Rodgers Rachael J, Reid Geoffrey D, Koch Juliette, Deans Rebecca, Ledger William L, Friedlander Michael, Gilchrist Robert B, Walters Kirsty A, Abbott Jason A
Department of Reproductive Medicine, Royal Hospital for Women, Barker St., Randwick 2031, Sydney, Australia.
School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
Hum Reprod. 2017 May 1;32(5):1033-1045. doi: 10.1093/humrep/dex027.
Can controlled ovarian hyperstimulation (COH) for fertility preservation be effectively conducted in women with breast cancer without worsening their prognosis?
COH with co-administration of letrozole suppresses oestradiol levels without significantly impacting oocyte yield or decreasing disease-free survival rates.
Oestradiol has the capacity to stimulate the proliferation of breast cancer cells. COH can cause oestradiol levels to rise by an order of magnitude above physiological levels. Concern exists regarding the effect of supra-physiological oestradiol levels in women with a recent diagnosis of breast cancer.
STUDY DESIGN, SIZE, DURATION: A systematic review of the literature was performed using MEDLINE (PubMed database), EMBASE and the Cochrane Library. The search was restricted to articles written in English. No restrictions regarding the date of publication were applied. Safety was assessed in terms of relapse rates and cancer-related mortality rates. Peak oestradiol concentrations were recorded for different stimulation protocols. Efficacy was measured in terms of the total number of oocytes collected and proportion of mature oocytes. The primary outcome was mortality/recurrence in premenopausal women with Stage I-IIIB breast cancer who underwent COH in the immediate post-operative period, prior to chemotherapy.
PARTICIPANTS/MATERIALS, SETTING, METHODS: This is a systematic review of randomized control trials (RCTs), case control and cohort studies reporting on the primary outcome of mortality/recurrence after COH in women with early breast cancer, or secondary outcomes of oocyte yield and peak oestrogen concentration. Owing to the small number of RCTs available, other study types were included. The last electronic search was run in April 2016. Two prospective non-randomized studies reported relapse and breast cancer-related mortality rates in 397 women with breast cancer, of whom 149 underwent COH. Twelve studies reported the peak oestradiol concentrations of 882 women undergoing COH with letrozole co-administration. Four studies compared the oocyte yield of 248 women who underwent COH plus letrozole with 254 women who underwent standard COH. Two studies compared peak oestradiol concentrations and oocyte yield in 61 women who underwent COH with tamoxifen co-administration and 49 women who underwent COH without tamoxifen. One study compared letrozole and tamoxifen co-administration, and another study compared the co-administration of letrozole and anastrozole.
The search identified 1002 records of which 15 were included in the final analysis. There was no evidence of a decline in relapse-free survival rates in the two studies of women with breast cancer who received COH with letrozole co-administration compared with women who did not undergo fertility preservation procedures. The largest of these studies reported recurrences in 6/120 (5.0%) women who received COH plus letrozole compared with 12/217 (5.5%) women who did not undergo COH (mean follow-up 5.0 versus 6.9 years; hazard ratio for recurrence 0.77, 95%CI 0.28-2.13). Conclusions regarding women with breast cancer who received tamoxifen during COH could not be made due to insufficient data. Peak oestradiol concentrations (338-829 pg/ml) were suppressed by letrozole when commenced on Days 2-3, with no decrease in oocyte yield. Tamoxifen does not suppress oestradiol concentrations, but may convey protection via its inhibitory action on the oestrogen receptor.
LIMITATIONS, REASONS FOR CAUTION: Any statements regarding the safety of COH in women with breast cancer are based on a limited number of observational studies. High quality evidence is unlikely to become available for ethical and practical reasons. Whilst available data do not indicate a decline in disease-free survival, a small effect cannot be excluded. Breast cancers are heterogeneous in their genetic profile and receptor status, making the results of studies difficult to generalize to individual cases. The implication of alterations in other hormone levels such as androgens, progestins or vascular endothelial growth factor secondary to COH in women with breast cancer has not been quantified.
The co-administration of 5 mg of letrozole daily commencing on Day 2 and continuing throughout COH is recommended as it reduces peak oestradiol concentrations without significantly decreasing oocyte yield. The use of a GnRH agonist trigger is beneficial as oestradiol concentrations rapidly decrease post-administration and rates of ovarian hyperstimulation are lower than with an hCG trigger, without a corresponding reduction in clinical pregnancy or live birth rates in cryopreservation cycles. The protective effect of tamoxifen has not been evaluated although theoretically may be of benefit due to its action on the oestrogen receptor.
STUDY FUNDING/COMPETING INTEREST(S): None.
None.
对于乳腺癌女性患者，能否在不恶化其预后的情况下有效地进行控制性卵巢过度刺激（COH）以保存生育能力？
在COH过程中联合使用来曲唑可抑制雌二醇水平，且不会显著影响卵母细胞产量或降低无病生存率。
雌二醇具有刺激乳腺癌细胞增殖的能力。COH可使雌二醇水平升高至生理水平之上一个数量级。近期诊断为乳腺癌的女性患者，超生理水平的雌二醇会产生何种影响，人们对此存在担忧。
研究设计、规模、持续时间：使用MEDLINE（PubMed数据库）、EMBASE和Cochrane图书馆对文献进行系统综述。检索仅限于用英文撰写的文章。未对发表日期进行限制。通过复发率和癌症相关死亡率评估安全性。记录不同刺激方案下的雌二醇峰值浓度。通过收集的卵母细胞总数和成熟卵母细胞比例来衡量疗效。主要结局是I-IIIB期绝经前乳腺癌女性患者在术后即刻、化疗前接受COH后的死亡率/复发率。
研究对象/材料、研究环境、方法：这是一项对随机对照试验（RCT）、病例对照研究和队列研究的系统综述，这些研究报告了早期乳腺癌女性患者COH后死亡率/复发率的主要结局，或卵母细胞产量和雌激素峰值浓度的次要结局。由于可用的RCT数量较少，纳入了其他研究类型。最后一次电子检索于2016年4月进行。两项前瞻性非随机研究报告了397例乳腺癌女性患者的复发率和乳腺癌相关死亡率，其中149例接受了COH。十二项研究报告了882例联合使用来曲唑进行COH的女性患者的雌二醇峰值浓度。四项研究比较了248例接受COH加来曲唑的女性与254例接受标准COH的女性的卵母细胞产量。两项研究比较了61例联合使用他莫昔芬进行COH的女性与49例未使用他莫昔芬进行COH的女性的雌二醇峰值浓度和卵母细胞产量。一项研究比较了来曲唑和他莫昔芬的联合使用，另一项研究比较了来曲唑和阿那曲唑的联合使用。
检索到1002条记录，其中15条纳入最终分析。在两项关于接受联合使用来曲唑进行COH的乳腺癌女性患者的研究中，与未进行生育力保存程序的女性相比，无证据表明无复发生存率下降。其中最大的一项研究报告，接受COH加来曲唑的6/120（5.0%）例女性出现复发，而未接受COH的12/217（5.5%）例女性出现复发（平均随访时间分别为5.0年和6.9年；复发风险比为0.77，95%CI 0.28 - 2.13）。由于数据不足，无法得出关于在COH期间接受他莫昔芬治疗的乳腺癌女性患者的结论。从第2 - 3天开始使用来曲唑可抑制雌二醇峰值浓度（338 - 829 pg/ml），且卵母细胞产量未降低。他莫昔芬不会抑制雌二醇浓度，但可能通过其对雌激素受体的抑制作用提供保护。
局限性、谨慎原因：关于乳腺癌女性患者COH安全性的任何陈述均基于有限数量的观察性研究。出于伦理和实际原因，不太可能获得高质量证据。虽然现有数据未表明无病生存率下降，但不能排除存在小的影响。乳腺癌在基因谱和受体状态方面具有异质性，则研究结果难以推广至个体病例。尚未对乳腺癌女性患者因COH导致的其他激素水平变化（如雄激素、孕激素或血管内皮生长因子）的影响进行量化。
建议从第2天开始每天联合使用5 mg来曲唑，并在整个COH过程中持续使用，因为它可降低雌二醇峰值浓度，且不会显著降低卵母细胞产量。使用促性腺激素释放激素（GnRH）激动剂触发是有益的，因为给药后雌二醇浓度迅速下降，卵巢过度刺激的发生率低于使用人绒毛膜促性腺激素（hCG）触发，且在冷冻保存周期中临床妊娠率或活产率没有相应降低。他莫昔芬的保护作用尚未评估，尽管从理论上讲，由于其对雌激素受体作用，可能有益。
研究资金/利益冲突：无。
无。
