Hormone replacement therapy in female-specific cancer survivors: considerations beyond cancer cure

Abstract

With rapid advances in disease diagnosis and treatment, patients with cancer will achieve longer survival. Among female cancer survivors, oncologic treatments often lead to premature ovarian insufficiency, negatively impacting their health and quality of life. Hormone replacement therapy (HRT) may mitigate these effects; however, concerns remain regarding its impact on oncologic outcomes. Updating the evidence base could help healthcare providers identify patients who may benefit from HRT without an increased risk of recurrence. This review provides an updated overview of HRT in women with a history of cervical, endometrial, ovarian, and breast cancers. For cervical cancer, HRT is not contraindicated in either squamous cell carcinoma or adenocarcinoma, regardless of stage. For endometrial cancer, HRT is not contraindicated in early-stage disease with no residual tumor, although it should be avoided in low-grade endometrial stromal sarcoma. HRT is not contraindicated in epithelial ovarian cancer regardless of stage, except in low-grade serous carcinoma. Currently, HRT is contraindicated for breast cancer. This review highlights the need to promote long-term healthcare strategies for cancer survivors. A shift in focus beyond cancer cure toward lifelong health management is warranted.

This review provides an updated overview of hormone replacement therapy in women with a history of female-specific cancer, including cervical, endometrial, ovarian, and breast cancers.

Introduction

Five-year survival rates have generally improved across various cancers [1]. Consequently, an increasing number of patients survive the treatment period and live as long-term cancer survivors. However, cancer treatments can lead to permanent or semipermanent sequelae. In particular, iatrogenic premature ovarian insufficiency induced by cancer treatments, such as gonadotoxic anticancer agents, pelvic radiotherapy, or oophorectomy, is a major concern in young premenopausal women with cancer. Furthermore, the median age at menopause is lower in women who have survived cancer (44 years) than in the general population [2]. Moreover, female cancer survivors are more likely to experience severe vasomotor symptoms than individuals without cancer [3].

Premature ovarian insufficiency increases the risk of cardiovascular diseases and osteoporosis [4]. Rocca et al. have reported that bilateral oophorectomy before 45 years of age for noncancerous conditions is associated with an increased risk of mortality [5]. Menopausal symptoms, such as hot flashes, cognitive decline, and sexual dysfunction, can also markedly reduce quality of life. The most effective treatment for these symptoms is hormone replacement therapy (HRT); however, concerns persist regarding its potential impact on oncological outcomes in cancer survivors.

Therefore, healthcare providers must carefully weigh the risks and benefits of HRT for cancer survivors. This review provides an updated overview of HRT use in women with a history of cervical, endometrial, ovarian, or breast cancers.

Cervical cancer

The annual number of new cervical cancer cases is approximately 661 000 [6]. Cervical cancer is the third most common cancer in women under 50 years of age worldwide [1], often affecting young women in their 20–30s. However, this number will decline in the near future owing to the effectiveness of human papillomavirus (HPV) vaccines. Cervical cancer treatment frequently leads to iatrogenic menopause. For instance, hysterectomy with bilateral salpingo-oophorectomy or pelvic radiotherapy can result in premature ovarian insufficiency. Consequently, a substantial number of patients with cervical cancer may require HRT.

Previous studies on HRT in cervical cancer survivors have primarily focused on squamous cell carcinoma or adenocarcinoma. Recently, these two histological types have been proposed to be further classified into HPV-associated or -independent [7]. Although it is still conflicting whether estrogen is related with HPV carcinogenesis [8], this may need to be considered when discussing HRT for patients with cervical cancer. Also, information on the safety of HRT in other rare histological subtypes, such as neuroendocrine carcinoma, remain limited. To date, both cervical squamous cell carcinoma and adenocarcinoma are considered hormone-independent diseases. Although estrogen and progesterone receptors are expressed in 39% and 33% of patients, respectively, their expression does not influence recurrence or overall survival [9]. A previous retrospective study conducted in Poland on stage I/II cervical cancer has reported no significant difference in recurrence or 5-year survival rates between HRT and non-HRT groups [10]. Since then, few studies have reported that exogenous estrogen levels are not associated with an increased risk of cervical cancer recurrence [11]. Meanwhile, regarding the risk of developing cervical cancer rather than its recurrence risk, some studies have suggested that HRT may be associated with an increased incidence of cervical adenocarcinoma. Jaakkola et al. have reported that HRT was linked to a decreased risk of cervical squamous cell carcinoma and an increased risk of cervical adenocarcinoma [12]. Nevertheless, HRT remain a consideration for patients with cervical adenocarcinoma, as no studies have demonstrated an increased risk of recurrence.

Therefore, the European Menopause and Andropause Society/International Gynecologic Cancer Society, and European Society of Gynecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines state that HRT is not contraindicated in patients with cervical cancer and should follow recommendations for natural menopause management [13,14]. Nonetheless, some researchers have indicated that fewer than half of patients with iatrogenic menopause receive HRT and the duration of HRT use is shorter than recommended in clinical guidelines [15–17]. Thus, healthcare support for young patients with cervical cancer may still be inadequate.

Endometrial cancer

The number of endometrial cancer cases diagnosed annually is approximately 420 000 [6]. Endometrial cancer is the sixth most common cancer in women of all ages worldwide [1]. Patients aged <40 years account for ~4% of those with endometrial cancer, and the incidence rate in young adults has gradually increased in Japan [18]. Hysterectomy with bilateral salpingo-oophorectomy is the standard treatment for curable endometrial cancer, although ovarian preservation could also be an option for young patients with early-stage, nonaggressive histology.

Epidemiologically, unopposed estrogen is considered the major cause of endometrial cancer. Especially in conventional “type I” cancer, most of which are well-differentiated endometrioid carcinoma, estrogen, and progesterone receptors are usually expressed [19]. However, a previous randomized trial (GOG137) showed that estrogen replacement therapy (ERT) after surgery in patients with stage I/II endometrial cancer did not increase the risk of recurrence (2.3% in the ERT group vs 1.9% in the placebo group) [20]. No current significant increase in recurrence risk with HRT use in low-grade, early-stage endometrial cancer survivors was observed [21–23]. A subgroup analysis examining racial differences in GOG137 has revealed that recurrence-free survival was poorer in Black women than in White women receiving ERT [24]. Since they received a similar treatment and follow-up in a clinical trial setting, the result suggested that there might be some racial differences in biological factors such as estrogen metabolism. On the other hand, HRT should be used cautiously in patients with advanced endometrial cancer, even if they may achieve cancer-free after treatment, since hormonal stimulation might promote microscopic residual disease and induce recurrence.

Recently, endometrial cancer has been proposed to be divided into four molecular classifications rather than “type 1” or “type 2” as follows: POLEmut, MMRd, NSMP (no specific molecular profile), and p53mut [7]. The NSMP group includes more hormone-receptor-positive tumors [25]. However, information on the association between these molecular features and HRT safety is limited. Therefore, more studies are needed to precisely reveal the benefits of HRT.

Uterine sarcomas, including leiomyosarcomas, low-grade endometrial stromal sarcoma, high-grade endometrial stromal sarcomas, and undifferentiated uterine sarcomas, may be hormone-dependent. In particular, low-grade endometrial stromal sarcomas often respond to anti-estrogen therapy. Although information on the safety of HRT in patients with uterine sarcoma is limited, nonhormonal therapies should be selected for these cases, particularly for low-grade endometrial stromal sarcoma in which HRT may be contraindicated [13,26].

Ovarian cancer

The number of patients with ovarian cancer is lower than that of those with cervical or endometrial cancer, with approximately 324 000 new cases annually [6]. More than 25% of patients with ovarian cancer are aged <50 years at diagnosis [27]. Bilateral oophorectomy is generally required for ovarian cancer, although ovarian preservation could also be an option for young patients with unilateral ovarian disease and low-grade histology. However, unlike cervical or endometrial cancers, ~40% of patients with ovarian cancer are diagnosed at an advanced stage. Additionally, as ovarian cancer has a higher risk of thrombosis, caution should be exercised when considering the initiation of HRT. Even without any evidence of pulmonary embolism or deep vein thrombosis, transdermal estrogen may be recommended particularly during bevacizumab maintenance therapy, since transdermal estrogen has lower risk of thrombosis than oral estrogen. On the other hand, PARP inhibitors do not increase the risk of thrombosis in general. Although less is known about the safety of concurrent use of HRT and these molecular targeted therapies, HRT is often initiated during maintenance therapy in clinical practice, since maintenance therapy may last for years after chemotherapy.

Malignant ovarian tumors include epithelial cancers, germ cell tumors, and sex cord-stromal tumors. Epithelial ovarian cancers account for 90%, and are further classified into high-grade serous, low-grade serous, endometrioid, clear-cell, and mucinous carcinomas. High-grade serous carcinoma accounts for most cases, although the percentage of each histological type differs across countries.

Regarding epithelial ovarian cancer, two meta-analyses, including two randomized controlled trials and four cohort studies, showed that HRT had no harmful effects on overall survival or recurrence, regardless of tumor grade and stage; although all of these studies had small sample sizes [28,29]. Another retrospective cohort study has indicated that HRT in nonserous epithelial ovarian cancer did not negatively influence disease-free or overall survival [30]. Disease-free survival was even better in HRT users aged <55 years. Another randomized controlled trial, including all epithelial ovarian cancer histologies, reported similar findings, with both recurrence-free and overall survivals significantly improved in HRT users after a long follow-up (median follow-up in living patients reached 19.1 years) [31]. Thus, HRT for epithelial ovarian cancer is generally not contraindicated in young survivors at all stages, except for patients with low-grade serous carcinoma. Low-grade serous carcinoma often affects younger patients, and estrogen and progesterone receptors are more frequently expressed in this histology [32]. Some researchers have reported that the oncological outcomes of patients with low-grade serous carcinoma may be improved by hormonal therapy, such as aromatase inhibitors [33]. Therefore, HRT is not recommended for low-grade serous carcinoma according to the statements of related international organizations [13,26].

Although information on rare nonepithelial tumors is limited, adult granulosa cell tumors are considered another histological type for which caution should be exercised regarding HRT use [34] since granulosa cell tumors are hormonally active estrogen-producing tumors.

Breast cancer

Breast cancer is the most common cancer in women aged >30 years, affecting approximately 2 295 000 individuals annually [6]. In premenopausal estrogen-receptor-positive breast cancer, endocrine therapy is commonly provided, often inducing menopausal symptoms. The frequency of menopausal symptoms at any grade in patients treated with tamoxifen plus ovarian suppression has been reported as follows: hot flushes, 93.4%; musculoskeletal symptoms, 75.1%; sweating, 61.8%; insomnia, 57.2%; vaginal dryness, 49.8%; and decreased libido, 47.5% [35]. Moreover, even without tamoxifen treatment, these symptoms occur at a high rate in postchemotherapy patients. In particular, breast cancer survivors treated with procarbazine or other alkylating agents are at higher risk of premature ovarian insufficiency [2]. However, most of these individuals did not receive treatment for these symptoms or were not informed regarding treatment options, despite experiencing them for >5 years after diagnosis [36,37]. Another concern is surgical menopause induced by risk-reducing salpingo-oophorectomy (RRSO) in patients with hereditary breast and ovarian cancer. According to guideline recommendations, RRSO should be offered between the ages of 35 and 40 years after the completion of childbearing in BRCA1 pathogenic variant carriers, or it could be delayed to 40–45 years in BRCA2 pathogenic variant carriers [38,39]. Therefore, RRSO inevitably results in premature menopause. Moreover, many patients undergoing RRSO have a history of breast cancer; thus HRT should be avoided in these patients [40].

HRT is generally considered contraindicated for patients with breast cancer, based on the results of the randomized controlled HABITS study [41]. This trial was terminated prematurely because of concerns regarding an increased risk of new breast cancer events in 26 women in the HRT group (11 local recurrences, five contralateral cancers, and 10 distant metastases among 219 patients) and eight women in the non-HRT group (two local recurrences, one contralateral cancer, and five distant metastases among 215 patients), with a hazard ratio (HR) of 3.3 (1.5–7.4). After an extended follow-up, a significantly increased risk of new breast cancer events persisted, although no increase in mortality was observed [42]. Patients with hormone-receptor-positive breast cancer accounted for more than half of the HRT group, and subgroup analysis showed no significant increase in risk in patients with hormone-receptor-negative breast cancer receiving HRT [HR, 1.8 (0.7–4.8), P = .205]. Another randomized controlled trial, the Stockholm trial, also closed early after the HABITS trial, reported no increased risk of recurrence with HRT [HR, 0.82 (0.35–1.9)] [43,44]. These two trials included similar patients, although the HRT regimens differed. Most patients in the HABITS trial received continuous combined or sequential estradiol hemihydrate and norethisterone, whereas estradiol plus medroxyprogesterone acetate was predominantly used in the Stockholm trial. It is well-established that progestogen, but not estrogen, increases the risk of breast cancer [45], and the differences in progestogen type and exposure might have influenced the results [46]. Bluming et al. reviewed 25 studies, including the HABITS and Stockholm trials, and identified that only one study (the HABITS trial) demonstrated an increased risk of recurrence [47]. It may be worth considering that HRT could still be an option in some patients with breast cancer, such as those with hormone-receptor-negative cancer, or in patients who have undergone hysterectomy, or those using less “breast-toxic” progestogens. However, higher-quality evidence is needed to identify the populations who may benefit from HRT without an increased risk of recurrence. Until then, HRT should be avoided in breast cancer survivors.

Nonhormonal therapies for vasomotor symptoms in these patients include cognitive-behavioral therapy, selective serotonin reuptake inhibitors, gabapentinoids, and fezolinetant [48]. Traditional Japanese herbal medicine (Kampo) could also be an effective treatment option for menopausal symptoms in breast cancer survivors [49]. Regarding atrophic vaginitis symptoms, several cohort studies have shown that vaginal estrogen therapy does not increase their risk of recurrence [50,51], although its safety has not been established in patients with hormone-receptor-positive breast cancer who are taking aromatase inhibitors [52]. Thus, the use of local vaginal estrogen therapy in breast cancer survivors remain controversial owing to insufficient data.

Conclusions

This review focused on HRT in female-specific cancer survivors, with the authors’ opinions summarized in Table 1. Although attitudes toward HRT vary between different cancer types, it can be generally stated that young female cancer survivors often experience paradoxical feelings: frustration over hormone deficiency, alongside fear of recurrence from HRT use. HRT is evidently beneficial for managing premature ovarian insufficiency, and therefore, healthcare professionals should not dismiss it solely because a patient is a cancer survivor. Additionally, cancer diagnosis and classifications have advanced over the years, including classifications based on molecular features. Further studies are needed to examine the safety of HRT in the context of these new classifications, and healthcare professionals should continually update their knowledge of oncological evidence.

Table 1.

HRT in female-specific cancer survivors.

Cervical cancer	Endometrial cancer	Ovarian cancer	Breast cancer
• HRT is not contraindicated in either squamous cell carcinoma or adenocarcinoma, regardless of stage. • Less is known about the safety of HRT in rare histology, including neuroendocrine carcinoma.	• HRT is not contraindicated in stage I/II endometrial cancer with no residual disease. • Less is known about the safety of HRT in advanced stages. • HRT should be avoided in uterine sarcomas, particularly for low-grade endometrial stromal sarcoma.	• HRT is not contraindicated in epithelial ovarian cancer regardless of stages, except for low-grade serous carcinoma. • Transdermal estrogen may be recommended, since it has lower risk of thrombosis than oral estrogen. • Less is known about the safety of HRT in non-epithelial tumors.	• HRT is contraindicated overall. • Non-hormonal therapies should be considered. • A high-quality prospective study is still needed to identify who may benefit from HRT without increased risk of recurrence.

Conflict of interest

Dr. Aoki has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events honoraria from Aska Pharmaceutical Co., Ltd.

Funding

None declared.