STUDY QUESTION Does ovarian stimulation with the addition of tamoxifen or letrozole affect the number of cumulus-oocyte complexes (COCs) retrieved compared to standard ovarian stimulation in women with breast cancer who undergo fertility preservation? SUMMARY ANSWER Alternative ovarian stimulation protocols with tamoxifen or letrozole did not affect the number of COCs retrieved at follicle aspiration in women with breast cancer. WHAT IS KNOWN ALREADY Alternative ovarian stimulation protocols have been introduced for women with breast cancer who opt for fertility preservation by means of banking of oocytes or embryos. How these ovarian stimulation protocols compare to standard ovarian stimulation in terms of COC yield is unknown. STUDY DESIGN, SIZE, DURATION This multicentre, open-label randomized controlled superiority trial was carried out in 10 hospitals in the Netherlands and 1 hospital in Belgium between January 2014 and December 2018. We randomly assigned women with breast cancer, aged 18–43 years, who opted for banking of oocytes or embryos to one of three study arms; ovarian stimulation plus tamoxifen, ovarian stimulation plus letrozole or standard ovarian stimulation. Standard ovarian stimulation included GnRH antagonist, recombinant FSH and GnRH agonist trigger. Randomization was performed with a web-based system in a 1:1:1 ratio, stratified for oral contraception usage at start of ovarian stimulation, positive estrogen receptor (ER) status and positive lymph nodes. Patients and caregivers were not blinded to the assigned treatment. The primary outcome was number of COCs retrieved at follicle aspiration. PARTICIPANTS/MATERIALS, SETTING, METHODS During the study period, 162 women were randomly assigned to one of three interventions. Fifty-four underwent ovarian stimulation plus tamoxifen, 53 ovarian stimulation plus letrozole and 55 standard ovarian stimulation. Analysis was according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE No differences among groups were observed in the mean (±SD) number of COCs retrieved: 12.5 (10.4) after ovarian stimulation plus tamoxifen, 14.2 (9.4) after ovarian stimulation plus letrozole and 13.6 (11.6) after standard ovarian stimulation (mean difference −1.13, 95% CI −5.70 to 3.43 for tamoxifen versus standard ovarian stimulation and 0.58, 95% CI −4.03 to 5.20 for letrozole versus standard ovarian stimulation). After adjusting for oral contraception usage at the start of ovarian stimulation, positive ER status and positive lymph nodes, the mean difference was −1.11 (95% CI −5.58 to 3.35) after ovarian stimulation plus tamoxifen versus standard ovarian stimulation and 0.30 (95% CI −4.19 to 4.78) after ovarian stimulation plus letrozole versus standard ovarian stimulation. There were also no differences in the number of oocytes or embryos banked. There was one serious adverse event after standard ovarian stimulation: one woman was admitted to the hospital because of ovarian hyperstimulation syndrome. LIMITATIONS, REASONS FOR CAUTION The available literature on which we based our hypothesis, power analysis and sample size calculation was scarce and studies were of low quality. Our study did not have sufficient power to perform subgroup analysis on follicular, luteal or random start of ovarian stimulation. WIDER IMPLICATIONS OF THE FINDINGS Our study showed that adding tamoxifen or letrozole to a standard ovarian stimulation protocol in women with breast cancer does not impact the effectiveness of fertility preservation and paves the way for high-quality long-term follow-up on breast cancer treatment outcomes and women’s future pregnancy outcomes. Our study also highlights the need for high-quality studies for all women opting for fertility preservation, as alternative ovarian stimulation protocols have been introduced to clinical practice without proper evidence. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by a grant (2011.WO23.C129) of ‘Stichting Pink Ribbon’, a breast cancer fundraising charity organization in the Netherlands. M.G., C.B.L. and R.S. declared that the Center for Reproductive Medicine, Amsterdam UMC (location VUMC) has received unconditional research and educational grants from Guerbet, Merck and Ferring, not related to the presented work. C.B.L. declared a speakers fee for Inmed and Yingming. S.C.L. reports grants and non-financial support from Agendia, grants, non-financial support and other from AstraZeneca, grants from Eurocept-pharmaceuticals, grants and non-financial support from Genentech/Roche and Novartis, grants from Pfizer, grants and non-financial support from Tesaro and Immunomedics, other from Cergentis, IBM, Bayer, and Daiichi-Sankyo, outside the submitted work; In addition, S.C.L. has a patent UN23A01/P-EP pending that is unrelated to the present work. J.M.J.S. reported payments and travel grants from Merck and Ferring. C.C.M.B. reports her role as unpaid president of the National guideline committee on Fertility Preservation in women with cancer. K.F. received unrestricted grants from Merck Serono, Good Life and Ferring not related to present work. K.F. declared paid lectures for Ferring. D.S. declared former employment from Merck Sharp & Dohme (MSD). K.F. declared paid lectures for Ferring. D.S. reports grants from MSD, Gedeon Richter and Ferring paid to his institution; consulting fee payments from MSD and Merck Serono paid to his institution; speaker honoraria from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono paid to his institution. D.S. has also received travel and meeting support from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono. No payments are related to present work. TRIAL REGISTRATION NUMBER NTR4108. TRIAL REGISTRATION DATE 6 August 2013. DATE OF FIRST PATIENT’S ENROLMENT 30 January 2014.

中文翻译：

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乳腺癌女性的生育能力保留：关于各种卵巢刺激方案的多中心随机对照试验

研究问题 与接受保留生育力的乳腺癌女性的标准卵巢刺激相比，添加他莫昔芬或来曲唑的卵巢刺激是否会影响卵丘-卵母细胞复合物 (COC) 的回收数量？摘要 答案 使用他莫昔芬或来曲唑的替代卵巢刺激方案不会影响乳腺癌女性在卵泡抽吸时回收的 COC 数量。已知情况 对于选择通过储存卵母细胞或胚胎来保留生育能力的乳腺癌女性，已经引入了替代性卵巢刺激方案。这些卵巢刺激方案在 COC 产量方面与标准卵巢刺激相比如何尚不清楚。研究设计、规模、持续时间这个多中心，2014 年 1 月至 2018 年 12 月，在荷兰的 10 家医院和比利时的 1 家医院进行了开放标签随机对照优势试验。我们随机分配了 18-43 岁的乳腺癌女性，她们选择储存卵母细胞或胚胎三个学习分支之一；促排卵加他莫昔芬、促排卵加来曲唑或标准促排卵。标准卵巢刺激包括 GnRH 拮抗剂、重组 FSH 和 GnRH 激动剂触发器。使用基于网络的系统以 1:1:1 的比例进行随机化，对卵巢刺激开始时口服避孕药的使用、雌激素受体 (ER) 阳性和淋巴结阳性进行分层。患者和护理人员对分配的治疗不知情。主要结果是在卵泡抽吸时回收的 COC 数量。参与者/材料、环境、方法 在研究期间，162 名女性被随机分配到三种干预措施中的一种。54 例接受了卵巢刺激加他莫昔芬，53 例接受了卵巢刺激加来曲唑，55 例接受了标准卵巢刺激。分析按照意向治疗原则进行。主要结果和机会的作用 在检索到的 COC 的平均 (±SD) 数量方面未观察到组间差异：促排卵加他莫昔芬后为 12.5 (10.4)，促排卵加来曲唑后为 14.2 (9.4)，促排后为 13.6 (11.6)标准卵巢刺激（他莫昔芬与标准卵巢刺激的平均差异为 -1.13, 95% CI -5.70 至 3.43，来曲唑与标准卵巢刺激的平均差异为 0.58, 95% CI -4.03 至 5.20）。在卵巢刺激开始时调整口服避孕药的使用后，ER 状态和淋巴结阳性，卵巢刺激加他莫昔芬与标准卵巢刺激后的平均差异为 -1.11（95% CI -5.58 至 3.35），卵巢刺激加来曲唑与标准的平均差异为 0.30（95% CI -4.19 至 4.78）卵巢刺激。储存的卵母细胞或胚胎数量也没有差异。标准卵巢刺激后发生了一件严重的不良事件：一名女性因卵巢过度刺激综合征入院。局限性、谨慎的原因 我们的假设、功效分析和样本量计算所依据的现有文献很少，研究质量低下。我们的研究没有足够的能力对卵泡、黄体或随机开始的卵巢刺激进行亚组分析。研究结果的更广泛意义 我们的研究表明，在乳腺癌女性的标准卵巢刺激方案中添加他莫昔芬或来曲唑不会影响生育力保留的有效性，并为乳腺癌治疗的高质量长期随访铺平了道路结果和妇女未来的怀孕结果。我们的研究还强调了对所有选择保留生育能力的女性进行高质量研究的必要性，因为在没有适当证据的情况下，替代卵巢刺激方案已被引入临床实践。研究资金/竞争利益 该研究得到了荷兰乳腺癌筹款慈善组织“Stichting Pink Ribbon”的赠款 (2011.WO23.C129) 的支持。MG、CBL 和 RS 宣布生殖医学中心，阿姆斯特丹 UMC（地点 VUMC）已收到来自 Guerbet、默克和 Ferring 的无条件研究和教育资助，与所介绍的工作无关。CBL 宣布向 Inmed 和 Yingming 收取演讲费用。SCL 报告来自 Agendia 的赠款和非财务支持、来自阿斯利康的赠款、非财务支持和其他、来自 Eurocept-pharmaceuticals 的赠款、来自基因泰克/罗氏和诺华的赠款和非财务支持、来自辉瑞的赠款、赠款和非财务支持来自 Tesaro 和 Immunomedics 的支持，其他来自 Cergentis、IBM、Bayer 和 Daiichi-Sankyo 的支持，在提交的工作之外；此外，SCL 有一项与当前工作无关的专利 UN23A01/P-EP 正在申请中。JMJS 报告了默克和辉凌的付款和差旅补助。CCMB 报告了她作为癌症女性生育力保存国家指导委员会无薪主席的角色。KF 从 Merck Serono、Good Life 和 Ferring 获得了与当前工作无关的无限制资助。KF宣布为辉凌提供付费讲座。DS 宣布曾在 Merck Sharp & Dohme (MSD) 工作。KF宣布为辉凌提供付费讲座。DS 报告 MSD、Gedeon Richter 和 Ferring 向其机构支付的拨款；MSD 和默克雪兰诺向其机构支付的咨询费；MSD、Gedeon Richter、辉凌制药和默克雪兰诺向他的机构支付了演讲酬金。DS 还获得了 MSD、Gedeon Richter、Ferring Pharmaceuticals 和 Merck Serono 的差旅和会议支持。没有付款与目前的工作有关。试用注册号 NTR4108。