编者按：虽然化疗可以改善乳腺癌患者生存，但是也有可能引起年轻女性卵巢功能早衰。根据2011年发表于《美国医学会杂志》的意大利PROMISE-GIM6研究结果，对于绝经前早期乳腺癌女性，促性腺激素释放激素激动剂（GnRHa）曲普瑞林可使化疗的早期绝经发生率由25.9%减少为8.9%（绝对差：-17%，95%置信区间：-26%～-7.9%，P<0.001；治疗相关早期绝经比例比：0.28，95%置信区间：0.14～0.59，P<0.001）。根据2015年发表于《新英格兰医学杂志》的美国西南肿瘤学组（SWOG）POEMS研究结果，对于激素受体阴性绝经前早期乳腺癌女性，GnRHa戈舍瑞林可使化疗的卵巢功能早衰发生率由22%减少为8%（比值比：0.30，95%置信区间：0.09～0.97，P=0.04），妊娠率由11%提高为21%（P=0.03），并且改善无病生存（P=0.04）和总生存（P=0.05）。根据2015年发表于《新英格兰医学杂志》的国际乳腺癌研究协作组（IBCSG）SOFT研究结果，对于高风险雌激素受体阳性绝经前早期乳腺癌女性，GnRHa＋他莫昔芬可使复发、新发、死亡的风险减少22%（P=0.03）。既往研究主要关注化疗联合GnRHa与否，对于化疗与GnRHa使用顺序的疗效区别尚不明确。
2018年1月13日，施普林格旗下《乳腺癌研究与治疗》在线发表复旦大学附属肿瘤医院和上海医学院、上海中医药大学附属岳阳中西医结合医院、昆明医科大学附属甘美医院、上海市奉贤区中心医院的研究报告，探讨了化疗和GnRHa同时或先后治疗雌激素受体阳性绝经前乳腺癌患者的卵巢功能和疗效。
该3期非盲平行随机对照研究（美国政府临床研究注册登记网站编号：NCT01712893）于2009年7月～2013年5月入组216例被诊断为雌激素受体阳性浸润性乳腺癌的45岁以下绝经前患者，并以1∶1的比例随机接受（新）辅助化疗联合GnRHa（戈舍瑞林或亮丙瑞林）的先后或同时治疗。所有患者被建议接受GnRHa至少2年。主要终点为早期绝经发生率，定义为末次化疗或GnRHa给药后绝经持续时间超过12个月、促卵泡激素和雌二醇达到绝经后水平或未知。次要终点为月经恢复、无病生存和总生存。
结果，中位随访时间为56.9个月（四分位距：49.5～72.4个月），先后组、同时组各108例，其中92例和78例有完整的主要终点数据：
早期绝经发生相似：22.8%、23.1%
未经校正的比例比：1.01（95%：0.50～2.08，P=0.969）
年龄校正的比例比：1.13（95%：0.54～2.37，P=0.737）
月经恢复时间相似：12.0、10.3个月（95%：9.3～14.7、8.2～12.4）
未经校正的风险比：0.83（95%：0.59～1.16，P=0.274）
年龄校正的风险比：0.90（95%：0.64～1.27，P=0.567）
两组无病生存相似（P=0.290）
两组总体生存相似（P=0.514）
因此，对于雌激素受体阳性绝经前患者，先后或同时使用化疗和GnRHa相比，卵巢功能保护作用和生存结局相似。由于未必所有化疗患者都会发生卵巢功能早衰，故先后使用化疗和GnRHa可能更为经济实惠，GnRHa或可推迟至化疗后月经恢复时再用。
Breast Cancer Res Treat. 2018 Jan 13. [Epub ahead of print]
Sequential versus simultaneous use of chemotherapy and gonadotropin-releasing hormone agonist (GnRHa) among estrogen receptor (ER)-positive premenopausal breast cancer patients: effects on ovarian function, disease-free survival, and overall survival.
Zhang Y, Ji Y, Li J, Lei L, Wu S, Zuo W, Jia X, Wang Y, Mo M, Zhang N, Shen Z, Wu J, Shao Z, Liu G.
Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Calmete Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; Shanghai Fengxian District Central Hospital, Shanghai, China.
OBJECTIVE: To investigate ovarian function and therapeutic efficacy among estrogen receptor (ER)-positive, premenopausal breast cancer patients treated with gonadotropin-releasing hormone agonist (GnRHa) and chemotherapy simultaneously or sequentially.
METHOD: This study was a phase 3, open-label, parallel, randomized controlled trial (NCT01712893). Two hundred sixteen premenopausal patients (under 45 years) diagnosed with invasive ER-positive breast cancer were enrolled from July 2009 to May 2013 and randomized at a 1:1 ratio to receive (neo)adjuvant chemotherapy combined with sequential or simultaneous GnRHa treatment. All patients were advised to receive GnRHa for at least 2 years. The primary outcome was the incidence of early menopause, defined as amenorrhea lasting longer than 12 months after the last chemotherapy or GnRHa dose, with postmenopausal or unknown follicle-stimulating hormone and estradiol levels. The menstrual resumption period and survivals were the secondary endpoints.
RESULT: The median follow-up time was 56.9 months (IQR 49.5-72.4 months). One hundred and eight patients were enrolled in each group. Among them, 92 and 78 patients had complete primary endpoint data in the sequential and simultaneous groups, respectively. The rates of early menopause were 22.8% (21/92) in the sequential group and 23.1% (18/78) in the simultaneous group [simultaneous vs. sequential: OR 1.01 (95% CI 0.50-2.08); p = 0.969; age-adjusted OR 1.13; (95% CI 0.54-2.37); p = 0.737]. The median menstruation resumption period was 12.0 (95% CI 9.3-14.7) months and 10.3 (95% CI 8.2-12.4) months for the sequential and simultaneous groups, respectively [HR 0.83 (95% CI 0.59-1.16); p = 0.274; age-adjusted HR 0.90 (95%CI 0.64-1.27); p = 0.567]. No significant differences were evident for disease-free survival (p = 0.290) or overall survival (p = 0.514) between the two groups.
CONCLUSION: For ER-positive premenopausal patients, the sequential use of GnRHa and chemotherapy showed ovarian preservation and survival outcomes that were no worse than simultaneous use. The application of GnRHa can probably be delayed until menstruation resumption after chemotherapy.
KEYWORDS: Breast cancer; ER-positive; GnRHa; Ovarian preservation; Premenopausal
PMID: 29332135
DOI: 10.1007/s10549-018-4660-y
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