Menopausal Hormone Therapy in Breast Cancer Survivors - A Review of the Current Literature

New inroads for treatment of menopausal symptoms in breast cancer survivors

The safety and efficacy of menopausal hormone therapy (MHT) have been under scrutiny since the day the Women’s Health Initiative study discontinued the estrogen/progestin treatment arm IN 2002 due to a statistically greater increase in breast cancer risk relative to the other treatment arms.

The messaging surrounding the interpretation of these results and the media frenzy that followed led to millions of women going untreated for their often debilitating symptoms. Fear of prescribing by providers and continued apprehension among symptomatic women continue to this day.

Fortunately, over the last 2 decades, a wealth of research has emerged that has more clearly defined the conditions for which MHT is effective and the parameters for patients at greater risk. Some examples of how this knowledge has evolved include:

• There is no longer a set duration of use after which MHT must be discontinued as compared to the 5-7 year recommendations issued 5-10 years ago.

• BRCA-positive women without a personal history of breast cancer do not incur any additional risk of breast cancer with MHT use compared to the BRCA-negative population.

• The severity and frequency of vasomotor symptoms (VMS) a.k.a “hot flashes” correlates with a greater risk of developing cardiovascular disease (CVD). This group may appreciate greater overall health benefits and risk reduction using MHT as compared to universal treatment of asymptomatic women for purposes of “disease prevention” or “longevity”.

The focus of this recent meta-analysis is on breast cancer survivors. According to the 2022 Menopause Society Position Statement on Hormone Therapy, systemic treatment with HT is not recommended in women with a prior history of breast cancer. However, these women have hot flashes too, and need relief.

This study is an important contribution to the literature because it defines risk categories based on tumor cell biology that can help providers and patients develop a risk/benefit analysis upon which to inform decision-making. Below is a summary and review of this study with my commentary to follow. Enjoy!

Eligibility criteria for using menopausal hormone therapy in breast cancer survivors: a safety report based on a systematic review and meta-analysis.

Coronado PJ, Gomez, A, Iglesias, E. et al. from the Women’s Health Institute Hospital Clinico San Carlos, Madrid, Spain.

Menopause: The Journal of the Menopause Society Vol 31 No. 3, 2024 pp 234-242

Goal of the study

Establish eligibility criteria for the use of MHT in breast cancer survivors

Study methods

Extensive literature search and review of MEDLINE, The Cochrane Library, and EMBASE up to June 2022. The evidence was graded according to grading quality of evidence and strength of recommendations.

Results

A total of 12 studies including 3 randomized controlled trials (RCTs), 3 prospective, and 6 retrospective studies were considered for evaluating the impact of MHT on breast cancer survivors. Below are the 3 RCTs included in this study:

• Stockholm

• Hormone Replacement Therapy After Breast Cancer - Is It Safe (HABITS)

• Livial Intervention Following Breast Cancer, Efficacy, Recurrence, and Tolerability Endpoints (LIBERATE)

BREAST CANCER RECURRENCE

When these studies were reviewed individually, there were conflicting results. The analyses that follow have strengths and limitations and should be interpreted with caution.

• The Stockholm study found no evidence of increased risk of recurrence in MHT users vs non-users/placebo at the 4 and 10-year follow-up periods.

• The HABITS study showed an increased risk of cancer recurrence in MHT users compared to non-users/placebo. It is worth noting that the group using MHT had a greater percentage (62.5%) of hormone receptor (HR)-positive tumors compared to the non-user group where 54.5% had a history of HR-positive tumors. The conclusion from this study is that the recurrence rate is greater in MHT users with HR-positive tumors and in those women taking Tamoxifen.

• When the results of the Stockholm study and the HABITS study were combined, there was no increased risk of recurrence after the 4-year follow-up and when incorporating the 10-year follow-up from the Stockholm study.

• The LIBERATE trial found an increased risk of cancer recurrence in women with a history of HR-positive tumors, however, there was no increased risk in women with a history of HR-negative tumors treated who were treated with tibolone.

It is important to note that the level of evidence of these trials is considered “moderate” because of the premature termination of these studies due to recruitment challenges and small sample sizes. These factors are important limitations to consider when applying this data in clinical practice.

• Incidentally, a combined analysis at the 10-year follow-up of the Stockholm, HABITS, and LIBERATE trials showed an increased risk of NEW breast cancer events.

• Whether only considering the RCT results or when all study types were considered (RCTs, retrospective, and prospective studies) no elevated risk of recurrence was observed.

  • However, the authors note that cohort studies (retrospective and prospective studies) need to be interpreted with extreme caution due to the high risk of confounding factors and selection bias that is inherent to these types of non-randomized studies.

ALL-CAUSE AND BREAST CANCER-RELATED MORTALITY (DEATH)

• A combined analysis of data from the Stockholm and HABITS trials showed no difference in overall mortality between MHT users and non-users. This finding was also true when the results of the RCTs and the prospective studies were pooled. Again, the authors recommend caution in interpretation due to the limitations of these studies noted above.

• Interestingly, a pooled analysis of 3 retrospective cohort studies showed a significant REDUCTION in breast cancer mortality rate in MHT users compared to non-users. This finding was maintained when data from the Stockholm and HABITS trials were added to the analysis.

• When all study types were pooled, there was no statistical difference in all-cause or breast cancer-related mortality rates in MHT users versus non-users.

Authors’ Discussion and Conclusions

The use of MHT in breast cancer survivors should not be considered as an absolute contraindication, particularly in cases of HR-negative tumors.

The results of these studies and this analysis need to be interpreted with caution due to a high degree of “heterogeneity” (variability) in MHT formulations, use of adjuvant therapies such as tamoxifen and aromatase inhibitors, differences in lymph node status, and varying patient characteristics among the studies.

The hormonal status of the tumor may influence breast cancer recurrence and is an important factor when considering the use of MHT. According to this analysis, HR-negative tumors pose less of a risk of recurrence. For women with HR-positive tumors, an excess risk of recurrence was noted. However, the pooled analysis did not show a significant difference in mortality (death) rates in HR-negative or HR-positive populations. Further analysis of the cohort studies showed some suggestion of a reduction in mortality rate in MHT users.

The data speaking to mortality (death) rate in MHT vs non-users should be interpreted with caution because this was a secondary endpoint of the study and because of the inherent biases and limitations of the studies analyzed.

In my humble opinion…..

This study is an invaluable contribution to the literature and lays the groundwork for continued study in breast cancer survivors. Here are my big takeaways:

• A personal history of breast cancer should not be considered an absolute contraindication to MHT use.

• HR status of the breast tumor matters with respect to recurrence rate.

• Future study would benefit from a focus on recurrence versus mortality rates, HT formulations with particular attention to progestin used, and the impact of HT use on women taking ancillary treatments such as aromatase inhibitors and Tamoxifen.

The use of ancillary treatments for breast cancer is also worth mentioning here. Aromatase inhibitors and tamoxifen have been used for decades as “maintenance” treatments that effectively reduce the level of systemic estrogen exposure to minimize stimulation or “activation” of estrogen-responsive cancer cells that may be present at subclinical levels in the tissues or circulation. More recently, a new class of pharmacotherapy has emerged called the tissue-specific estrogen receptor complex (TSEC). Bazedoxifene (a “SERM” or selective estrogen receptor modulator) combined with estrogens has emerged as a potential therapy that could be effective for the treatment of menopausal symptoms (hot flashes and bone loss) by selectively targeting some estrogen receptors while potentially providing a protective effect in other tissues such as the breast. There is definitely more to come on this front so stay tuned!

The last point that I would like to make is regarding all-cause mortality. We know from decades of research that when MHT is used in symptomatic women < age 60 and <10 years from the onset of menopause, there is a reduction in all-cause mortality. This reduction in mortality seen with MHT use needs to be entered into the equation because it is possible that the benefits of MHT use for mortality risk reduction may outweigh the risks of death that could result from cancer recurrence.

So, to only consider breast cancer recurrence rate as the determinant of whether or not MHT is safe is short-sighted; because at the end of the day, it’s all about living!

I am so encouraged by the direction of this research! My hope is that this work continues so that all women have options for managing their symptoms in this stage of life.