Effect of Goserelin on the Protection of Ovarian Reserve During (Neo)Adjuvant Chemotherapy for Young Breast Cancer Patients: A Prospective Cohort Trial

6.6-12% of women with breast cancer were diagnosed before the age of 40 year and breast cancer accounted for 40% of all cancer in women before the age of 40 year.Attributed to improved treatment, of which chemotherapy plays a major role, more than 70% of breast cancer patients at reproductive age obtain 10-year survival rates. Consequently, the question of pregnancy and premature ovarian failure after breast cancer treatment are presented more frequently. Fortunately, most of the available literature provides good evidence that pregnancy after breast cancer may improve survival. Unfortunately, no therapy has been shown to preserve fertility in patients receiving chemotherapy so far, although chemotherapy induced ovarian failure ,which finally results in infertility and premature ovarian failure, has been reported 60 years before. The greater rate of prepubertal than of postpubertal women with normal ovarian function after chemotherapy supports the concept that the suppressed ovary has a greater tolerance during cytotoxic treatments.While inhibiting the pituitary ovarian axis, Gonadotropin-releasing hormone agonist (GnRHa) is thought to block follicular development and reduce chemotherapy toxicity. Several studies had revealed GnRHa co-treatment yielded a statistically significant improvement in the proportion of spontaneous menstrual resumption after chemotherapy, compared to controls.It is noteworthy that menses and fertility are not necessarily linked. Absence of regular menses, particularly if the patient is taking tamoxifen(endocrine therapy for breast cancer), does not necessarily imply lack of fertility. Conversely, the presence of menses does not guarantee fertility.Currently, anti-Müllerian hormone(AMH) is considered as the best biochemical marker for assessment of reproductive capacity in reproductive medicine settings. Because it is produced by granulosa cells of growing antral follicles, AMH is significant positive correlation with both quantity and quality of oocytes. Moreover, it can be measured on any day for minimal fluctuation during the menstrual cycle.Antral follicle count (AFC) by vaginal ultrasound is also a good predictor of response to exogenous FSH and correlates independently with the number of oocytes retrieved during in vitro fertilization(IVF). Our study is designed to make sure the effect of GnRHa on the preservation of ovarian reserve function in breast cancer patients at reproductive age treated with (neo)adjuvant chemotherapy by observing the dynamic changes of ovarian reserve marker (AMH, AFC, E2 and FSH) pre and post chemotherapy and long-term pregnancy outcomes. Meanwhile, to evaluate the safety of this protective approach in young breast cancer patients by disease-free survival (DFS) and overall survival (OS) outcomes, and objective response rate(ORR) and pathological complete response (pCR) rate (for patitents treated with neoadjuvant chemotherapy). Finally, to explore whether patients with GnRH receptor or androgen receptor over-expression could benefit survival from this approach.

Patients: Premenopausal patients aged 18-45 years were eligible for enrollment, with stages I to III of newly diagnosed breast cancer, for which treatment with adjuvant or neoadjuvant chemotherapy was planned. Exceptions were made up of the use of hormonal contraception, previous chemotherapy, bilateral oophorectomy or ovarian irradiation before enrollment, and GnRHa -containing endocrine therapy planned.

Study Design: In our study, patients will be informed comprehensively and assigned without interference to receive either (neo)adjuvant chemotherapy with goserelin (goserelin group) or without goserelin (chemotherapy group) as their own selection. AMH, follicle stimulating hormone (FSH), and estradiol (E2) are used as biochemical markers and AFC is used as biophysical marker. The markers and menstrual status will be evaluated before, during, and at 0.5-year, 1-year, 2-year after chemotherapy. Additionally, pregnancy and disease related outcomes within 5 years, assessed annually.

Patients in goserelin group are given a subcutaneously dose of 3.6 mg (Zoladex, AstraZeneca) at least 1 week before the first cycle of chemotherapy and then every 4 weeks for the duration of chemotherapy. Subgroup analysis is stratified by age (≤ 40 years and 41-45 years), baseline level of AMH(≤1ng/ml and >1ng/ml), chemotherapy regimen (AC, AC-T(H), others) and endocrine therapy regimen (with or without Tamoxifen).

The primary end point is to compare the recovery rate of AMH value (≥ 0.5ng/ml) (according to the "the Bologna criteria") between the two treatment groups at 2-year after chemotherapy. Secondary endpoints included descriptions of the dynamic changes of each marker from pre- to post-chemotherapy and time to resumption of menstrual activity (reappearance of two consecutive menstrual periods within 21 to 35 days); recovery rate of AMH value at 1 year and the rates of the other markers returning to the premenopausal range (E2 ≥ 40 pg/ml, FSH < 25 U/L, AFC ≥ 5) were assessed at both 1 year and 2 years. Additional end points included pregnancy and disease related outcomes within 5 years, assessed annually. Events in the analysis of disease-free survival (DFS) included local recurrence, distant metastases, contralateral or ipsilateral breast tumor, second primary malignancy, and death due to any cause. Events in the analysis of overall survival (OS) included deaths due to any cause. Explore whether patients with GnRH receptor or androgen receptor over-expression could benefit survival by subtype analysis.