选择适当的生物标志物监测ER+乳腺癌患者卵巢功能抑制的有效性

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来源:觅健 2024-03-24 11:20:14

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关键词：化疗他莫昔芬紫杉醇内分泌治疗中内分泌治疗

中国医学论坛报今日肿瘤 2024-03-23 20:02 北京 2人听过

药物性卵巢功能抑制通常通过促性腺激素释放激素（GnRH）激动剂实现，其广泛应用为接受芳香化酶抑制剂（AI）或他莫昔芬治疗的雌激素受体阳性（ER+）乳腺癌患者提供了可逆的卵巢功能抑制。2024年1月19日，NPJ Breast Cancer上发表了一篇名为“Selection of appropriate biomarkers to monitor effectiveness of ovarian function suppression in pre-menopausal patients with ER+ breast cancer”的综述文章[1]，探讨了雌二醇（E2）、促卵泡激素（FSH）和黄体生成素（LH）等多种生物标志物在监测ER+乳腺癌患者应用药物性卵巢功能抑制有效性中的作用。现特将重点内容整理如下，以供参考。

卵巢功能抑制在绝经前ER+乳腺癌中的应用

在美国，约20%的乳腺癌患者为绝经前妇女[2,3]。对年轻患者，卵巢功能的保留非常重要，因为这关系到她们未来多年的生育能力。OPTION、PROMISE-GIM6和POEMS等多项研究显示，内分泌治疗中联合卵巢功能抑制可防止早期卵巢功能不全、受损生育力和早期更年期，提高月经恢复和化疗后怀孕潜力[4-7]。SOFT、TEXT及ASTRRA试验显示，内分泌治疗中联合卵巢功能抑制还可以提高卵巢癌患者的无病生存率、远距离复发自由度和总体生存率[8-10]。此外，研究提示，尽管卵巢功能抑制与他莫昔芬联合使用仍可选，但相较于仅用他莫昔芬，与AI联合使用时，卵巢功能抑制带来的益处更明显，尤其是在高风险肿瘤患者中[11]。

GnRH激动剂可下调GnRH受体，抑制FSH和LH释放，减少卵巢产生环状E2，从而诱导可逆的医学性卵巢消融，实现药物性卵巢功能抑制（图1）[12]。一旦停止GnRH激动剂治疗，环状E2、FSH和LH恢复至正常水平，生育能力也随着卵泡成熟的恢复而恢复[12]。与外科手术或放射性消融的不可逆性相比，药物性卵巢功能抑制的可逆性在绝经前妇女中尤为有利[12]。但研究者在设计评估GnRH激动剂作为卵巢功能抑制药物的新研究时面临着一个问题，即在绝经前ER+乳腺癌患者中，哪种生物标志物是最有意义的卵巢功能抑制的替代指标？GnRH激动剂在绝经前乳腺癌中的作用模式

生物标志物在绝经前ER+乳腺癌中的应用

大约有21%~71%患有乳腺癌的年轻女性由于化疗而面临早期更年期的风险[13]。其中一半患者的卵巢功能在完成化疗后的6个月内恢复；四分之一的患者卵巢功能恢复更慢，在完成化疗后的6~24个月内恢复[14]。Breast Cancer in Young Women（BCY5）指南指出，如果能在化疗治疗后2年内使卵巢功能恢复，支持将GnRH激动剂添加到他莫昔芬中[15]。在发生治疗性闭经的患者中，有学者建议定期监测生物标志物，如E2、FSH和LH，以预测卵巢功能的恢复[16,17]。这些生物标志物有可能能够协助确定卵巢功能是否已经恢复或是否需要启动卵巢抑制疗法[16,17]。

E2水平是衡量卵巢功能是否受到抑制的关键生物标志物。在没有规律月经周期的情况下，E2水平≥40 pg/mL通常可判定女性为绝经前状态[18]。同时，E2水平的检测对于监测患者对内分泌治疗的敏感性、治疗的遵从性和治疗方案的调整也是有用的[19,20]。如果接受GnRH激动剂治疗的女性的E2水平处于绝经前范围内，表明卵巢功能抑制可能不完整，不充分的卵巢功能抑制可能会降低AI的疗效作用[21-23]。一般来说，E2水平≤10 pg/mL符合绝经状态，是卵巢功能抑制的适当水平，患者可以使用AI[23]。

值得注意的是，E2水平的检测标准尚未明确，且不同实验室的检测方法可能有所不同，这些因素都可能影响E2水平的准确性和可靠性[24]。此外，因为E2呈昼夜节律，早晨的峰值可能与白天的随机样本不同，所以血液采样的时间也可能影响E2检测结果[25,26]。

FSH

绝经前乳腺癌患者通常不检测FSH，某些临床试验可能将FSH作为确定绝经前状态、随机分层和/或确认卵巢功能抑制的参数之一[14,27,28]。在GnRH激动剂治疗期间，FSH的分泌最初会下降，但在1个月后逐渐恢复到基线水平[23]。这归因于当达到完全卵巢功能抑制时的抑制素反馈作用[28]。在卵巢功能未完全抑制的情况下，如E2水平上升时，也有报道FSH水平升高[28]。NCCN指出，E2和FSH水平均可用于支持绝经判断，然而尚缺乏明确的FSH和E2解释标准[29]。月经停止的情况下，血清E2水平≥40 pg/mL和FSH水平<30 mIU/mL的阈值已被用来判定卵巢功能恢复[18]。目前来说，FSH通常不作为单独的生物标志物用于治疗决策。

在乳腺癌女性中，有时会在基线时检测LH以确认患者的绝经前状态和是否需要抑制卵巢功能。然而，在使用GnRH激动剂治疗期间，肿瘤学家不会常规地监测LH，因为它在治疗决策中没有临床作用。大多数临床实践指南，例如美国临床肿瘤学会（ASCO）和欧洲医学肿瘤学会（ESO-ESMO）的BCY5指南，并不建议在乳腺癌患者中监测LH水平[15,21,22]。某些临床试验将LH评估作为符合资格的标准之一，例如ABCSG-12和GABG IV-B-93试验中使用LH>50 pg/mL作为参数之一，以在没有规律月经周期的情况下确认患者绝经状态[30,31]。

其他考量

ER+乳腺癌患者的治疗目标是抑制雌激素，因此检测E2至关重要。然而，不充分的雌激素抑制可能部分原因是患者的身体质量指数（BMI）过高。由于血清雌激素的主要来源是脂肪组织，超重的患者可能拥有更多的雌激素前体通过芳香化酶代谢[32]。即使是接受过卵巢切除术的患者也可能E2水平高于绝经后的范围，这是因为脂肪组织作为外源性雌激素的来源。高BMI和卵巢完整的患者可能有更高的卵巢功能不完全抑制的风险[32]。SOFT研究的一项亚分析表明，BMI较高（中位数27 kg/m2）的患者，其E2水平高于严格的2.72 pg/mL次优阈值，也有较低的基线FSH（中位数8 IU/L）和LH（中位数7 IU/L）水平[16,19]。定期监测E2是检测卵巢功能突破性恢复潜力的主要生物标志物[19]。卵巢功能抑制的阈值被认为是E2<40 pg/mL，尽管有记录表明阈值水平低至10 pg/mL[3,23]。

关于AI或他莫昔芬等伴随治疗对E2水平的任何潜在混杂影响都不值得关注。由于AI主要抑制循环雄激素向雌激素的外周转化（从雄烯二酮到E1，从睾酮到E2的次要途径），如果患者的卵巢功能没有通过其他手段（如GnRH激动剂疗法）抑制，AI不会将雌激素抑制到亚生理水平[33]。同样，他莫昔芬的混合激动剂/拮抗剂作用被认为可以被戈舍瑞林的雌激素消耗作用抵消[34]。

评估GnRH激动剂的疗效

ASCO关于卵巢抑制的指南是基于1月制剂的GnRH激动剂的试验数据[22]。既往临床试验表明，大多数绝经前妇女在接受GnRH激动剂治疗后能够达到显著的卵巢功能抑制（E2<30 pg/mL）[27,35-37]。无论年龄、化疗史、紫杉醇方案和肿瘤特征如何，不同药物（亮丙瑞林和戈舍瑞林）之间的E2水平都是一致的[35]。而其他生物标志物则不太一致，试验者观察到FSH水平因患者年龄（P=0.02）、cERB-B2（+）肿瘤（P=0.05）以及化疗方案中缺乏紫杉醇（P=0.05）不同存在差异；LH水平因GnRH激动剂（P=0.03）和肿瘤分期（T1 + T2 vs T3 + T4，P=0.03）不同存在差异[35]。

在前列腺癌的情境中，在GnRH激动剂治疗期间，睾酮是在记录去势水平的首选生物标志物，既不检测FSH也不检测LH[38-40]。从前列腺癌的情境推断，将E2作为乳腺癌中GnRH激动剂疗效的主要生物标志物也是合理的。

小结

基于以上讨论，研究者建议在乳腺癌试验中，通过E2水平来衡量卵巢功能抑制的主要终点。因为E2最能反映卵巢功能，是乳腺中激活雌激素受体的激素（图1）[3]。ASCO指南指出，在接受GnRH激动剂治疗期间检测出E2处于绝经前水平，这表明卵巢处于不完全抑制状态[22]。FSH和/或LH水平的检测则可能作为次要终点。当然，无论激素水平如何，月经期的恢复都表明GnRH激动剂治疗失败。在对各类剂型GnRH激动剂进行评估时，应该关注到，在两剂GnRH激动剂用药的间隔期，可能会存在E2逃逸的潜在风险。研究者建议在下一剂GnRH激动剂用药前再次检测E2水平，以确保其卵巢抑制效果仍然存在。在临床实践中，对月经恢复状况的评估和/或更年期症状的周期性波动的关注至关重要[22]，但是否在临床试验方案中纳入此类评估，需予以权衡。

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