In the United States, uterine cancer is the fourth most common cancer among women, behind breast, lung/bronchus, and colorectal cancer. There are expected to be almost 66,000 new cases of uterine cancer in 2022.1 The majority of uterine cancers are endometrioid in histology and tend to be low grade, diagnosed at an early stage, and have a good prognosis. While our molecular understanding of endometrial cancers (EC) has changed significantly in recent years, low-grade endometrioid adenocarcinomas have historically been described as type 1 ECs. Type 1 ECs are typically caused by excess estrogen exposure (often unopposed or lacking progesterone protection) and are preceded by endometrial hyperplasia. Excess estrogen can come from exogenous sources (such as unopposed estrogen replacement therapy or tamoxifen, a commonly used treatment in estrogen receptor–positive breast cancer that acts as an estrogen agonist in the endometrium in postmenopausal patients) or endogenous ones (such as obesity).
Peripheral adipose tissue converts androgens into estrogens; paired with the decreased levels of sex hormone–binding globulin seen in obesity, there is more unbound or free serum estrogen (specifically estradiol) in obese women. Estrogen acts on the endometrium to cause proliferation and, if unopposed or imbalanced in relation to progesterone exposure, can ultimately lead to hyperplasia and malignancy.
If excess and unopposed estrogen exposure are major risk factors for the development of EC, is it safe to consider estrogen replacement therapy (ERT) in patients after EC treatment?
The short answer is the data are limited, but in a patient with a history of low-risk early-stage EC who undergoes appropriate counseling, it is likely safe to consider ERT.
Among EC survivors, there has been only one prospective randomized controlled trial that assessed the effect of recurrence rate and survival in women on ERT after EC treatment.2 Patients with stage I or occult stage II endometrial adenocarcinoma treated with at least a total hysterectomy and bilateral salpingo-oophorectomy were randomized to ERT versus placebo for 3 years of treatment, with therapy starting once recovered and within 20 weeks after surgery. Trial participation required an indication for ERT, such as vasomotor symptoms, vaginal atrophy, or increased risk of cardiovascular disease or osteoporosis.
The trial accrued 1,236 patients, falling short of its goal of 2,108 patients after enrollment decreased following the publication of the Women’s Health Initiative results in 2002. This publication prompted a review of the ERT study protocol that found that between decreased accrual and lower than expected recurrence rate, goal accrual would be impossible. Of those enrolled, participants were overwhelmingly white (84%-85%), 41-70 years old (80%-82%), and had stage IA or IB disease (88%). Median follow-up was almost 3 years.
Twenty-six (2.1%) patients experienced cancer recurrence, with similar rates in both groups. Three-year progression-free and overall survival were high overall among all study participants (94.8% and 96.5%). Unfortunately, because the study was closed early, definitive conclusions about the noninferiority of ERT versus placebo regarding oncologic outcomes in early-stage endometrial adenocarcinoma could not be made.
A subsequent meta-analysis looked at the effect of hormone therapy (HT) on recurrence rate in EC survivors.3 Five observational studies were included along with the previously discussed randomized controlled trial. Among 1,975 participants across six studies, there were cancer recurrences in 19 of 896 (2.1%) HT users and 64 of 1,079 (5.9%) controls. HT did not negatively affect cancer recurrence or overall survival. There was significant heterogeneity between studies as to dosing, duration, and type of HT given (some used estrogen-only replacement, others used estrogen and progesterone replacement, and some used both estrogen only and the combination of estrogen and progesterone replacement). Among the five nonrandomized studies included, a protective effect of combined HT on EC recurrence was noted. One study included patients with stage III disease, but only four patients received HT in this cohort.
Given the data we have, ERT does not appear to significantly affect oncologic outcomes in low-risk, early-stage EC survivors. We do not have data to support this same assertion in more advanced, high-risk disease. Before initiation of any ERT in an EC survivor, there should be a detailed discussion to weigh the risks and benefits of starting therapy. The goal of treatment should be to use the lowest dose of ERT possible to treat symptoms, with planned surveillance visits for symptom check-in and assessment of readiness to start tapering treatment.