Posted on January 10, 2024

By Krystal Redman (KR), DrPH, MHA, (they/she), Executive Director

Understanding the Connections Between Hormone Replacement Therapy and Breast Cancer Risk

In the session titled Prevention, Early Detection, and Interception, Carol J. Fabian, MD, professor and director of Breast Cancer Prevention Research Center at the University of Kansas Cancer Center, provided a presentation titled Hormone Replacement and Alternatives for Relief of Vasomotor Symptoms in Women at Increased Risk for Breast Cancer.

Vasomotor symptoms (VMS) refer to a group of physiological and subjective symptoms that are often associated with changes in the function of blood vessels, particularly with regard to the regulation of blood flow. These symptoms are commonly experienced during hormonal fluctuations, such as those occurring during menopause. The most well-known VMS are hot flashes and night sweats (Arch Womens Ment Health, 2007).

As presented by Dr. Fabian, 70% of women will experience VMS sufficient to impact their quality of life during the transition to menopause and early menopause. She also noted that moderate-to-severe VMS are more likely in women with any of the following characteristics:

  • Abrupt early menopause (e.g., due to oophorectomy, chemotherapy)
  • BMI ≥ 30 kg/m2
  • High baseline anxiety
  • Smoking ≥40 packs per year
  • African American
  • Polymorphisms of Neurokinin-3 Receptor (NK3R) 

The symptoms are believed to stem from imbalances in neurotransmitters, triggered by a decrease in ovarian hormones and an increase in the secretion of gonadotropins. For example, insufficient estrogen levels can lead to a decrease in serotonin, potentially contributing to an increased risk of hot flashes and disruptions in sleep patterns. Affected individuals experience VMS until acclimation to persistently low estrogen levels occurs, which takes about 7 years on average. Estrogen (with or without progestin) replacement therapy is associated with the greatest likelihood of VMS relief as it reduces gonadotropin and NK3R signaling and increases serotonin levels. 

Dr. Fabian emphasized that there remains a lack of clarity among healthcare providers and patients regarding the heightened risk of breast cancer and thromboembolic events. This uncertainty is influenced by factors such as the specific type of agent used, the method of delivery, age, duration of treatment, and the presence of obesity (as defined by the National Institutes of Health).

Dr. Fabian discussed an important clinical study, conducted in the Women’s Health Initiative (WHI), which she described as the primary source of placebo-controlled randomized clinical trial data on hormone replacement therapy (HRT) involving estrogen or estrogen combined with progestin. In this study, the WHI focused on women aged 50–79 years. Participants received oral conjugated estrogen at a dose of 0.625 mg if they were without a uterus. For people with a uterus, medroxyprogesterone acetate was added to conjugated estrogen to prevent endometrial hyperplasia and cancer. The median age upon entering the WHI trial was 63 years, with a considerable proportion of women having prior hormone use. Valuable insights into risk assessments for women initiating hormone therapy at a clinically relevant age (45–55 years) and employing hormonal preparations other than oral conjugated estrogen and medroxyprogesterone acetate have been provided by extensive longitudinal cohort studies.

Findings from the study showed that a duration of 5–7 years of estrogen-only HRT is generally associated with minimal increase in breast cancer risk. Conversely, combined estrogen and progestin replacement in women aged over 50 years leads to an approximately 30% relative increase in breast cancer risk when used for up to 5 years and a doubling of breast cancer risk was associated with a 10-year treatment duration. Bioidentical hormones, often compounded as oral troches containing estradiol, progesterone, and testosterone, are also linked to an elevated risk of breast cancer. Notably, vaginal hormones have not been found to increase the risk of breast cancer. The heightened risk of thromboembolism is primarily observed in women over 50 years using oral rather than transdermal preparations. Additionally, the increased risk for stroke and dementia, as noted in the WHI, is associated with oral hormone use in women over 65 years. Importantly, the WHI did not find an increase in cancer-related cardiovascular disease, or overall mortality with the use of estrogen or estrogen and progestin.

For high-risk peri- and post-menopausal women who would like to reduce or alleviate their vasomotor symptoms with no increase in risk for breast cancer, Dr. Fabian recommended several options: 

  1. The tissue-selective estrogen complex bazedoxifene, in combination with conjugated estrogen
  2. Non-hormonal alternatives, such as NK3R antagonists (e.g., fezolinetant)
  3. Other non-hormonal options like gabapentin, selective serotonin reuptake inhibitors (SSRIs), and serotonin and norepinephrine uptake inhibitors (SNRIs)

Bazedoxifene and conjugated estrogen, along with fezolinetant, have been reported to alleviate hot flashes in 70% or more individuals, while the effectiveness of paroxetine (an SSRI) is reported to be 50%. All three drugs have received Food and Drug Administration (FDA) approval for reducing VMS. The combination of bazedoxifene and conjugated estrogen is also under investigation for breast cancer risk reduction. These agents differ in terms of side effects, with an increased risk of blood clots associated with bazedoxifene and conjugated estrogen, an increased risk of nausea, diarrhea, and liver dysfunction for fezolinetant, and side effects like drowsiness and dry mouth for SSRIs.

Drug costs may also dramatically affect insurance coverage and patient uptake of a particular strategy. It comes as no surprise for our BCAction community and patient advocates that the costs of these drugs are financially challenging and can result in medications being inaccessible to many individuals who fall deeper within the societal margins and are under-resourced. To provide some perspective, the combined estradiol and levonorgestrel transdermal patches cost about $240, oral conjugated estrogen $200, oral conjugated estrogen + medoxyprogesterone acetate $240, and bazedoxifene and conjugated estrogen cost $200. On the other hand, non-hormonal therapies such as gabapentin ($11) and paroxetine ($30) cost much less, with the exception of fezolinetant, which costs $550. All of the above costs are per 30-day supply. 

Overall, while the data is interesting, I’d say that the above findings to us as patient advocates is fairly surprising, considering that the combination of estrogen and progestin is most commonly used to treat vasomotor symptoms. So, through a patient advocate lens, there is some concern as to whether our providers are discussing the significant increase in risk for breast cancer associated with hormone replacement therapy. 

The combination of estrogen and progestin is a common form of HRT used to alleviate VMS, particularly hot flashes and night sweats, that are associated with hormonal fluctuations, such as those occurring during menopause. 

Here are two key considerations regarding HRT and breast cancer risk:

Estrogen and Progestin Combination

HRT that includes both estrogen and progestin has been associated with a slightly increased risk of breast cancer in postmenopausal individuals. This risk appears to be higher with combined HRT than with estrogen alone.

Duration of Use

The risk of breast cancer associated with HRT may increase with prolonged use. Short-term use for managing menopausal symptoms may have different risk profiles than long-term use.

Besides the use of HRT for treating VMS, I also think about communities that are even more vulnerable and reside deeper within those societal margins, specifically gender-expansive and trans folks who are currently receiving HRT. Has the increased risk of breast cancer been discussed with them? 

In the context of trans and gender-expansive folks, HRT is also known as hormone-affirming therapy, a medical intervention that involves the administration of hormones to induce physical changes that align with an individual’s gender identity. The fact that this study, as well as many others, solely focuses on cis-gendered women is concerning. Certainly, there needs to be a deeper discussion on the effects of HRT on trans folks with regard to their increased risk of breast and/or chest cancer.

The relationship between HRT and cancer risk is complex and varies based on several factors, including the type of hormone therapy, the duration of use, the specific hormones involved, and individual health characteristics. It’s important for individuals considering or undergoing HRT to have a thorough discussion with their healthcare providers about the potential risks and benefits. It is also equally important for said providers to be transparent around the increased risk of breast cancer to the patient.