绝经前乳腺癌化疗致闭经相关因素分析及绝经评估的研究
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摘要
目的探讨绝经前乳腺癌化疗致闭经(CIA)的影响因素,了解化疗后卵巢功能的变化规律及CIA与绝经的关系。方法回顾性收集300例接受化疗(至少4个周期)的绝经前乳腺癌的临床资料,记录患者的年龄、病理类型、肿块分期、腋窝淋巴结转移数、激素受体、人表皮生长因子受体-2(HER-2)、化疗方案、放疗、内分泌治疗、靶向治疗、月经变化等情况和血清性激素水平[卵泡剌激素(FSH),黄体生成素(LH),雌二醇(E2)]并进行分析。采用ROC曲线、Fisher精确概率检验及卡方检验分析各因素与CIA之间的关系。使用Kaplan-Meier生存分析统计CIA发生时间与性激素水平达到绝经时间的差异。结果 204例患者出现CIA,年龄与CIA发生具有明显相关性,曲线下面积为0.899(P<0.001,95%CI:0.863～0.935),年龄影响CIA的最佳临界值为43岁。CIA的发生与病理类型、肿块分期、腋窝淋巴结转移数、雌激素受体(ER)、孕激素受(PR)、HER-2状态无关、化疗方案、是否放疗、曲妥珠单抗靶向治疗、内分泌治疗无关(P>0.05)。CIA患者中,年龄≤45岁者更易恢复月经(91.4%vs 35.8%,P<0.001),月经恢复的中位时间为6.7月(3.0～11.3月);绝经更多见于年龄>45岁者(1.4%vs 50.0%,P<0.001)。Kaplan-Meier分析显示,CIA的发生时间明显早于性激素水平达到绝经的时间(2.6月vs 13.6月,P<0.001);在46～50岁、>50岁两个年龄组中,CIA均明显早于性激素水平达绝经的时间[(2.6月vs 17.2月,P<0.001),(1.9月vs 12.1月,P<0.001)]。结论年龄是CIA发生、月经恢复的独立且具有预测意义的重要影响因素。绝经多发生在确诊乳腺癌时年龄>45岁的患者,月经恢复多见于≤45岁患者。CIA的发生明显早于性激素水平达绝经状态,这一时间间隔对乳腺癌患者出现CIA后绝经状态的判断具有重要的参考价值,对合理选择内分泌治疗药物具有重要的临床意义。
Objective To investigate influencing factors of Chemotherapy-Induced Amenorrhea(CIA) and identify their ovarian function and actual menstrual status. Methods Patients with premenopausal breast cancer undergoing at least 4 cycles of chemotherapy were recruited. The patient′s age, pathological type, tumor stage, the number of axillary lymph node metastasis, the hormone receptor, HER-2, chemotherapy, radiotherapy, endocrine therapy, targeted therapy, the changes of menstruation, and serum sex hormone levels(FSH, LH, E2) were analyzed. ROC curve, Fisher′s exact probability test, and chi-square test were used to determine the relationship between the factors and CIA. Meanwhile, Kaplan Meier-survival was applied to analyze the interval between CIA and menopause. Results The CIA was observed in 204 patients. Age exhibited apparent correlation with the CIA, AUC 0.899(P<0.001,95% CI: 0.863～0.935) and the CIA′s best threshold was 43. The occurrence of CIA was not significantly associated with tumor stage, pathological type, the number of axillary lymph node metastasis, the status of ER, PR, and HER-2, chemotherapy regimens, whether received radiotherapy,targeted therapy or endocrine therapy(P>0.05). Among the individuals with CIA, age less than or equal to 45 years old were more likely to restore menstruation(91.4% vs 35.8%, P<0.001), the median time of menstrual recovery was 6.7 months(3.0～11.3 months). Menopause generally occurred in cases over 45 years old(1.4% vs 50.0%, P<0.001). Through Kaplan Meier-analysis, the time of CIA occurred evidently earlier than menopause(2.6 months vs 13.6 months, P<0.001); in the group of 46～50 years old and over 50 years old, the time interval was significantly(2.6 months vs 17.2 months, P<0.001;1.9 months vs 12.1 months, P<0.001). Conclusions Age is an independent and major predictor for the occurrence of CIA, menstrual resumption, and menopause. Menopause generally occurs in patients over 45 years old, while menstruation recovery is found in patients less than or equal to 45. The occurrence of CIA is earlier than menopausal, which is critical in judging actual menopause status and for optimizing endocrine regimen.
Objective To investigate influencing factors of Chemotherapy-Induced Amenorrhea(CIA) and identify their ovarian function and actual menstrual status. Methods Patients with premenopausal breast cancer undergoing at least 4 cycles of chemotherapy were recruited. The patient′s age, pathological type, tumor stage, the number of axillary lymph node metastasis, the hormone receptor, HER-2, chemotherapy, radiotherapy, endocrine therapy, targeted therapy, the changes of menstruation, and serum sex hormone levels(FSH, LH, E2) were analyzed. ROC curve, Fisher′s exact probability test, and chi-square test were used to determine the relationship between the factors and CIA. Meanwhile, Kaplan Meier-survival was applied to analyze the interval between CIA and menopause. Results The CIA was observed in 204 patients. Age exhibited apparent correlation with the CIA, AUC 0.899(P<0.001,95% CI: 0.863～0.935) and the CIA′s best threshold was 43. The occurrence of CIA was not significantly associated with tumor stage, pathological type, the number of axillary lymph node metastasis, the status of ER, PR, and HER-2, chemotherapy regimens, whether received radiotherapy,targeted therapy or endocrine therapy(P>0.05). Among the individuals with CIA, age less than or equal to 45 years old were more likely to restore menstruation(91.4% vs 35.8%, P<0.001), the median time of menstrual recovery was 6.7 months(3.0～11.3 months). Menopause generally occurred in cases over 45 years old(1.4% vs 50.0%, P<0.001). Through Kaplan Meier-analysis, the time of CIA occurred evidently earlier than menopause(2.6 months vs 13.6 months, P<0.001); in the group of 46～50 years old and over 50 years old, the time interval was significantly(2.6 months vs 17.2 months, P<0.001;1.9 months vs 12.1 months, P<0.001). Conclusions Age is an independent and major predictor for the occurrence of CIA, menstrual resumption, and menopause. Menopause generally occurs in patients over 45 years old, while menstruation recovery is found in patients less than or equal to 45. The occurrence of CIA is earlier than menopausal, which is critical in judging actual menopause status and for optimizing endocrine regimen.
引文
[1] 黄哲宙,陈万青,吴春晓,等.中国女性乳腺癌的发病和死亡现况——全国32个肿瘤登记点2003-2007年资料分析报告[J]. 肿瘤,2012,32(6):435-439.
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[6] Gray J M,Rasanayagam S,Engel C,et al. State of evidence 2017: an update on the connection between breast cancer and the environment[J].Environ Health,2017,16(1):94.
[7] Fan L,Zheng Y,Yu K D,et al. Breast cancer in a transitional society over 18 years: trends and presentstatus in Shanghai, China[J]. Breast Cancer Res Treat,2009,117(2):409-416.
[8] Swain S M,Jeong J H,Jr G C,et al. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer[J]. N Engl J Med,2010,362(22):2053-2065.
[9] Torino F,Barnabei A,De V L,et al.Chemotherapy-induced ovarian toxicity in patients affected by endocrine-responsive early breast cancer[J]. Critical Reviews in Oncology/Hematology,2014,89(1):27-42.
[10] Yoo C,Yun M R,Ahn J H,et al. Chemotherapy-induced amenorrhea, menopause-specific quality of life, and endocrine profiles in premenopausal women with breast cancer who received adjuvant anthrax cycline-based chemotherapy: a prospective cohort study[J]. Cancer Chemmother Pharmacol,2013,72(3): 565-575.
[11] 凌宇,傅建民,石剑,等.钙及维生素D对绝经前早期乳腺癌患者内分泌治疗初期骨量的影响[J]. 广东医学,2012,33(11):1601-1603.
[12] Liem G S,Mo F K F,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.
[13] Yeo W,Lee H M,Chan A,et al. Risk factors and natural history of breast cancer in younger Chinese women[J]. World J Clinical Oncology,2014,5(5):1097-1106.
[14] Rosendahl M,Ahlgren J,Andersen J,et al. The risk of amenorrhea after adjuvant chemotherapy for early stage breast cancer is related to inter-individual variations in chemotherapy-induced leukocyte nadir in young patients: data from the randomized SBG 2000-1 study[J]. Eur J Cancer,2009,45(18):3198-3204.
[15] Jeruss J S,Woodruff T K. Preservation of fertility in patients with cancer[J]. N Engl J Med,2009,360(9):902-911.
[16] Sonmezer M,Oktay K. Fertility preservation in young women undergoing breast cancer therapy[J]. The Oncologist,2006,11(5):422-434.
[17] 李惠平,汪有蕃. 乳腺癌化疗致闭经的利弊及随后的内分泌治疗[J].中国癌症杂志,2007,17(2): 165-169.
[18] Swain S M,Land S R,Ritter M W,et al. Amenorrhea in premenopausal women on the doxorubicin and cyclophosphamide followed by docetaxel arm of NSABPB-30 trial[J]. Breast Cancer Res Treat,2009,113(2):315-320.
[19] Su H I,Sammel M D,Velders L,et al. Association of cyclophosphamide drug-metabolizing enzyme polymorphisms and chemotherapy-related ovarian failure in breast cancer survivors[J]. Fertil Steril,2010,94(2):645-654.
[20] Zhou W B,Yin H,Liu X A,et al. Incidence of chemotherapy-induced amenorrhea associated with epirubicin,docetaxel and navelbine in younger breast cancer patients[J]. BMC Cancer,2010,10(1): 281.
[21] Colleoni M,Gelber S,Goldhirsch A,et al. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93[J]. J Clin Oncol,2006,24(9):1332-1341.
[22] Tham Y L,Sexton K,Weiss H,et al. The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane[J]. Am J Clin Oncol,2007,30(2):126-132.
[23] Najafi S,Djavid G E,Mehrdad N,et al. Taxane-based regimens as a risk factor for chemotherapy-induced amenorrhea[J]. Menopause,2011,18(2):208-212.
[24] Ebctcg. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials[J]. Lancet,2005,365(9472):1687-1717.
[25] Sch?r J,Sickmann A,Beier D,et al. Critical research gaps and translational priorities for the successful prevention and treatment ofbreast cancer[J]. Breast Cancer Res, 2013,15(5):92.
[26] Fallowfield L J,Bliss J M,Porter L S,et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer[J]. J Clin Oncol,2006,24(6):910-917.
[27] Cuzick J,Sestak I,Baum M,et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial [J]. Lancet Oncol,2010,11(12):1135-1141.
[28] Bodai B I,Tuso P. Breast cancer survivorship: a comprehensive review of long-term medical issues and lifestyle recommendations[J]. Perm J,2015,19(2):48-79.
[2] Goldhirsch A,Wood W C,Coates A S,et al. Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011[J]. Annals of Oncology,2011,22(8):1736-1747.
[3] Qin Y,Jiao X,Simpson J L,et al. Genetics of primary ovarian insufficiency: new developments and opportunities [J]. Hum Reprod Update,2015,21(6):787-808.
[4] Siegel R L,Miller K D,Jemal A. Cancer statistics, 2015[J]. CA Cancer J Clin,2015,65(1):11-30.
[5] Yeo W,Mo F,Pang E,et al. Profiles of lipids, blood pressure and weight changes among premenopausal Chinese breast cancer patients after adjuvant chemotherapy[J]. BMC Womens Health,2017,17(1):55.
[6] Gray J M,Rasanayagam S,Engel C,et al. State of evidence 2017: an update on the connection between breast cancer and the environment[J].Environ Health,2017,16(1):94.
[7] Fan L,Zheng Y,Yu K D,et al. Breast cancer in a transitional society over 18 years: trends and presentstatus in Shanghai, China[J]. Breast Cancer Res Treat,2009,117(2):409-416.
[8] Swain S M,Jeong J H,Jr G C,et al. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer[J]. N Engl J Med,2010,362(22):2053-2065.
[9] Torino F,Barnabei A,De V L,et al.Chemotherapy-induced ovarian toxicity in patients affected by endocrine-responsive early breast cancer[J]. Critical Reviews in Oncology/Hematology,2014,89(1):27-42.
[10] Yoo C,Yun M R,Ahn J H,et al. Chemotherapy-induced amenorrhea, menopause-specific quality of life, and endocrine profiles in premenopausal women with breast cancer who received adjuvant anthrax cycline-based chemotherapy: a prospective cohort study[J]. Cancer Chemmother Pharmacol,2013,72(3): 565-575.
[11] 凌宇,傅建民,石剑,等.钙及维生素D对绝经前早期乳腺癌患者内分泌治疗初期骨量的影响[J]. 广东医学,2012,33(11):1601-1603.
[12] Liem G S,Mo F K F,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.
[13] Yeo W,Lee H M,Chan A,et al. Risk factors and natural history of breast cancer in younger Chinese women[J]. World J Clinical Oncology,2014,5(5):1097-1106.
[14] Rosendahl M,Ahlgren J,Andersen J,et al. The risk of amenorrhea after adjuvant chemotherapy for early stage breast cancer is related to inter-individual variations in chemotherapy-induced leukocyte nadir in young patients: data from the randomized SBG 2000-1 study[J]. Eur J Cancer,2009,45(18):3198-3204.
[15] Jeruss J S,Woodruff T K. Preservation of fertility in patients with cancer[J]. N Engl J Med,2009,360(9):902-911.
[16] Sonmezer M,Oktay K. Fertility preservation in young women undergoing breast cancer therapy[J]. The Oncologist,2006,11(5):422-434.
[17] 李惠平,汪有蕃. 乳腺癌化疗致闭经的利弊及随后的内分泌治疗[J].中国癌症杂志,2007,17(2): 165-169.
[18] Swain S M,Land S R,Ritter M W,et al. Amenorrhea in premenopausal women on the doxorubicin and cyclophosphamide followed by docetaxel arm of NSABPB-30 trial[J]. Breast Cancer Res Treat,2009,113(2):315-320.
[19] Su H I,Sammel M D,Velders L,et al. Association of cyclophosphamide drug-metabolizing enzyme polymorphisms and chemotherapy-related ovarian failure in breast cancer survivors[J]. Fertil Steril,2010,94(2):645-654.
[20] Zhou W B,Yin H,Liu X A,et al. Incidence of chemotherapy-induced amenorrhea associated with epirubicin,docetaxel and navelbine in younger breast cancer patients[J]. BMC Cancer,2010,10(1): 281.
[21] Colleoni M,Gelber S,Goldhirsch A,et al. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93[J]. J Clin Oncol,2006,24(9):1332-1341.
[22] Tham Y L,Sexton K,Weiss H,et al. The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane[J]. Am J Clin Oncol,2007,30(2):126-132.
[23] Najafi S,Djavid G E,Mehrdad N,et al. Taxane-based regimens as a risk factor for chemotherapy-induced amenorrhea[J]. Menopause,2011,18(2):208-212.
[24] Ebctcg. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials[J]. Lancet,2005,365(9472):1687-1717.
[25] Sch?r J,Sickmann A,Beier D,et al. Critical research gaps and translational priorities for the successful prevention and treatment ofbreast cancer[J]. Breast Cancer Res, 2013,15(5):92.
[26] Fallowfield L J,Bliss J M,Porter L S,et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer[J]. J Clin Oncol,2006,24(6):910-917.
[27] Cuzick J,Sestak I,Baum M,et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial [J]. Lancet Oncol,2010,11(12):1135-1141.
[28] Bodai B I,Tuso P. Breast cancer survivorship: a comprehensive review of long-term medical issues and lifestyle recommendations[J]. Perm J,2015,19(2):48-79.