北京大学学报(医学版) ›› 2019, Vol. 51 ›› Issue (3): 536-541. doi: 10.19723/j.issn.1671-167X.2019.03.024

• 论著 • 上一篇    下一篇

抗缪勒管激素用于戈舍瑞林在年轻乳腺癌患者化疗期间保护卵巢储备功能的评价

王思源,王殊()   

  1. 北京大学人民医院乳腺外科, 北京 100044
  • 收稿日期:2019-03-15 出版日期:2019-05-09 发布日期:2019-06-26
  • 作者简介:王殊,主任医师,博士生导师,北京大学人民医院乳腺外科主任。1996年毕业于北京医科大学(现称北京大学医学部)临床医学系,2002年获得北京大学外科学博士学位,毕业后一直致力于乳腺疾病的临床和科研工作,擅长乳腺癌的综合治疗,在乳腺癌的影像诊断、外科手术、化疗、内分泌治疗、靶向治疗、晚期乳腺癌解救治疗及术后乳房重建等方面有丰富经验。2006—2007 年于美国M.D.Anderson 肿瘤中心和UMASS 肿瘤中心做访问学者和博士后,对乳腺癌的DNA 损伤修复进行研究。2010年在国内率先开展采用荧光示踪术中实时成像引导前哨淋巴结活检手术,对其可行性、操作规范进行了深入的研究,证实该技术在中国乳腺癌患者中安全可靠,有显著的优势。2016年11月“乳腺癌腋窝淋巴结手术方式及评估策略的规范应用和优化”项目荣获北京市科学技术奖三等奖。学术兼职有中国临床肿瘤学会理事会理事,中国临床肿瘤学会乳腺癌专家委员会常务委员,中国医师协会外科医师分会乳腺外科医师委员会青年委员会副主任委员,北京乳腺病防治学会学术专业委员会副主任委员,中国抗癌协会乳腺癌专业委员会常务委员,北京乳腺病防治学会外科专业委员会副主任委员,中华医学会肿瘤学分会青年委员会委员等。
  • 基金资助:
    北京大学人民医院研究与发展基金(RD 2014-13, 2015-Z-24)

Anti-Müllerian hormone as a new marker of the ovarian reserve function preservation by goserelin during (neo)adjuvant chemotherapy for young breast cancer patients

Si-yuan WANG,Shu WANG()   

  1. Department of Breast Surgery, Peking University People’s Hospital, Beijing 100044, China
  • Received:2019-03-15 Online:2019-05-09 Published:2019-06-26
  • Supported by:
    Supported by the Research and Development Fund of Peking University People’s Hospital(RD 2014-13 and 2015-Z-24)

摘要: 目的 监测反映卵巢储备功能的最佳生化指标——抗缪勒管激素(anti-Müllerian hormone,AMH)在化疗前和化疗结束后1年内的动态变化,评价促性腺激素释放激素激动剂(gonadotropin-releasing hormone agonist, GnRHa)戈舍瑞林在年轻乳腺癌患者化疗期间保护卵巢储备功能的效果。方法 选择2015年12月至2017年6月在北京大学人民医院乳腺外科就诊的年龄≤45岁Ⅰ~Ⅲ期乳腺癌患者101位,根据患者意愿,无干预分至化疗联合戈舍瑞林组(戈舍瑞林组)和单纯化疗组(化疗组)。在化疗开始前、化疗期间、化疗结束后半年、化疗结束后1年,连续监测两组患者的血清AMH和月经状态。首要研究终点是化疗结束后1年AMH低水平(<0.4 μg /L),次要研究终点是闭经(入组后停经时间超过12个月)。结果 51位患者选择单纯化疗,50位患者选择化疗联合戈舍瑞林保护卵巢功能。临床病理基线资料显示,未婚未育、生育意愿强烈、成功保乳、激素受体阴性、处于疾病Ⅰ期或Ⅱ期的乳腺癌患者更多地在化疗前选用戈舍瑞林保护卵巢功能。化疗结束后1年,化疗组患者AMH低水平率显著高于戈舍瑞林组患者 (74.5% vs. 38.0%, P<0.001), 闭经率也与AMH低水平率相一致(56.9% vs.24.0%, P=0.001),并且戈舍瑞林组的患者更多在化疗结束后6个月内恢复月经(78.9% vs.54.5%), AMH升至0.4 μg /L以上(71.0% vs.53.8%)。亚组分析中,无论年龄分组、化疗方案分组或化疗后是否口服他莫昔芬分组,戈舍瑞林组患者的血清AMH值和月经均恢复得更多。在化疗结束后1年,化疗组月经恢复的22人中有8人(36.4%), 戈舍瑞林组月经恢复的38人中有7人(18.4%)AMH仍处于低水平。此外,对化疗组20位患者和戈舍瑞林组21位患者在化疗过程中动态监测AMH和月经状态,化疗组患者的AMH均值在化疗开始后快速下降,在第3周期化疗前降至极低水平,此时70%的患者还未停经;戈舍瑞林组患者在第3周期化疗前全部停经,但AMH均值未降至低水平。结论 由于选择联合治疗的患者其血清AMH值在化疗结束后更多、更早地恢复,故对戈舍瑞林保护年轻乳腺癌患者卵巢储备功能的有效性提供了证据。相比月经状态,AMH更能精准地用于临床评价化疗前后年轻乳腺癌患者的卵巢储备功能。

关键词: 抗缪勒管激素, 戈舍瑞林, 年轻乳腺癌患者, 卵巢储备功能

Abstract: Objective: To observe the dynamic change of anti-Müllerian hormone (AMH) in 1 year after chemotherapy which is the best biochemical marker of ovarian reserve in reproductive medicine setting and to evaluate the effect of gonadotropin-releasing hormone agonist (GnRHa)goserelin to prevent ovarian reserve function during (neo)adjuvant chemotherapy for young breast cancer patients.Methods: Between December 2015 and June 2017, 101 breast cancer patients of age ≤ 45 years with stagesⅠtoⅢ had been enrolled. The patients were assigned without interference to receive either (neo)adjuvant chemotherapy with goserelin (goserelin group) or without goserelin (chemotherapy group) as their own selection. AMH and menstrual status were evaluated before, during and 0.5 year, 1 year after chemotherapy. Primary end point was the incidence of low AMH value (<0.4 μg/L) at the end of 1 year. Secondary end point was the incidence of amenorrhea(the absence of menses in the preceding 12 months after assignment). Results: In the study, 51 patients chose to join the chemotherapy group, while the other 50 patients selected goserelin to preserve their ovarian reserve function. More unmarried or childless, hormone receptors negative,receiving breast conservation therapy patients with earlier stage selected goserelin before chemotherapy. The incidence of low AMH value was significantly higher in chemotherapy group than in goserelin group (74.5% vs. 38.0%, P<0.001) in 1 year after chemotherapy. The incidence of amenorrhea was consistent with AMH (56.9% vs. 24.0%, P=0.001). And more patients’ menstruation (78.9% vs. 54.5%) and AMH value (71.0% vs. 53.8%) recovered in goserelin group within 6 months after chemotherapy. In sub-group analysis, AMH and menstruation seemingly recovered more in goserelin group independent of age, chemotherapy regimen and use of tamoxifen. Especially, AMH value of 36.4% (8/22) patients in chemotherapy group and 18.4% (7/38) patients in goserelin group still maintained low level (<0.4 μg /L) although their menstruation had recovered 1 year after chemotherapy. In addition, 41 patients (20 patients in chemotherapy group, 21 patients in goserelin group) could be evaluated for the dynamic change of AMH and menstrual status during chemotherapy. The mean level of AMH in chemotherapy group declined rapidly to very low level before the 3rd cycle, while 70% of the patients kept presence of menstruation. At the same time, the mean level of AMH in goserelin group was still above 0.4 μg /L, but all of the patients had menopause.Conclusion: Our study has offered evidence that Goserelin with chemotherapy could protect against ovarian reserve failure for young breast cancer patients, now that more patients’ AMH value recovered earlier who had selected co-treatment. AMH may be a more precise marker than menstrual status to clinically evaluate ovarian reserve function pre-, during and post- chemotherapy.

Key words: Anti-Müllerian hormone;, Goserelin, Young breast cancer patients, Ovarian reserve function

中图分类号: 

  • R737.9

表1

两组患者的基线临床病理特征"

Characteristic Chemotherapy group, n (N=51) Goserelin group, n (N=50) P value*
Age distribution/years 0.185 8
≤40 26 (51.0%) 32 (64.0%)
41-45 25 (49.0%) 18 (36.0%)
Marital status 0.015 8
Married 50 (98.0%) 42 (84.0%)
Unmarried 1 (2.0%) 8 (16.0%)
Full-term pregnancies before breast cancer diagnosis, No. 0.002 3
0 2 (3.9%) 11 (22.0%)
1 14 (27.5%) 21 (42.0%)
2 23 (45.1%) 9 (18.0%)
≥3 12 (23.5%) 9 (18.0%)
Fertility desires <0.000 1
Weak 49 (96.1%) 17 (34.0%)
Strong 2 (3.9%) 33 (66.0%)
Family history of cancer 0.777 1
No 14 (27.5%) 15 (30.0%)
Yes 37 (72.5%) 35 (70.0%)
Breast conserving therapy 0.003 9
Yes 16 (31.4%) 30 (60.0%)
No 35 (68.6%) 20 (40.0%)
Stage of cancer 0.015 8
10 (19.6%) 19 (38.0%)
31 (60.8%) 29 (58.0%)
10 (19.6%) 2 (4.0%)
ER 0.011 0
Negative 13 (25.5%) 25 (50.0%)
Positive 38 (74.5%) 25 (50.0%)
PR 0.034 4
Negative 15 (29.4%) 25 (50.0%)
Positive 36 (70.6%) 25 (50.0%)
HER-2 0.480 3
Negative 36 (70.6%) 32 (64.0%)
Positive 15 (29.4%) 18 (36.0%)
Subtypes 0.126 6
Luminal A 19 (37.3%) 11 (22.0%)
Luminal B 19 (37.3%) 17 (34.0%)
HER-2 overexpression 4 (7.8%) 11 (22.0%)
Triple negative 9 (17.6%) 11 (22.0%)
Chemotherapy regimens 0.479 0
AC 9 (17.6%) 9 (18.0%)
AC-T 25 (49.0%) 24 (48.0%)
AC-TH 11 (21.6%) 15 (30.0%)
Others 6 (11.8%) 2 (4.0%)
Taking tamoxifen 0.050 6
Yes 38 (74.5%) 28 (56.0%)
No 13 (25.5%) 22 (44.0%)

图1

两组患者化疗结束后1年的AMH低水平率和闭经率"

图2

两组患者化疗期间AMH均值的动态变化"

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