依维莫司治疗激素受体阳性、HER2阴性进展期乳腺癌的疗效及安全性研究
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摘要
目的探讨依维莫司对激素受体(HR)阳性、人类表皮生长因子受体2(HER2)阴性进展期乳腺癌患者的疗效及安全性。方法回顾性分析41例接受依维莫司治疗的HR阳性、HER2阴性的进展期乳腺癌患者的临床资料,评估依维莫司的临床疗效、无进展生存期(PFS)及不良反应。结果 41例患者使用维莫司治疗的时间为0.1～23.0个月,其中9例因不良反应停药,2例因经济原因停药,故有30例患者可评估疗效,其中4例(13.3%)部分缓解,16例(53.4%)疾病稳定,10例(33.3%)疾病进展。中位无进展生存期(mPFS)为5.2个月(1.2～22.2个月)。中位总生存期为12.0个月(1.3～30.0个月)。在可评估疗效的30例患者中,4例患者使用依维莫司时间超过12个月。药物不良反应方面,2例患者因经济原因停药,故有39例患者可评估不良反应,其中呼吸困难6例(2例出现肺间质病变,其中1例为4级病变),皮疹8例(2例为4级皮疹),骨髓抑制1例,39例患者均存在不同程度的口腔溃疡(4例为4级口腔溃疡)。进一步分析HR表达情况、使用依维莫司时所处疾病线数、患者是否存在内脏转移与生存的关系发现,雌激素受体(ER)≤50%和﹥50%的患者mPFS分别为3.0、6.0个月(χ2=4.178,P=0.041)。结论经多线化疗和内分泌治疗后,依维莫司联合内分泌治疗对HR阳性、HER2阴性的进展期乳腺癌患者仍有一定疗效,但需密切监测患者不良反应。
Objective To investigate the efficacy and safety of everolimus in patients with hormone receptor(HR)positive and human epidermal growth factor receptor 2(HER2) negative advanced breast cancer,and to analyze the factors affecting the efficacy of everolimus.Method A retrospective analysis including the clinical data of 41 patients with HR-positive and HER2-negative advanced breast cancer who were treated with everolimus was performed to evaluate the clinical efficacy,progression-free survival(PFS),and adverse reactions of everolimus.Result The treatment duration of41 patients was 0.1 to 23.0 months,9 of which were discontinued due to side effects and 2 were discontinued for economic reasons.Therefore,there were 30 cases left available for efficacy evaluation.Among the evaluable cases,partial response was achieved in 4 cases(13.3%),stable disease was achieved in 16 cases(53.4%),and progressive disease occurred in 10 cases(33.3%).The median progression-free survival(mPFS) was 5.2 months(1.2-22.2 months).The median overall survival(mOS) was 12.0 months(1.3-30.0 months).4 evaluable cases experienced a more than 12 months consecutive everolimus treatment.In terms of adverse effects,there are 39 cases available for analysis but 2 drug discontinuation cases for economic reasons in the all 41 patients.The adverse effects included dyspnea in 6 cases(2 cases with pulmonary interstitial disease,and 1 case with grade 4 lesions),rash in 8 cases(2 cases with grade 4 rash) and myelosuppression in 1 case.All the 39 cases experienced a varying degree of oral ulcers(4 cases with grade 4 oral ulcers).In addition,we analyzed the potential effect factors of everolimus efficacy,including the HR expression level,the number of disease lines,and the interaction between presence of visceral metastases and survival,and found that in the patients with estrogen receptor(ER)≤50% and ER>50%,their mPFS was 3.0 months and 6.0 months,respectively(χ2=4.178,P=0.041).Conclusion After multiline chemotherapy and endocrine therapy,everolimus combined with endocrine therapy still has a certain therapeutic effect on HR positive and HER2 negative advanced breast cancer,but the adverse effects should be closely monitored.
Objective To investigate the efficacy and safety of everolimus in patients with hormone receptor(HR)positive and human epidermal growth factor receptor 2(HER2) negative advanced breast cancer,and to analyze the factors affecting the efficacy of everolimus.Method A retrospective analysis including the clinical data of 41 patients with HR-positive and HER2-negative advanced breast cancer who were treated with everolimus was performed to evaluate the clinical efficacy,progression-free survival(PFS),and adverse reactions of everolimus.Result The treatment duration of41 patients was 0.1 to 23.0 months,9 of which were discontinued due to side effects and 2 were discontinued for economic reasons.Therefore,there were 30 cases left available for efficacy evaluation.Among the evaluable cases,partial response was achieved in 4 cases(13.3%),stable disease was achieved in 16 cases(53.4%),and progressive disease occurred in 10 cases(33.3%).The median progression-free survival(mPFS) was 5.2 months(1.2-22.2 months).The median overall survival(mOS) was 12.0 months(1.3-30.0 months).4 evaluable cases experienced a more than 12 months consecutive everolimus treatment.In terms of adverse effects,there are 39 cases available for analysis but 2 drug discontinuation cases for economic reasons in the all 41 patients.The adverse effects included dyspnea in 6 cases(2 cases with pulmonary interstitial disease,and 1 case with grade 4 lesions),rash in 8 cases(2 cases with grade 4 rash) and myelosuppression in 1 case.All the 39 cases experienced a varying degree of oral ulcers(4 cases with grade 4 oral ulcers).In addition,we analyzed the potential effect factors of everolimus efficacy,including the HR expression level,the number of disease lines,and the interaction between presence of visceral metastases and survival,and found that in the patients with estrogen receptor(ER)≤50% and ER>50%,their mPFS was 3.0 months and 6.0 months,respectively(χ2=4.178,P=0.041).Conclusion After multiline chemotherapy and endocrine therapy,everolimus combined with endocrine therapy still has a certain therapeutic effect on HR positive and HER2 negative advanced breast cancer,but the adverse effects should be closely monitored.
引文
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[5] Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+)breast cancer:BOLERO-2 final progression-free survival analysis[J]. Adv Ther, 2013, 30(10):870-884.
[6] Piccart M, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer:overall survival results from BOLERO-2[J]. Ann Oncol, 2014, 25(12):2357-2362.
[7] Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors:a GINECO study[J]. J Clin Oncol, 2012, 30(22):2718-2724.
[8] Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer[J]. Nat Rev Cancer,2009, 9(9):631-643.
[9] Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism[J]. Cell, 2006, 124(3):471-484.
[10] Beeram M, Tan QT, Tekmal RR, et al. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling[J]. Ann Oncol, 2007, 18(8):1323-1328.
[11] Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours:revised RECIST guideline(version 1.1)[J]. Eur J Cancer, 2009, 45(2):228-247.
[12] Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0:development of a comprehensive grading system for the adverse effects of cancer treatment[J]. Semin Radiat Oncol,2003, 13(3):176-181.
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[14]曲金荣,邸立军(综述),李惠平(审校). ER阳性HER2阴性复发转移性乳腺癌一线治疗现状[J].癌症进展, 2016,14(12):1170-1173; 1186.
[15] Massarweh S, Romond E, Black EP, et al. A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor(ER)-positive breast cancer after aromatase inhibitor(AI)failure[J]. Breast Cancer Res Treat, 2014, 143(2):325-332.
[16] Ballinger TJ, Meier JB, Jansen VM. current landscape of targeted therapies for hormone-receptor positive, her2 negative metastatic breast cancer[J]. Front Oncol, 2018, 8:308.
[17] AlFakeeh A, Brezden-Masley C. Overcoming endocrine resistance in hormone receptor-positive breast cancer[J].Curr Oncol, 2018, 25(Suppl 1):S18-S27.
[18] D'Souza A, Spicer D, Lu J. Overcoming endocrine resistance in metastatic hormone receptor-positive breast cancer[J]. J Hematol Oncol, 2018, 11(1):80.
[19] Yamnik RL, Holz MK. mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen receptor alpha serine 167 phosphorylation[J]. FEBS Lett, 2010, 584(1):124-128.
[20] Efeyan A, Sabatini DM. mTOR and cancer:many loops in one pathway[J]. Curr Opin Cell Biol, 2010, 22(2):169-176.
[21] Liu CY, Wu CY, Petrossian K, et al. Treatment for the endocrine resistant breast cancer:current options and future perspectives[J]. J Steroid Biochem Mol Biol, 2017, 172:166-175.
[22] Boulay A, Rudloff J, Ye J, et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer[J]. Clin Cancer Res, 2005, 11(14):5319-5328.
[23] Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer[J]. J Clin Oncol,2009, 27(16):2630-2637.
[24] Noguchi S, Masuda N, Iwata H, et al. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2[J]. Breast Cancer, 2014, 21(6):703-714.
[25]李惠平,邵彬,王晶,等.依维莫司治疗激素受体阳性进展期乳腺癌疗效和安全性的回顾性研究[J].癌症进展,2015, 13(2):120-124.
[26] Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer[J]. N Engl J Med, 2012, 366(6):520-529.
[2] Torre LA, Sauer AM, Chen MS Jr, et al. Cancer statistics for Asian Americans, Native Hawaiians, and Pacific Islanders, 2016:converging incidence in males and females[J].CA Cancer J Clin, 2016, 66(3):182-202.
[3] Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer[J]. Nat Genet, 2013, 45(12):1446-1451.
[4] Ma CX, Reinert T, Chmielewska I, et al. Mechanisms of aromatase inhibitor resistance[J]. Nat Rev Cancer, 2015, 15(5):261-275.
[5] Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+)breast cancer:BOLERO-2 final progression-free survival analysis[J]. Adv Ther, 2013, 30(10):870-884.
[6] Piccart M, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer:overall survival results from BOLERO-2[J]. Ann Oncol, 2014, 25(12):2357-2362.
[7] Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors:a GINECO study[J]. J Clin Oncol, 2012, 30(22):2718-2724.
[8] Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer[J]. Nat Rev Cancer,2009, 9(9):631-643.
[9] Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism[J]. Cell, 2006, 124(3):471-484.
[10] Beeram M, Tan QT, Tekmal RR, et al. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling[J]. Ann Oncol, 2007, 18(8):1323-1328.
[11] Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours:revised RECIST guideline(version 1.1)[J]. Eur J Cancer, 2009, 45(2):228-247.
[12] Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0:development of a comprehensive grading system for the adverse effects of cancer treatment[J]. Semin Radiat Oncol,2003, 13(3):176-181.
[13] Smith IE, Dowsett M. Aromatase inhibitors in breast cancer[J]. N Engl J Med, 2003, 348(24):2431-2442.
[14]曲金荣,邸立军(综述),李惠平(审校). ER阳性HER2阴性复发转移性乳腺癌一线治疗现状[J].癌症进展, 2016,14(12):1170-1173; 1186.
[15] Massarweh S, Romond E, Black EP, et al. A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor(ER)-positive breast cancer after aromatase inhibitor(AI)failure[J]. Breast Cancer Res Treat, 2014, 143(2):325-332.
[16] Ballinger TJ, Meier JB, Jansen VM. current landscape of targeted therapies for hormone-receptor positive, her2 negative metastatic breast cancer[J]. Front Oncol, 2018, 8:308.
[17] AlFakeeh A, Brezden-Masley C. Overcoming endocrine resistance in hormone receptor-positive breast cancer[J].Curr Oncol, 2018, 25(Suppl 1):S18-S27.
[18] D'Souza A, Spicer D, Lu J. Overcoming endocrine resistance in metastatic hormone receptor-positive breast cancer[J]. J Hematol Oncol, 2018, 11(1):80.
[19] Yamnik RL, Holz MK. mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen receptor alpha serine 167 phosphorylation[J]. FEBS Lett, 2010, 584(1):124-128.
[20] Efeyan A, Sabatini DM. mTOR and cancer:many loops in one pathway[J]. Curr Opin Cell Biol, 2010, 22(2):169-176.
[21] Liu CY, Wu CY, Petrossian K, et al. Treatment for the endocrine resistant breast cancer:current options and future perspectives[J]. J Steroid Biochem Mol Biol, 2017, 172:166-175.
[22] Boulay A, Rudloff J, Ye J, et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer[J]. Clin Cancer Res, 2005, 11(14):5319-5328.
[23] Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer[J]. J Clin Oncol,2009, 27(16):2630-2637.
[24] Noguchi S, Masuda N, Iwata H, et al. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2[J]. Breast Cancer, 2014, 21(6):703-714.
[25]李惠平,邵彬,王晶,等.依维莫司治疗激素受体阳性进展期乳腺癌疗效和安全性的回顾性研究[J].癌症进展,2015, 13(2):120-124.
[26] Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer[J]. N Engl J Med, 2012, 366(6):520-529.