Summary
Londero et al. [1] performed a systematic review and meta-analysis aimed at investigating the effect of hormone therapy (HT) on the oncological outcomes of endometrial cancer (EC) survivors. They identified studies detailing the effect size for the relationship between HT use in EC and oncological outcomes (survival and disease recurrence). Authors evaluated the different recurrence rates among women treated for EC who subsequently underwent HT and those who did not. Studies were evaluated for quality, heterogeneity, and publication bias, and a pooled odds ratio (OR) or hazard ratio (HR) was calculated with corresponding 95% confidence intervals (CI). In total, investigators collated 5,291 studies, and after the review process, one randomized trial and seven observational studies were included, comprising 1,801 EC survivors treated with HT and 6,015 controls. In four studies the authors were able to conduct time-dependent analysis, and considering the disease-free survival, the pooled HR of 0.90 (95% CI 0.28 to 2.87) showed no significant difference. However, among Black American women treated with continuous estrogen HT, the HR was 7.58 (95% CI 1.96 to 29.31), showing a significantly increased risk of recurrence for women in this ethnic group. Considering the pooled OR of all included studies 0.63 (95% CI 0.48 to 0.83), a significantly reduced risk of recurrence was found among EC survivors treated with HT. Considering the type of HT, the most risk-reducing was combined estrogen and progestin therapy and the cyclic regimen. Despite the fact that supporting evidence is based mainly upon observational studies, evidence of no increased risk or even decreased risk was generally found, apart from Black American women where a significantly increased recurrence risk was evident. The investigators conclude that the data are rather reassuring for the short-term administration of HT to symptomatic EC survivors and recommend future studies with a longer follow-up to better clarify the long-term effects of HT.
Commentary
This meta-analysis focused mainly on the use of HT in early staged EC survivors. The results showed that HT did not increase the risk of cancer recurrence overall regardless of the use of estrogen alone (E) or estrogen and progesterone combined regimens (EP), and some studies have even shown reduced recurrence rates in patients who receive HT. In addition, subgroup analysis showed that different methods of administration had different effects on the recurrence rate of EC. The EC recurrence was not increased in the estrogen alone group [HR=1.21, (95% CI:0.11-13.15], while estrogen plus progestin could lower the recurrence rate [HR=0.67, (95% CI:0.32-1.40)]. It is generally accepted that since survivors with early-stage endometrial cancer undergo hysterectomy and the cancer cells have not spread, the protective effect of progesterone on the endometrium can be disregarded in HT, and only estrogen is needed to relieve menopausal symptoms and bone protection. Despite this, this meta-analysis showed that the addition of progestin can reduce the risk of EC recurrence in patients after hysterectomy compared with E alone. This finding provides a reference value that favours for the EP treatment scheme.
However, an exception is Black American women, who have an increased risk of recurrence with continuous estrogen HT [HR=7.58, (95% CI:1.96-29.31)], significantly higher than patients of all other regions and ethnic groups. This may be related to polymorphisms of genes related with tumorigenesis. For example, the over expression rate of mutant p53 in black female patients with stage I EC is 3 times higher than that in white patients. The authors also suggested that genes involved in estrogen synthesis and metabolism pathways may influence the effect of HT on recurrence rate, but clinical data are still lacking. Although there is no precise explanation for the effect of ethnic group on recurrence rates in patients undergoing HT, this finding highlights the importance of taking ethnic differences into account in medical research and treatment selection.
The strength of this report is the use of time-to-event pooled analyses and the inclusion of large recent cohort studies, which allow for a larger sample size and more reliable data. However, limitations include potential language bias, study type bias, and publication bias. It may also be a source of bias because the disease-free intervals of the included studies varied greatly. These limitations may affect the accuracy and generalizability of the findings.
There is a need for studies with larger sample size and longer follow-up, that also explore the mechanism of the effect of treatment regimens and ethnic groups. Although there are still many unanswered questions, we can still draw the following conclusions: For survivors of early stage EC except black women, the positive effects of HT outweigh the potential risks, and EP may be a safer option. The influence of ethnic differences on treatment outcomes also indicates the importance of individualized medicine in the choice of medical treatment for patients with cancer after surgery.
WanQi Lang, PhD student1
Qi Yu, MD2
1 Eight-year Medical Doctor Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
2 Peking Union Medical College Hospital, Beijing, People’s Republic of China
References
- Londero AP, Parisi N, Tassi A, Bertozzi S, Cagnacci A. Hormone Replacement Therapy in Endometrial Cancer Survivors: A Meta-Analysis. J Clin Med. 2021;10(14):3165.
https://pubmed.ncbi.nlm.nih.gov/34300331/
If you would like to add a comment or contribute to a discussion based on this issue, please contact Menopause Live Editor, Peter Chedraui, at peter.chedraui@cu.ucsg.edu.ec.
