中国年轻乳腺癌患者卵巢功能保护

　　由于化疗所致闭经的研究终点定义不一致，既往关于化疗期间促性腺激素释放激素激动剂戈舍瑞林保护卵巢功能的研究结果也不一致。抗米勒管激素（抗苗勒氏激素）和囊状卵泡计数被生殖医学专家认为是最敏感的卵巢储备指标，不过从未被作为评定化疗期间戈舍瑞林对卵巢储备潜在保护作用的生物学指标。

　　2021年1月7日，欧洲人类生殖与胚胎学会官方期刊《人类生殖》在线发表北京大学人民医院王思源和王殊等学者的研究报告，根据抗米勒管激素和囊状卵泡计数，探讨了戈舍瑞林对中国年轻乳腺癌患者术前或术后化疗期间卵巢储备的保护作用。

NCT02430103: Effect of Goserelin on the Protection of Ovarian Reserve During (Neo)Adjuvant Chemotherapy for Young Breast Cancer Patients: A Prospective Cohort Trial

　　该单中心前瞻队列研究于2015年12月～2019年11月从北京大学人民医院入组月经周期正常、年龄18～45岁、新诊断为I～III期乳腺癌、计划进行术后（辅助）或术前（新辅助）化疗的绝经前患者242例。而是根据患者意愿接受化疗±戈舍瑞林。戈舍瑞林组化疗之前至少1周、化疗期间每4周皮下注射戈舍瑞林3.6毫克。化疗前后评估卵巢储备指标和月经状态。主要终点为抗米勒管激素恢复率，次要终点为囊状卵泡计数、雌二醇、促卵泡激素和月经恢复率。

　　结果，化疗后1年数据完整患者149例，其中对照组76例、戈舍瑞林组73例，抗米勒管激素校正后恢复率分别为46.5%、21.8%（比值比：3.08，P=0.002）。囊状卵泡计数、促卵泡激素恢复率与抗苗勒管激素恢复率变化趋势一致。值得注意的是，41.3%的月经恢复患者抗米勒管激素水平仍然较低。

　　因此，该研究结果表明，化疗＋戈舍瑞林与单纯化疗相比，1年后卵巢储备恢复率显著较高。化疗＋戈舍瑞林可为这些年轻乳腺癌患者提供明显的卵巢储备保护，希望这些结果将适用于年轻乳腺癌患者的临床实践。不过，由于伦理学原因，未行随机分组，故通过倾向评分加权以减少选择偏倚。此外，由于52例（21.5%）入组患者接受过包括促性腺激素释放激素激动剂的内分泌治疗并且化疗后1年时和2年时无法分析。

Hum Reprod. 2021 Jan 7:deaa349.

Protective effect of goserelin on ovarian reserve during (neo)adjuvant chemotherapy in young breast cancer patients: a prospective cohort study in China.

Wang S, Pei L, Hu T, Jia M, Wang S.

Peking University People's Hospital, Beijing, China.

STUDY QUESTION: Does goserelin, a GnRH agonist, have a protective effect in young breast cancer patients in terms of ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) during chemotherapy?

SUMMARY ANSWER: Compared with chemotherapy alone, concurrent goserelin is associated with a higher probability of ovarian reserve recovery at 1 year after chemotherapy.

WHAT IS KNOWN ALREADY: Previous studies on the administration of goserelin to protect ovarian function during chemotherapy have produced conflicting results because of the endpoint used, namely, chemotherapy-induced amenorrhoea. Reproductive medicine specialists consider AMH and AFC as the most sensitive ovarian reserve markers; however, they have never been used as biomarkers to assess the potential protective effects on ovarian reserve of goserelin during chemotherapy.

STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study in which patients were assigned to receive (neo)adjuvant chemotherapy with goserelin (the goserelin group) or without goserelin (the control group) according to each patient's preference. Of 242 breast cancer patients enrolled between December 2015 and November 2019, 76 in control group and 73 in goserelin group were able to be assessed at 1 year after chemotherapy.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal patients with a regular menstrual cycle and aged 18-45 years were eligible for enrolment if they were newly diagnosed with stages I-III breast cancer for which treatment with adjuvant or neoadjuvant chemotherapy was planned. Each patient in the goserelin group was given a subcutaneous dose of 3.6 mg at least 1 week before the first cycle of chemotherapy and then every 4 weeks for the duration of chemotherapy. Ovarian reserve markers and menstrual status were evaluated before and after chemotherapy in the two treatment groups. The primary endpoint was the AMH recovery rate, the secondary endpoints were the recovery rates of AFC, estradiol (E2), follicle-stimulating hormone (FSH) and menstruation.

MAIN RESULTS AND THE ROLE OF CHANCE: Among 149 patients (76 in the control group and 73 in the goserelin group) with complete data at 1 year after chemotherapy, the adjusted recovery rate of AMH was 46.5% and 21.8% in the goserelin group and control group, respectively (odds ratio: 3.08; P = 0.002). The trends in AFC and FSH recovery rates were consistent with that in AMH recovery rate. Notably, AMH levels remained low in 41.3% of patients whose menstrual activity had resumed.

LIMITATIONS, REASONS FOR CAUTION: Randomisation was not performed because of ethical considerations, so selection bias was inevitable, although propensity score weighting was done. The study was also underpowered because 21.5% (52/242) of enrolled patients received GnRH agonist-containing endocrine therapy and could not be analysed at 1 and 2 years after chemotherapy.

WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that co-administration of goserelin with chemotherapy provides obvious ovarian reserve protection in these young breast cancer patients. We expect that these results will be applicable in clinical practice for young breast cancer patients.

STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Key R&D Program of China No. 2016YFC0901302, by the Research and Development Fund of Peking University People's Hospital No. RD2014-13, RDY2017-19 and by AstraZeneca. The authors have no disclosures.

TRIAL REGISTRATION NUMBER: NCT02430103

KEYWORDS: Goserelin; anti-Müllerian hormone; antral follicle count; ovarian reserve protection; young breast cance

PMID: 33411897

DOI: 10.1093/humrep/deaa349