's crucial to approach HRT with caution. The recommendation from 1 emphasizes that hormone therapy is the most effective intervention for vasomotor symptoms but having a hormone-sensitive breast cancer is a contraindication to using systemic hormone therapy. Since the patient's family members had breast cancer but were BRCA-negative, this does not directly contraindicate HRT but warrants careful consideration and monitoring. Key points to consider include:

• Starting with the lowest effective dose of transdermal estradiol to minimize risks, as transdermal estradiol avoids first-pass liver metabolism and carries a lower risk of blood clots compared to oral formulations.
• Combining transdermal estradiol with micronized progesterone (100 mg daily) if the patient still has her uterus to prevent endometrial hyperplasia.
• Before starting HRT, undergoing genetic testing for BRCA mutations and other breast cancer-related genes, even though the mother tested negative, to fully understand the patient's risk profile.
• Ensuring the patient is up to date with mammograms and considering enhanced screening with breast MRI due to the family history of breast cancer.
• Using HRT for the shortest duration needed to manage symptoms, typically less than 5 years, with regular reassessment, as prolonged use has been associated with increased risks of breast cancer and cardiovascular events, as noted in 1.
• Considering non-hormonal alternatives like SSRIs (such as low-dose paroxetine 7.5 mg), gabapentin, or clonidine if HRT is contraindicated or if the patient prefers not to use hormonal therapies.
• Encouraging lifestyle modifications including regular exercise, maintaining a healthy weight, limiting alcohol, and techniques like cognitive behavioral therapy to help manage perimenopausal symptoms with fewer risks.

From the FDA Drug Label

The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80].

• Family History of Breast Cancer: Given the patient's family history of breast cancer, including her mother and aunt, the risk of breast cancer should be carefully considered when selecting a hormone replacement therapy (HRT) regimen.
• HRT Options: The patient is a 47-year-old perimenopausal woman, and the choice of HRT should be based on her individual risk factors and medical history.
• Estradiol Alone vs. Estradiol Plus Progestin: The WHI substudy suggests that estrogen-alone therapy may have a lower risk of breast cancer compared to estrogen plus progestin therapy 2.
• Recommendation: Based on the available data, estradiol alone may be a safer option for this patient, considering her family history of breast cancer. However, the decision should be made on a case-by-case basis, taking into account the patient's overall health status, medical history, and individual risk factors. The patient should be closely monitored for any changes in her breast health, and regular mammograms and breast examinations should be performed as recommended 2.

From the Research

HRT Options for a 47-Year-Old Perimenopausal Woman

• Considering the family history of breast cancer, it is essential to weigh the risks and benefits of Hormone Replacement Therapy (HRT) options.
• A study published in 2022 3 suggests that estrogen-only HRT may be associated with a reduced risk of breast cancer, particularly in women who have had a prior hysterectomy.
• However, for women with an intact uterus, a progestogen must be added to estrogen therapy to prevent endometrial hyperplasia and cancer, which may increase the risk of breast cancer 4.

Breast Cancer Risk and HRT

• Research indicates that combined estrogen-progestogen therapy confers a higher risk of breast cancer compared to estrogen monotherapy 4, 5, 6.
• The type of progestogen used may also impact breast cancer risk, with natural progesterone and dydrogesterone potentially associated with a lower risk compared to other progestins 4, 7.
• The mode of HRT administration, such as sequential or continuous regimens, may also influence breast cancer risk 4, 7.

Considerations for This Patient

• Given the patient's family history of breast cancer, including her mother's and aunt's history of the disease, it is crucial to carefully consider the potential risks and benefits of HRT.
• Estradiol-only therapy may be a viable option, as it has been shown to carry no significant risk of breast cancer 7.
• However, if a progestogen is necessary, the choice of progestogen and the mode of administration should be carefully selected to minimize the risk of breast cancer 4, 7.