中国早期乳腺癌卵巢功能抑制临床应用专家共识（2021年版）

doi:10.19401/j.cnki.1007-3639.2022.02.010

摘要/Abstract

摘要：

卵巢功能抑制（ovarian function suppression,OFS）已经应用于乳腺癌治疗数十年,早期辅助治疗研究证实,单独进行OFS能够降低50岁以下乳腺癌患者的复发风险,改善生存情况。鉴于新的循证医学数据不断累积,中国抗癌协会乳腺癌专业委员会遂召集国内乳腺癌专家,在《中国早期乳腺癌卵巢功能抑制临床应用专家共识（2018年版）》的基础上共同商讨制订了《中国早期乳腺癌卵巢功能抑制临床应用专家共识（2021年版）》。2021年版共识建议,将药物去势[促性腺激素释放激素激动剂（gonadotropin releasing hormone agonist,GnRHa）]作为绝经前激素受体阳性的早期乳腺癌OFS的首选。中高危绝经前激素受体阳性乳腺癌患者推荐接受OFS的内分泌治疗;低危患者推荐选择性雌激素受体调节剂（selective estrogen receptor modulators,SERM）单药治疗;使用芳香化酶抑制剂（aromatase inhibitor,AI）代替SERM治疗的绝经前患者,需要同时接受OFS治疗。关于OFS联合方案,对绝经前激素受体阳性早期乳腺癌的中危和高危患者,或亚群处理效果模式图（subpopulation treatment effect pattern plot,STEPP）分析的较高风险患者推荐OFS联合AI治疗,OFS联合SERM治疗也是合理的选择。对存在SERM禁忌证的任何风险级别患者,推荐OFS联合AI治疗。关于OFS的使用时机,建议根据激素受体阳性乳腺癌患者化疗前的卵巢功能状态,决定辅助内分泌治疗方案。如果考虑卵巢保护,推荐GnRHa同步化疗,不影响患者的生存获益;如果不考虑卵巢保护,推荐GnRHa可以在化疗结束后直接序贯使用。已接受化疗的患者不推荐确认卵巢功能状态后再使用GnRHa。GnRHa辅助内分泌治疗的标准疗程应为5年。完成5年联合OFS的内分泌治疗后,如未绝经且耐受性良好,推荐继续5年联合OFS的内分泌治疗或5年SERM治疗。低危选择OFS替代化疗的患者,可考虑OFS联合内分泌治疗时长为2年。推荐与患者充分沟通可能出现的不良事件,选用合适的药物去势治疗方案。合理的安全管理能够有效地缓解不良反应,增加患者治疗的依从性。对于接受药物去势的患者,不常规推荐在药物去势治疗过程中监测雌激素水平并根据检测报告来决定是否继续药物去势。但在药物去势后,怀疑不完全的卵巢功能抑制时[包括改变用法如注射人员缺乏相关经验、更换剂型或出现某些可能提示卵巢功能恢复的生理变化如月经恢复和（或）更年期症状的周期性波动时],可以进行雌激素水平检测。绝经前乳腺癌患者,无论激素受体阳性或阴性,推荐在（新）辅助化疗前和化疗过程中使用OFS药物保护卵巢功能,降低卵巢功能早衰的发生风险,减少生育能力损害。推荐化疗前2周开始使用GnRHa,每28 d 1次,直至化疗结束后2周给予最后一剂药物。此外共识还建议,激素受体阳性乳腺癌患者抗肿瘤药物的临床试验,应尽可能纳入绝经前女性,在雌激素充分抑制的前提下,探索抗肿瘤药物对肿瘤生物学特性和患者长期生活质量的影响。

关键词: 乳腺癌, 卵巢功能抑制, 内分泌治疗, 专家共识

Abstract:

Ovarian function suppression (OFS) has been used in the treatment of breast cancer for decades. Early adjuvant treatment studies have confirmed that the application of OFS alone can reduce the recurrence risk of breast cancer patients under the age of 50 and improve their survival. With the emergence of new evidence-based medical data, the Breast Cancer Professional Committee of the China Anti-Cancer Association convened domestic clinical experts in the field of breast cancer treatment, who jointly discussed and formulated the "Chinese Consensus of Ovarian Function Suppression in Early Breast Cancer (2021 edition) " on the basis of the 2018 edition. Consensus suggests that gonadotropin-releasing hormone agonist (GnRHa) should be the first choice of OFS for premenopausal hormone receptor-positive (HR positive) early breast cancer. Medium- and high-risk premenopausal HR positive breast cancer patients are recommended for endocrine therapy including OFS; low-risk patients are recommended for selective estrogen receptor modulator (SERM) monotherapy; premenopausal patients who use aromatase inhibitor (AI) instead of SERM need to receive OFS at the same time. For the medium- and high-risk patients with premenopausal HR positive early breast cancer, or the medium/high-risk patients analyzed by subpopulation treatment effect pattern plot (STEPP), the combination of OFS and AI is recommended, and the combination of OFS and SERM is also an alternative choice. For patients with contraindications or at risk of contraindications to SERM, OFS combined with AI is recommended. The adjuvant endocrine therapy should be decided based on the status of ovarian function before adjuvant chemotherapy. If ovarian function protection is considered, GnRHa plus chemotherapy is recommended, which does not affect the survival benefits. If not, it is recommended that GnRHa can be used sequentially after chemotherapy. It is recommended that patients with confirmed ovarian function status after chemotherapy should not use GnRHa. The GnRHa adjuvant endocrine therapy should be used for 5 years. After 5 years, it is recommended to continue endocrine therapy combined with OFS for 5 years or 5 years of SERM therapy if the patients are still premenopausal and well tolerated. For low-risk patients who choose OFS instead of chemotherapy, OFS combined with endocrine therapy can be considered for 2 years. Full communication with patients based on adverse events of the OFS is needed before decision making. The sound management of adverse events will effectively relieve symptoms and increase the treatment compliance. For patients with OFS, it is not recommended to monitor estrogen levels routinely during the treatment and make decisions according to the test. However, when incomplete ovarian function suppression is suspected (including changes in usage such as unskilled injection, replacement of dosage forms, or indications of ovarian function recovery, such as menstrual recovery and/or the fluctuating perimenopausal symptoms), estrogen testing can be performed. For premenopausal patients, no matter HRs are positive or negative, it is recommended to use ovarian function suppression drugs before and during (neo)adjuvant chemotherapy to protect ovarian function and reduce the risk of ovarian function failure and impaired fertility. It is recommended to start using GnRHa 2 weeks before chemotherapy, once every 28 days, until 2 weeks after the last dose of chemotherapy.In addition, the consensus suggests that premenopausal patients with sufficient OFS should be included in the clinical trials so as to investigate the impact of HR positive breast cancer drugs on tumor biological characteristics and long-term quality of life.

Key words: Breast cancer, Ovarian function suppression, Endocrine therapy, Expert consensus

中图分类号:

R737.9

中国抗癌协会乳腺癌专业委员会. 中国早期乳腺癌卵巢功能抑制临床应用专家共识（2021年版）[J]. 中国癌症杂志, 2022, 32(2): 177-190.

Chinese Anti-Cancer Association, Committee of Breast Cancer Society. Expert consensus on clinical applications of ovarian function suppression for Chinese women with early breast cancer 2021 CACA-CBCS[J]. China Oncology, 2022, 32(2): 177-190.

图/表 4

表 1

图1

表2

表3

参考文献 50

[1]	曹毛毛,, 陈万青. GLOBOCAN 2020全球癌症统计数据解读[J]. 中国医学前沿杂志(电子版), 2021,13(3):63-69.
	CAO M M,, CHEN W Q. Interpretation on the global cancer statistics of GLOBOCAN 2020[J]. Chin J Front Med Sci Electron Version, 2021,13(3):63-69.
[2]	FAN L,, STRASSER-WEIPPL K,, LI J J, et al. Breast cancer in China[J]. Lancet Oncol, 2014,15(7):e279-e289.
[3]	EARLY BREAST CANCER TRIALISTS’ COLLABORATIVE GROUP(EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials[J]. Lancet, 2005,365(9472):1687-1717.
[4]	DAVIES C,, PAN H C,, GODWIN J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial[J]. Lancet, 2013,381(9869):805-816.
[5]	GRAY R G,, REA D,, HANDLEY K, et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6, 953 women with early breast cancer[J]. J Clin Oncol, 2013,31(18_suppl):5.
[6]	LHRH-AGONISTS IN EARLY BREAST CANCER OVERVIEW GROUP, CUZICK J,, AMBROISINE L, et al. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials[J]. Lancet, 2007,369(9574):1711-1723.
[7]	FRANCIS P A,, PAGANI O,, FLEMING G F, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer[J]. N Engl J Med, 2018,379(2):122-137.
[8]	NOH W C,, LEE J W,, NAM S J, et al. Role of adding ovarian function suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or resume menstruation after chemotherapy: the ASTRRA study[J]. J Clin Oncol, 2018,36(15_suppl):502.
[9]	PERRONE F,, DE LAURENTIIS M,, DE PLACIDO S, et al. The HOBOE-2 multicenter randomized phase Ⅲ trial in premenopausal patients with hormone-receptor positive early breast cancer comparing triptorelin plus either tamoxifen or letrozole or letrozole + zoledronic acid[J]. Ann Oncol, 2018, 29: viii704.
[10]	HARRISON G S,, WIERMAN M E,, NETT T M, et al. Gonadotropin-releasing hormone and its receptor in normal and malignant cells[J]. Endocr Relat Cancer, 2004,11(4):725-748.
[11]	DOISNEAU-SIXOU S F,, SERGIO C M,, CARROLL J S, et al. Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells[J]. Endocr Relat Cancer, 2003,10(2):179-186.
[12]	TAN S H,, WOLFF A C. Luteinizing hormone-releasing hormone agonists in premenopausal hormone receptor-positive breast cancer[J]. Clin Breast Cancer, 2007,7(6):455-464.
[13]	MCDONALD WADE S 3rd,, HACKNEY M H,, KHATCHERESSIAN J, et al. Ovarian suppression in the management of premenopausal breast cancer: methods and efficacy in adjuvant and metastatic settings[J]. Oncology, 2008,75(3/4):192-202.
[14]	中国抗癌协会乳腺癌专业委员会. 中国抗癌协会乳腺癌诊治指南与规范(2021年版)[J]. 中国癌症杂志, 2021,31(10):954-1040.
	The Society of Breast Cancer China Anti-cancer Association. Guidelines for breast cancer diagnosis and treatment by China Anti-cancer Association (2021 edition)[J]. China Oncol, 2021,31(10):954-1040.
[15]	中国抗癌协会乳腺癌专业委员会. 中国绝经前女性乳腺癌患者辅助治疗后绝经判断标准及芳香化酶抑制剂临床应用共识(草案修正案)[J]. 中国癌症杂志, 2011,21(5):418-420.
	The Society of Breast Cancer China Anti-cancer Association. Postmenopausal criteria for menopausal women and clinical consensus on aromatase application in China’s pre-menopausal women with breast cancer (draft amendment)[J]. China Oncol, 2011,21(5):418-420.
[16]	FRANCIS P A,, REGAN M M,, FLEMING G F, et al. Adjuvant ovarian suppression in premenopausal breast cancer[J]. N Engl J Med, 2015,372(5):436-446.
[17]	DEES E C,, DAVIDSON N E. Ovarian ablation as adjuvant therapy for breast cancer[J]. Semin Oncol, 2001,28(4):322-331.
[18]	JONAT W,, KAUFMANN M,, SAUERBREI W, et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the Zoladex Early Breast Cancer Research Association Study[J]. J Clin Oncol, 2002,20(24):4628-4635.
[19]	BUI K T,, WILLSON M L,, GOEL S, et al. Ovarian suppression for adjuvant treatment of hormone receptor-positive early breast cancer[J]. Cochrane Database Syst Rev, 2020, 3: CD013538.
[20]	BURSTEIN H J,, LACCHETTI C,, ANDERSON H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression[J]. J Clin Oncol, 2016,34(14):1689-1701.
[21]	THOMSSEN C,, BALIC M,, HARBECK N, et al. St. Gallen/Vienna 2021: a brief summary of the consensus discussion on customizing therapies for women with early breast cancer[J]. Breast Care (Basel), 2021,16(2):135-143.
[22]	PALUCH-SHIMON S,, CARDOSO F,, PARTRIDGE A H, et al. ESO-ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4)[J]. Ann Oncol, 31(6):674-696.
[23]	CARDOSO F,, KYRIAKIDES S,, OHNO S, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2019,30(8):1194-1220.
[24]	Lan B,, Ma F, et al. Int J Cancer, 2018, 143:184;J Clin Oncol, 2007, 1;25(25):3837-3845; Ann Oncol, 2008,19(8):1423-1429.
[25]	EARLY BREAST CANCER TRIALISTS’ COLLABORATIVE GROUP(EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials[J]. Lancet, 2015,386(10001):1341-1352.
[26]	REGAN M M,, FRANCIS P A,, PAGANI O, et al. Absolute benefit of adjuvant endocrine therapies for premenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: TEXT and SOFT trials[J]. J Clin Oncol, 2016,34(19):2221-2231.
[27]	REGAN M M,, FRANCIS P A,, PAGANI O, et al. Absolute improvements in freedom from distant recurrence with adjuvant endocrine therapy for premenopausal women with HR + HER2 -negative breast cancer: results from TEXT and SOFT [J]. J Clin Oncol, 2018,36(suppl 15):503-503.
[28]	LAMBERTINI M,, BONI, MICHELOTTI A, et al. Ovarian suppression with triptorelin during adjuvant breast cancer chemotherapy and long-term ovarian function, pregnancies, and disease-free survival: a randomized clinical trial[J]. JAMA, 2015,314(24):2632-2640.
[29]	LAMBERTINI M,, MOORE H C F,, LEONARD R C F, et al. Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: a systematic review and meta-analysis of individual patient-level data[J]. J Clin Oncol, 2018,36(19):1981-1990.
[30]	PAN H C,, GRAY R,, BRAYBROOKE J, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years[J]. N Engl J Med, 2017,377(19):1836-1846.
[31]	NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines®). Breast Cancer, Version 1. 2022[EB/OL]. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419[2021].
[32]	HICKEY M,, SAUNDERS C,, PARTRIDGE A, et al. Practical clinical guidelines for assessing and managing menopausal symptoms after breast cancer[J]. Ann Oncol, 2008,19(10):1669-1680.
[33]	LOIBL S,, LINTERMANS A,, DIEUDONNÉ A S, et al. Management of menopausal symptoms in breast cancer patients[J]. Maturitas, 2011,68(2):148-154.
[34]	PETREK J A,, NAUGHTON M J,, CASE L D, et al. Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: a prospective study[J]. J Clin Oncol, 2006,24(7):1045-1051.
[35]	LIEM G S,, MO F K,, PANG E, et al. Chemotherapy-related amenorrhea and menopause in young Chinese breast cancer patients: analysis on incidence, risk factors and serum hormone profiles[J]. PLoS One, 2015,10(10):e0140842.
[36]	SMITH I E,, DOWSETT M,, YAP Y S, et al. Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines[J]. J Clin Oncol, 2006,24(16):2444-2447.
[37]	宋三泰,, 陈建魁,, 单彬. 规范乳腺癌性激素化验报告理顺应用AIs的绝经标准[J]. 中华乳腺病杂志(电子版), 2012,6(3):238-243.
	SONG S T,, CHEN J K,, SHAN B. To standardize the sex hormone test report of breast cancer and straighten out the application of AIs’s menopausal standard[J]. Chin J Breast Dis Electron Ed, 2012,6(3):238-243.
[38]	江泽飞,, 王晓迪. 乳腺癌内分泌治疗十个热点问题的思考[J]. 中华外科杂志, 2015,2(12):895-900.
	JIANG Z F,, WANG X D. Consideration and discussion on ten hot issues of endocrine therapy for breast cancer[J]. Chin J Surg, 2015,2(12):895-900.
[39]	GNANT M,, MLINERITSCH B,, STOEGER H, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial[J]. Lancet Oncol, 2011,12(7):631-641.
[40]	MOORE H C,, UNGER J M,, PHILLIPS K A, et al. Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy[J]. N Engl J Med, 2015,372(10):923-932.
[41]	MOORE H C F,, UNGER J M,, PHILLIPS K A, et al. Final analysis of the prevention of early menopause study (POEMS)/SWOG intergroup S0230[J]. J Natl Cancer Inst, 2019,111(2):210-213.
[42]	DEL MASTRO L,, BONI, MICHELOTTI A, et al. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial[J]. JAMA, 2011,306(3):269-276.
[43]	LAMBERTINI M,, BONI L C,, MICHELOTTI A, et al. Ovarian suppression with triptorelin during adjuvant breast cancer chemotherapy and long-term ovarian function, pregnancies, and disease-free survival[J]. JAMA, 2015,314(24):2632.
[44]	LAMBERTINI M,, BONI L,, MICHELOTTI A, et al. Final analysis of the PROMISE-GIM6 phase Ⅲ trial assessing GnRH agonist use during chemotherapy as a strategy to preserve ovarian function in premenopausal patients with early breast cancer[J]. J Clin Oncol, 39(suppl 15):516-516.
[45]	LAMBERTINI M,, MOORE H C F,, LEONARD R C F, et al. Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: a systematic review and meta-analysis of individual patient-level data[J]. J Clin Oncol, 2018,36(19):1981-1990.
[46]	PALUCH-SHIMON S,, CARDOSO F,, PARTRIDGE A H, et al. ESO-ESMO 4th international consensus guidelines for breast cancer in young women (BCY4)[J]. Ann Oncol, 2020,31(6):674-696.
[47]	CARDOSO F,, KYRIAKIDES S,, OHNO S, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2019,30(10):1674.
[48]	中国年轻乳腺癌诊疗与生育管理专家共识专家委员会. 年轻乳腺癌诊疗与生育管理专家共识[J]. 中华肿瘤杂志, 2019,41(7):486-495.
	Expert Committee on China’s Young Breast Cancer Diagnosis and Treatment and Fertility Management Expert Consensus. Expert consensus on diagnosis and treatment and birth management for young breast cancer[J]. Chin J Oncol, 2019,41(7):486-495.
[49]	Premenopausal women with breast cancer: developing drugs for treatment guidance for industry[P]. FDA, 2020, 2020-D-1553.
[50]	GAO J J,, KROL D,, NARAYAN P, et al. Bringing safe and effective therapies to premenopausal women with breast cancer: efforts to broaden eligibility criteria[J]. Ann Oncol, 2021,32(8):950-953.

《中国抗癌协会乳腺癌诊治指南与规范（2021版）》^[14]	《中国绝经前女性乳腺癌患者辅助治疗后绝经判断标准及芳香化酶抑制剂临床应用共识（草案修正案）》^[15]
年龄≥60岁患者	年龄≥50岁患者,化疗后或在服用SERM药物期间闭经至少12个月,且E2及 FSH水平连续测定至少3次均达到绝经后水平
年龄<60岁患者,自然停经≥12个月,在近1年未接受化疗、他莫昔芬、托瑞米芬或卵巢去势的情况下,FSH和 E2水平在绝经后范围内	年龄在45~50岁患者,化疗后或在服用SERM药物期间闭经至少24个月,且 E2及FSH水平连续测定至少3次均达到绝经后水平
年龄<60岁正在服用他莫昔芬或托瑞米芬的患者,FSH和 E2水平在绝经后范围内	年龄小于45岁患者,由于卵巢功能恢复的概率较大,原则上不适用本标准
	上述标准中年龄可参考患者家族女性平均停经年龄作出个例调整

危险度	判别要点
危险度	转移淋巴结	ER/PR	其他情况
低危	阴性	阳性	同时具备以下条件a：pT≤2 cm;组织学Ⅰ级;LVI阴性;HER2阴性;年龄≥35岁;Ki-67≤20%或实验室中位值;
			HER2阴性且不满足上述条件,但多基因检测低危
中危	不符合低/高危定义的其他情况
高危	1~3枚阳性	阳性	具备以下条件之一^b：组织学Ⅲ级;pT>5 cm;HER2阳性;多基因检测高危;
		阴性	任何情况
	≥4枚阳性	任何情况	任何情况

相关不良事件	药物治疗	非药物治疗
血管舒缩症状：潮热,盗汗	SSRI帕罗西汀（不宜与SERM合用） SNRIs：文拉法辛加巴喷丁可乐定中医中药	针灸合适的衣物
阴道症状：阴道干燥,阴道萎缩	阴道雌激素^△：Ovestin（阴道雌三醇）	非激素润滑剂阴道保湿霜
性功能障碍：性欲减退	非激素润滑剂,阴道保湿霜
阴道雌激素：Ovestin（阴道雌三醇）	充分的医患沟通放松心情
骨骼肌症状：骨质疏松,骨折	双膦酸盐,地舒单抗,维生素D和钙^*	负重练习戒烟限酒
关节痛	NSAID和COX-2抑制剂维生素D	减肥全身抗阻力练习物理治疗
精神系统症状：情绪变化,如抑郁	SSRI（如西酞普兰,依他普仑）
SNRIs（如文拉法辛）	规律运动均衡饮食心理治疗