What is the aim of this review?
The aim of this Cochrane Review was to find out whether adding ovarian function suppression to treatment for early breast cancer improves survival, reduces the risk of cancer coming back, and is safe for premenopausal women with hormone receptor-positive early breast cancer. Cochrane Review authors collected and analysed all relevant studies to answer these questions and found 15 studies.
Adding ovarian suppression function to therapy improved survival (women lived longer) and reduced the chance of cancer returning in women with operable early breast cancer, but the use of ovarian function suppression appears to increase the risk of hot flushes and may affect bone health. The decision to use OFS needs to be personalised after the risk and benefit profile is considered.
What was studied in the review?
Around eight out of ten premenopausal women who develop breast cancer have a type of cancer that is sensitive to hormones, termed 'hormone receptor-positive' disease. To slow the growth of any cancer cells that remain after surgery, hormonal therapy can be used to reduce the availability of natural hormone oestrogen to cancer cells. This can be done by blocking oestrogen receptors on the cells with drugs such as tamoxifen, by suppressing the production of oestrogen by drugs called luteinising hormone releasing hormone (LHRH) agonists, or by removing the ovaries with surgery or impairing their ability to produce hormones using radiotherapy.
This review examined the role of ovarian function suppression (i.e. LHRH agonists, removal of the ovaries, or radiation-induced ovarian suppression) for premenopausal women with hormone receptor-positive early-stage breast cancer. The practice of suppressing ovarian function in addition to providing other treatments has been of interest over the last five years, as new data from clinical trials have become available. A review of these data is needed to find the benefits of adding ovarian function suppression to treatment, to identify side effects from ovarian function suppression, and to discover how treatment is affecting a woman's overall well-being (quality of life).
The funding source for the conduct of these studies was government (four studies), government and pharmaceutical companies combined (three studies), government and not-for-profit organisations combined (two studies), not-for-profit organisations and pharmaceutical companies (two studies), and a pharmaceutical company (one study); three studies did not report a funding source.
What are the main results of the review?
Review authors found 15 relevant studies involving 11,538 women. To achieve ovarian function suppression, nine studies used LHRH agonists (most used goserelin), two studies induced ovarian function suppression through surgery, and four studies allowed any method (LHRH agonists, surgery, or radiotherapy). LHRH agonists were given to women for a minimum of one year.
The woman's health was monitored for at least two years from the start of the study. Some studies monitored women for over 12 years.
Review authors found that adding ovarian suppression function to treatment:
• improves survival and reduces the risk of cancer coming back compared to treatment without ovarian function suppression;
• appears to increase the chance of severe hot flushes compared to treatment without ovarian function suppression;
• probably reduces the risk of a second breast cancer in the other breast compared to treatment without ovarian function suppression;
• may or may not have an effect on mood (e.g. anxiety, depression) compared to treatment without ovarian function suppression;
• may increase the risk of osteoporosis compared to treatment without ovarian function suppression (however, this finding was based on one study); and
• may make little or no difference in quality of life for women compared to treatment without ovarian function suppression. Five of 15 studies provided some information on the quality of life of women.
How up-to-date is this review?
The review authors searched for studies that had been published up to September 2019.
This review found evidence that supports adding OFS for premenopausal women with early, hormone receptor-positive breast cancers. The benefit of OFS persisted when compared to observation, and when added to endocrine therapy (tamoxifen) or chemotherapy and endocrine therapy (tamoxifen). The decision to use OFS may depend on the overall risk assessment based on tumour and patient characteristics, and may follow consideration of all side effects that occur with the addition of OFS.
Approximately 80% of breast cancers amongst premenopausal women are hormone receptor-positive. Adjuvant endocrine therapy is an integral component of care for hormone receptor-positive breast cancer and in premenopausal women includes oestrogen receptor blockade with tamoxifen, temporary suppression of ovarian oestrogen synthesis by luteinising hormone releasing hormone (LHRH) agonists, and permanent interruption of ovarian oestrogen synthesis with oophorectomy or radiotherapy. Recent international consensus statements recommend single-agent tamoxifen or aromatase inhibitors with ovarian function suppression (OFS) as the current standard adjuvant endocrine therapy for premenopausal women (often preceded by chemotherapy). This review examined the role of adding OFS to another treatment (i.e. chemotherapy, endocrine therapy, or both) or comparing OFS to no further adjuvant treatment.
To assess effects of OFS for treatment of premenopausal women with hormone receptor-positive early breast cancer.
For this review update, we searched the Specialised Register of the Cochrane Breast Cancer Group, MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 8), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov on 26 September 2019. We screened the reference lists of related articles, contacted trial authors, and applied no language restrictions.
We included all randomised trials assessing any method of OFS, that is, oophorectomy, radiation-induced ovarian ablation, or LHRH agonists, as adjuvant treatment for premenopausal women with early-stage breast cancer. We included studies that compared (1) OFS versus observation, (2) OFS + chemotherapy versus chemotherapy, (3) OFS + tamoxifen versus tamoxifen, and (4) OFS + chemotherapy + tamoxifen versus chemotherapy + tamoxifen.
Two review authors independently extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). Toxicity, contralateral breast cancer, and second malignancy were represented as risk ratios (RRs), and quality of life data were extracted when provided.
This review update included 15 studies involving 11,538 premenopausal women with hormone receptor-positive early breast cancer; these studies were conducted from 1978 to 2014. Some of these treatments are not current standard of care, and early studies did not assess HER2 receptor status. Studies tested OFS versus observation (one study), OFS plus chemotherapy versus chemotherapy (six studies), OFS plus tamoxifen versus tamoxifen (six studies), and OFS plus chemotherapy and tamoxifen versus chemotherapy and tamoxifen (two studies). Of those studies that reported the chemotherapy regimen, an estimated 72% of women received an anthracycline. The results described below relate to the overall comparison of OFS versus no OFS.
High-certainty evidence shows that adding OFS to treatment resulted in a reduction in mortality (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.78 to 0.94; 11 studies; 10,374 women; 1933 reported events). This treatment effect was seen when OFS was added to observation, to tamoxifen, or to chemotherapy and tamoxifen. The effect on mortality was not observed when OFS was added to chemotherapy without tamoxifen therapy (HR 0.95, 95% CI 0.82 to 1.09; 5 studies; 3087 women; median follow-up: range 7.7 to 12.1 years). The addition of OFS resulted in improved DFS (HR 0.83, 95% CI 0.77 to 0.90; 10 studies; 8899 women; 2757 reported events; high-certainty evidence). The DFS treatment effect persisted when OFS was added to observation, to tamoxifen, and to chemotherapy and tamoxifen. The effect on DFS was reduced when OFS was added to chemotherapy without tamoxifen therapy (HR 0.90, 95% CI 0.79 to 1.01; 5 studies; 2450 women). Heterogeneity was low to moderate across studies for DFS and OS (respectively).
Evidence suggests that adding OFS slightly increases the incidence of hot flushes (grade 3/4 or any grade; risk ratio (RR) 1.60, 95% CI 1.41 to 1.82; 6 studies; 5581 women; low-certainty evidence, as this may have been under-reported in these studies). Two other studies that could not be included in the meta-analysis reported a higher number of hot flushes in the OFS group than in the no-OFS group. Seven studies involving 5354 women collected information related to mood; however this information was reported as grade 3 or 4 depression, anxiety, or neuropsychiatric symptoms, or symptoms were reported without the grade. Two studies reported an increase in depression, anxiety, and neuropsychiatric symptoms in the OFS group compared to the no-OFS group, and five studies indicated an increase in anxiety in both treatment groups (but no difference between groups) or no difference overall in symptoms over time or between treatment groups. A single study reported bone health as osteoporosis (defined as T score < -2.5); this limited evidence suggests that OFS increases the risk of osteoporosis compared to no-OFS at median follow-up of 5.6 years (RR 1.16, 95% CI 1.10 to 28.82; 2011 women; low-certainty evidence).
Adding OFS to treatment likely reduces the risk of contralateral breast cancer (HR 0.75, 95% CI 0.57 to 0.97; 9 studies; 9138 women; moderate-certainty evidence).
Quality of life was assessed in five studies; four studies used validated tools, and the fifth study provided no information on how data were collected. Two studies reported worse quality of life indicators (i.e. vaginal dryness, day and night sweats) for women receiving OFS compared to those in the no-OFS group. The other two studies indicated worsening of symptoms (e.g. vasomotor, gynaecological, vaginal dryness, decline in sexual interest, bone and joint pain, weight gain); however these side effects were reported in both OFS and no-OFS groups. The study that did not use a validated quality of life tool described no considerable differences between groups.