Do Hot Flashes During Anti-Estrogen Therapy Impact Breast Cancer Prognosis?

Do Hot Flashes During Anti-Estrogen Therapy Impact Breast Cancer Prognosis?

Women smiling. Hot Flashes During Anti-Estrogen Therapy.

Understanding randomized clinical trials versus population-based observational studies

Most breast cancers are estrogen receptor-positive (ER+), approximately 70-80%. There is little doubt that HOT FLASHES are the most common adverse effect. Some hot flashes are mild, yet others can be severe enough to adversely impact the quality of life. For those unaware, hot flashes are characterized by a sudden feeling of warmth, usually most intense over the face, neck, and chest, and profuse sweating, commonly due to menopause. Unfortunately, they can also be caused by anti-estrogen therapy (AET), which can sometimes be severe enough to cause patients to prematurely stop their treatment. Most importantly, does the early cessation of AET affect breast cancer outcomes? Several studies have been carried out looking at this very question. All were within the confines of a clinical trial most of which were examining other issues. Many of the results were conflicting. In a recent article from Sweden by Zeng et. al. The authors examined in a real-world setting whether hot flashes predicted treatment discontinuation and consequently a worse breast cancer prognosis.

Randomized clinical trials versus population-based observational studies

This would be an important time to understand that there are inherent differences between randomized clinical trials and population-based observational studies. These population-based studies are called real-world results. It is important to understand that although most improvements in treatments and outcomes in the last number of decades have been identified in randomized clinical trials, patients seen in routine practice are quite different from those seen participating in trials. It should also be remembered that less than 10% of cancer patients enter trials. For instance, patients with more advanced stages and greater comorbidities as well as those from lower socioeconomic groups are generally underrepresented in randomized trials. It is possible, and at times likely, that small but significantly improved outcomes may disappear when given to a nonselective population with more comorbidities and older age groups. Whereas different outcomes in a randomized trial versus a population-based study may make one aware of potential biases present in the original randomized trial, a particular randomized trial may be statistically significant but not clinically relevant. It may at the same time support the treatment in question and potentially a new effective therapy.

A variety of databases and populations were used for this study, including the Stockholm-Gotland breast cancer registry, the national breast cancer registry, as well as the Swedish prescribed drug register (which records all dispensed prescriptions since 2005). Excluded patients (7830) included patients who had a breast cancer event of any type before the end of the first year of treatment, patients treated with chemotherapy or unknown therapy, or patients who use drugs for hot flashes within one year before initiating antiestrogen therapy. The remaining 7152 patients were in the final cohort or study group. The patients in the study group were followed from six months after beginning antiestrogen therapy until discontinued, local recurrence, distant metastases, contralateral breast cancer, death, immigration, endometrial cancer, venous thromboembolism, completion of five years of treatment, or the end of the study period, whichever came first.


Follow-up range from 3.9 to 10 years with a median follow-up of 6.8 years. Patients who began to use drugs for hot flashes shortly after initiating antiestrogen therapy had a significantly shorter disease-free survival, approximately 67% (HR equals 1.67). Though the association with disease-free survival was similar for both tamoxifen and aromatase inhibitors, disease-free survival among aromatase inhibitors did not reach statistical significance. Antiestrogen therapy was discontinued at a median time of 3.5 years with a five-year discontinuation rate of 48.9%. It is important to know that for most subgroups of patients in the study that the use of drugs for hot flashes was associated with a higher risk of antiestrogen discontinuation.

Most importantly, it was shown in this study that patients who discontinued antiestrogen therapy were more likely to have a shorter disease-free survival with a hazard ratio of 1.46 (46% reduction in disease-free survival). The researchers found that when patients began the new use of drugs for hot flashes, they were 14% more likely to discontinue their antiestrogen therapy, which potentially lead to shorter disease-free survival. As noted before clinical trials may bring bias to a study that may have different outcomes when compared to population-based studies. For instance, the Women’s Healthy Healing and Living trial observed that women reporting hot flashes were less likely to develop breast cancer recurrence, suggesting that hot flashes may in fact predict a higher success rate with antiestrogen therapy. The authors also suggested that “clinical trials may have detected low-grade hot flashes by using a patient-reported questionnaire”, whereas this study likely captured more severe hot flashes by using prescribed drugs utilized for hot flashes.

The authors stated that they also found the association much more pronounced for low-income patients. They noted that “these patients may have weak health awareness of adverse effects management and sub-optimal social or medical support, suggesting that more frequent reminders or telephone appointments might be impactful in treatment adherence”. The researchers also noted “that our findings reinforce the concept that anti-hormonal therapy-related hot flashes may lead to treatment discontinuation and thereby affect breast cancer prognosis”. They go on further to note that the “use of low-dose tamoxifen has been shown to be associated with fewer adverse effects, which could potentially be an alternative to reduce treatment discontinuation and improve breast cancer outcomes in clinical practice”.

Dr. Alan Stolier, MD, FACS, clinical breast oncologist

Dr. Alan Stolier, MD, FACS, clinical breast oncologist, shares his expert medical perspective with a series of educational and scientific articles.