What Systemic Hormone Therapy Black Box Removal Means for Breast Cancer Survivors

On November 10, 2025, the US Department of Health and Human Services announced that the US Food and Drug Administration would begin removal of black box warnings for menopausal hormone therapy (MHT). This pivot follows a significant period of trepidation toward MHT after the Women’s Health Initiative findings that demonstrated increased breast cancer risk (6 additional breast cancer cases annually per 10 000 person-years for ages 50–59 years)¹ with combined conjugated equine estrogen and medroxyprogesterone acetate. (Although the term MHT is often broadly used, the focus of this article is on systemic hormone therapy [combined estrogen plus progesterone and estrogen alone] as opposed to localized hormone therapy [specifically vaginal estrogen].)Warnings persisted even when studies published since the early Women’s Health Initiative publications demonstrated discrepancies in risk based on factors such as combined estrogen plus progesterone vs estrogen alone (where estrogen alone did not increase breast cancer risk, with 5 fewer breast cancers per 10 000 person-years for ages 50–59 years),¹ formulation (medroxyprogesterone acetate carrying higher risk than micronized progesterone²), and age at MHT initiation (with initiation before age 60 years or within 10 years of menopause possibly providing more benefit and less risk).³ These subsequent data allow for improved clinical stratification for which risk remains for certain patients, and benefits could outweigh risks for others. Benefits could include decreased vasomotor symptoms, decreased bone fracture risk, possible decreased cardiovascular risk, and possible improvement in quality of life. With the removal of MHT black box warnings, a lingering question still remains: what does this mean for current breast cancer survivors or the 1 in 8 women who will develop breast cancer in their lifetime?

With a lifetime risk of 13.1%, invasive breast cancer is the most common cancer among women in the US. As of January 2025, there are 4.3 million women nationwide living with a history of breast cancer; this is anticipated to increase to 5.3 million by 2035.⁴ There is also an increasing trend toward early-onset breast cancer among women 50 years or younger. Most breast cancers are diagnosed at stage I and carry 91% 5-year survival, reflecting a combination of early detection through screening mammography, widespread community breast cancer awareness and advocacy, and improved breast cancer treatments. Although these data are incredibly promising, they also highlight a patient population for whom MHT is generally contraindicated, despite potential benefits. Up to 10% of breast cancers are associated with germline pathogenic variants in moderate- or high-risk cancer genes. Some patients have a concurrent increased lifetime risk of ovarian cancer, with recommendation for risk-reducing salpingo-oophorectomy prior to age 50 years. Some individuals experience early menopause for a variety of reasons, including temporary or permanent chemotherapy-induced menopause, medically induced menopause for ovarian suppression, or surgical ovarian ablation.

A review of more than 20 studies published from 1980 to 2013, ranging from retrospective to prospective randomized clinical trials, overwhelmingly showed no elevated risk of new breast cancer events, recurrences, or mortality among breast cancer survivors taking MHT.⁵ Some studies from this review even demonstrate a decreased risk of breast cancer events and reduced mortality with MHT in this population. Additionally, a systematic review and meta-analysis of MHT in breast cancer survivors showed no significant differences in tumor recurrence with combined MHT or tibolone in analysis of the 3 randomized clinical trials (relative risk [RR], 1.46 [95% CI, 0.99–2.24]). In the combined analysis of all studies, there was no increased risk of recurrence (RR, 0.85 [95% CI, 0.54–1.33]) or death (RR, 0.91 [95% CI, 0.38–2.19]).⁶

The Hormonal Replacement Therapy After Breast Cancer—Is It Safe? (HABITS) trial, a prospective, randomized, noninferiority trial initiated in 1997, was terminated early after demonstrating an increased risk of local recurrence or a contralateral breast cancer following the administration of MHT among breast cancer survivors (26 of 174 [15%] vs 8 of 171 [5%]). Numerous limitations to the study included possible discrepancies of MHT formulations across institutions, MHT exposure in the non-MHT group, and a high proportion of participants with unknown hormone receptor status. The follow-up 2008 study showed a statistically significant increased risk of breast cancer events for those who took MHT (hazard risk, 2.4 [95% CI, 1.3–4.2]), with no statistically significant difference in survival (P = .51).⁷ However, a combined 10-year follow-up analysis of the Stockholm trial (a similar study with the goal of minimizing the use of progestin with estrogen in breast cancer survivors) and the HABITS trial did not show a significant difference between new breast cancer events in the MHT vs the control group (hazard ratio, 1.3 [95% CI, 0.9–1.9]) and no differences in mortality.⁸ Fahlén et al suggest that the increased risk of recurrence in HABITS could have been attributed to higher progesterone exposure in this trial and that early termination of both studies does not allow for appropriate conclusions to be made.⁸

Hormone receptor–negative breast cancer is also an important subgroup in the broader discussion of MHT. These subtypes account for 15% to 20% of all breast cancer cases and are more commonly diagnosed in women who are premenopausal. Although there are no prospective studies in hormone receptor–negative cancers specifically, these patients are represented in larger studies of MHT. For instance, in the HABITS trial, there was no significant increase in risk of recurrence in the hormone receptor–negative cohort.⁷ Interestingly, there is evidence that estrogen-alone MHT may decrease the risk or recurrence of a second primary breast cancer in this patient population.⁹ Additionally, systematic reviews and meta-analyses of MHT in breast cancer survivors show no increased risk in those with hormone receptor–negative tumors.^6,10

If 13.1% of women nationwide will experience breast cancer, there may be a subgroup of this substantial patient population for which the benefits of MHT may outweigh the risks. MHT for breast cancer survivors can and should be approached the same way that breast cancer itself is treated: individually. Every breast cancer diagnosis carries its own unique combination of treatments (surgery, chemotherapy, radiation, immunotherapy, and endocrine therapy) that are based on factors such as stage, oncotype, hormone receptor status, and age. Similarly, MHT eligibility for breast cancer survivors should consider factors that impact present and future breast cancer risk, recurrence, and mortality (eg, age, stage, tumor grade, oncotype, the presence of intact breast tissue, and time from initial diagnosis). Importantly, whether or not the uterus is present is another key consideration. It will require a nuanced evaluation of eligibility, timing, and dosing to ensure safety. There must also be more research on the potential differences of MHT on those who have undergone natural vs induced (either permanently or temporarily) menopause as a result of breast cancer treatment.

This approach is not without its challenges. The potential risks should be discussed openly and interpreted with care. As with many other areas of medicine for which there is significant controversy without formal consensus, shared decision-making and ensuring patient understanding of possible risks are essential. Attention to health disparities is critical, as Black women in particular are less likely to receive MHT at baseline and carry a high breast cancer–related mortality.

The discussion of systemic MHT among breast cancer survivors is not a simple one and extends far beyond the confines of this article. The recent black box removal is an opportunity to broaden the conversation to breast cancer survivors, some of whom could potentially benefit from MHT. It is crucial that the medical community think deeply and critically about what the accumulated data of the past 20 years mean for breast cancer survivors and those who may eventually be diagnosed with breast cancer. This change does not necessarily signify that MHT is universally indicated for any patient, at any age, or under any condition. Through a personalized approach and shared decision-making, the appropriate patient, duration of treatment, and formulation that offers the greatest ratio of benefit to risk could be possible.