HR+HER2-晚期乳腺癌内分泌治疗临床应用的研究进展
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摘要
晚期乳腺癌目前难以治愈,是导致乳腺癌患者死亡的主要原因。内分泌治疗具有不良反应少、给药方式简单和延长患者生存期的优点,是无内脏危象的绝经后激素受体(HR)阳性且人类表皮生长因子受体2(HER2)阴性(HR+HER2-)晚期乳腺癌患者的首选治疗方式,其治疗药物主要包括他莫昔芬(TAM)、芳香化酶抑制剂(AI)和氟维司群。随着对乳腺癌耐药机制的深入研究,众多克服内分泌耐药的药物相继问世,如CDK4/6抑制剂和mTOR抑制剂,使内分泌治疗药物的选择不断优化。本文对晚期乳腺癌内分泌治疗药物的临床研究进行综述。对于HR+HER2-晚期乳腺癌患者,一线内分泌治疗药物的疗效:氟维司群>AI>TAM;内分泌治疗耐药者可选择内分泌治疗联合CDK4/6抑制剂或mTOR抑制剂,如CDK4/6抑制剂+AI、CDK4/6抑制剂+氟维司群、mTOR抑制剂+TAM、mTOR抑制剂+AI、mTOR抑制剂+氟维司群。具体药物选择需对患者的既往用药情况、肿瘤负荷、疾病进展速度和经济情况进行综合考量。对于一线化疗获益患者,维持治疗可延长患者的无进展生存期(PFS)及总生存期(OS)。本文系统地总结了国内外相关临床研究的结论,探讨HR+HER2-晚期乳腺癌患者内分泌治疗的疗效以及一线化疗后维持治疗使患者获益的情况,以期提高HR+HER2-晚期乳腺癌患者的预后生存质量。
引文
[1]HUOBER J,THRLIMANN B.The role of combination chemotherapy in the treatment of patients with metastatic breast cancer[J].Breast Care(Basel),2009,4(6):367-372.
[2]CARDOSO F,FALLOWFIELD L,COSTA A,et al.Locally recurrent or metastatic breast cancer:ESMO clinical practice guidelines for diagnosis,treatment and follow-up[J].Ann Oncol,2011,22(Suppl 6):vi25-vi30.
[3]WILCKEN N,HORNBUCKLE J,GHERSI D.Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer[J].Cochrane Database Syst Rev,2003(2):CD002747.
[4]CARDOSO F,COSTA A,SENKUS E,et al.3rd ESO-ESMO international consensus guidelines for advanced breast cancer(ABC 3)[J].Ann Oncol,2017,28(12):3111.
[5]NABHOLTZ J M,BUZDAR A,POLLAK M,et al.Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women:results of a North American multicenter randomized trial.Arimidex Study Group[J].J Clin Oncol,2000,18(22):3758-3767.
[6]BONNETERRE J,BUZDAR A,NABHOLTZ J M,et al.Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma[J].Cancer,2001,92(9):2247-2258.
[7]MOURIDSEN H T.Letrozole in advanced breast cancer:the PO25 trial[J].Breast Cancer Res Treat,2007,105(Suppl 1):19-29.
[8]PARIDAENS R J,DIRIX L Y,BEEX L V,et al.PhaseⅢstudy comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women:the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group[J].J Clin Oncol,2008,26(30):4883-4890.
[9]MAURI D,PAVLIDIS N,POLYZOS N P,et al.Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer:meta-analysis[J].J Natl Cancer Inst,2006,98(18):1285-1291.
[10]ROBERTSON J F,LINDEMANN J P,LLOMBART-CUSSAC A,et al.Fulvestrant 500 mg versus anastrozole 1mg for the first-line treatment of advanced breast cancer:follow-up analysis from the randomized'FIRST'study[J].Breast Cancer Res Treat,2012,136(2):503-511.
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[12]JFR R,BONDARENKO I M,TRISHKINA E,et al.Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer(FALCON):An international,randomised,double-blind,phase 3trial[J].Lancet,2016,388(10063):2997-3005.
[13]YARDLEY D A,NOGUCHI S,PRITCHARD K I,et al.Everolimus plus exemestane in postmenopausal patients with HR(+)breast cancer:BOLERO-2final progression-free survival analysis[J].Adv Ther,2013,30(10):870-884.
[14]DI LEO A,JERUSALEM G,PETRUZELKA L,et al.Results of the CONFIRM phaseⅢtrial comparing fulvestrant250mg with fulvestrant 500mg in postmenopausal women with estrogen receptor-positive advanced breast cancer[J].J Clin Oncol,2010,28(30):4594-4600.
[15]DI LEB A,JERUSALEM G,PETRUZELKA L,et al.Final overall survival:fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial[J].J Natl Cancer Inst,2014,106(1):djt337.
[16]FINN R S,CROWN J P,LANG I,et al.The cyclindependent kinase 4/6inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive,HER2-negative,advanced breast cancer(PALOMA-1/TRIO-18):a randomised phase 2study[J].Lancet Oncol,2015,16(1):25-35.
[17]FINN R S,MARTIN M,RUGO H S,et al.Palbociclib and letrozole in advanced breast cancer[J].N Engl J Med,2016,375(20):1925-1936.
[18]HORTOBAGYI G N,STEMMER S M,BURRIS H A,et al.Ribociclib as first-line therapy for HR-positive,advanced breast cancer[J].N Engl J Med,2016,375(18):1738-1748.
[19]GOETZ M P,TOI M,CAMPONE M,et al.MONARCH3:Abemaciclib as initial therapy for advanced breast cancer[J].J Clin Oncol,2017,35(32):3638-3646.
[20]CRISTOFANILLI M,TURNER N C,BONDARENKO I,et al.Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive,HER2-negative metastatic breast cancer that progressed on previous endocrine therapy(PALOMA-3):final analysis of the multicentre,double-blind,phase 3 randomised controlled trial[J].Lancet Oncol,2016,17(4):425-439.
[21]SLEDGE G W,TOI M,NEVEN P,et al.MONARCH 2:Abemaciclib in combination with fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy[J].J Clin Oncol,2017,35(25):2875-2884.
[22]SLAMON D J,NEVEN P,CHIA S,et al.PhaseⅢrandomized study of ribociclib and fulvestrant in hormone receptor-positive,human epidermal growth factor receptor2-negative advanced breast cancer:MONALEESA-3[J].J Clin Oncol,2018,36(24):2465-2472.
[23]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 GINECOstudy[J].J Clin Oncol,2012,30(22):2718-2724.
[24]ROYCE M,BACHELOT T,VILLANUEVA C,et al.Everolimus plus endocrine therapy for postmenopausal women with estrogen receptor-positive,human epidermal growth factor receptor 2-negative advanced breast cancer:A Clinical Trial[J].JAMA Oncol,2018,4(7):977-984.
[25]KORNBLUM N,ZHAO F M,MANOLA J,et al.Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptorpositive,human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy:Results of PrE0102[J].J Clin Oncol,2018,36(16):1556-1563.
[26]WILSON F R,VARU A,MITRA D,et al.Systematic review and network meta-analysis comparing palbociclib with chemotherapy agents for the treatment of postmenopausal women with HR-positive and HER2-negative advanced/metastatic breast cancer[J].Breast Cancer Res Treat,2017,166(1):167-177.
[27]KLOKE O,KLAASSEN U,OBERHOFF C,et al.Maintenance treatment with medroxyprogesterone acetate in patients with advanced breast cancer responding to chemotherapy:results of a randomized trial.Essen Breast Cancer Study Group[J].Breast Cancer Res Treat,1999,55(1):51-59.
[28]LIM S,LEE S,HAN J,et al.Prolonged clinical benefit from the maintenance hormone therapy in patients with metastatic breast cancer[J].Breast,2013,22(6):1205-1209.
[29]DUFRESNE A,PIVOT X,TOURNIGAND C,et al.Maintenance hormonal treatment improves progression free survival after a first line chemotherapy in patients with metastatic breast cancer[J].Int J Med Sci,2008,5(2):100-105.
[30]BERTELLI G,GARRONE O,BERTOLOTTI L,et al.Maintenance hormone therapy with letrozole after first-line chemotherapy for advanced breast cancer[J].Oncology,2005,68(4-6):364-370.
[31]ALBA E,RUIZ-BORREGO M,MARGELM,et al.Maintenance treatment with pegylated liposomal doxorubicin versus observation following induction chemotherapy for metastatic breast cancer:GEICAM 2001-01study[J].Breast Cancer Res Treat,2010,122(1):169-176.
[32]PARK Y H,JUNG K H,IM S A,et al.PhaseⅢ,multicenter,randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as firstline chemotherapy:KCSG-BR07-02[J].J Clin Oncol,2013,31(14):1732-1739.
[33]SI W,ZHU YY,LI Y,et al.Capecitabine maintenance therapy in patients with recurrent or metastatic breast cancer[J].Braz J Med Biol Res,2013,46(12):1074-1081.
[34]DONG G L,JIA Y,WANG X R,et al.The comparison of maintenance treatment with capecitabine(CMT)and nonmaintenance treatment with capecitabine(non-CMT)in patients with metastatic breast cancer[J].Int J Clin Exp Med,2015,8(5):8283-8287.
[35]SURMELI Z G,VAROL U,CAKAR B,et al.Capecitabine maintenance therapy following docetaxel/capecitabine combination treatment in patients with metastatic breast cancer[J].Oncol Lett,2015,10(4):2598-2602.
[36]赵韬,邵清,张汀荣,等.希罗达在转移性乳腺癌维持治疗中的疗效观察[J].实用临床医药杂志,2011,15(7):88-90.
[37]CHEN X L,DU F,HONG R X,et al.Hormonal therapy might be a better choice as maintenance treatment than capecitabine after response to first-line capecitabine-based combination chemotherapy for patients with hormone receptorpositive and HER2-negative,metastatic breast cancer[J].Chin J Cancer,2016,35:39.
[38]LIANG X,YAN Y,WANG L N,et al.First-line chemotherapy with docetaxel plus capecitabine followed by capecitabine or hormone maintenance therapy for the treatment of metastatic breast cancer patients[J].Oncol Lett,2015,9(2):987-993.
[39]齐帆.晚期乳腺癌维持治疗的优化及循环肿瘤DNA在临床应用的探索性研究[D].北京:中国人民解放军军事医学科学院,2015.
[2]CARDOSO F,FALLOWFIELD L,COSTA A,et al.Locally recurrent or metastatic breast cancer:ESMO clinical practice guidelines for diagnosis,treatment and follow-up[J].Ann Oncol,2011,22(Suppl 6):vi25-vi30.
[3]WILCKEN N,HORNBUCKLE J,GHERSI D.Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer[J].Cochrane Database Syst Rev,2003(2):CD002747.
[4]CARDOSO F,COSTA A,SENKUS E,et al.3rd ESO-ESMO international consensus guidelines for advanced breast cancer(ABC 3)[J].Ann Oncol,2017,28(12):3111.
[5]NABHOLTZ J M,BUZDAR A,POLLAK M,et al.Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women:results of a North American multicenter randomized trial.Arimidex Study Group[J].J Clin Oncol,2000,18(22):3758-3767.
[6]BONNETERRE J,BUZDAR A,NABHOLTZ J M,et al.Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma[J].Cancer,2001,92(9):2247-2258.
[7]MOURIDSEN H T.Letrozole in advanced breast cancer:the PO25 trial[J].Breast Cancer Res Treat,2007,105(Suppl 1):19-29.
[8]PARIDAENS R J,DIRIX L Y,BEEX L V,et al.PhaseⅢstudy comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women:the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group[J].J Clin Oncol,2008,26(30):4883-4890.
[9]MAURI D,PAVLIDIS N,POLYZOS N P,et al.Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer:meta-analysis[J].J Natl Cancer Inst,2006,98(18):1285-1291.
[10]ROBERTSON J F,LINDEMANN J P,LLOMBART-CUSSAC A,et al.Fulvestrant 500 mg versus anastrozole 1mg for the first-line treatment of advanced breast cancer:follow-up analysis from the randomized'FIRST'study[J].Breast Cancer Res Treat,2012,136(2):503-511.
[11]ELLIS M J,LLOMBART-CUSSAC A,FELTL D,et al.Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer:overall survival analysis from the phaseⅡFIRST Study[J].J Clin Oncol,2015,33(32):3781-3787.
[12]JFR R,BONDARENKO I M,TRISHKINA E,et al.Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer(FALCON):An international,randomised,double-blind,phase 3trial[J].Lancet,2016,388(10063):2997-3005.
[13]YARDLEY D A,NOGUCHI S,PRITCHARD K I,et al.Everolimus plus exemestane in postmenopausal patients with HR(+)breast cancer:BOLERO-2final progression-free survival analysis[J].Adv Ther,2013,30(10):870-884.
[14]DI LEO A,JERUSALEM G,PETRUZELKA L,et al.Results of the CONFIRM phaseⅢtrial comparing fulvestrant250mg with fulvestrant 500mg in postmenopausal women with estrogen receptor-positive advanced breast cancer[J].J Clin Oncol,2010,28(30):4594-4600.
[15]DI LEB A,JERUSALEM G,PETRUZELKA L,et al.Final overall survival:fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial[J].J Natl Cancer Inst,2014,106(1):djt337.
[16]FINN R S,CROWN J P,LANG I,et al.The cyclindependent kinase 4/6inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive,HER2-negative,advanced breast cancer(PALOMA-1/TRIO-18):a randomised phase 2study[J].Lancet Oncol,2015,16(1):25-35.
[17]FINN R S,MARTIN M,RUGO H S,et al.Palbociclib and letrozole in advanced breast cancer[J].N Engl J Med,2016,375(20):1925-1936.
[18]HORTOBAGYI G N,STEMMER S M,BURRIS H A,et al.Ribociclib as first-line therapy for HR-positive,advanced breast cancer[J].N Engl J Med,2016,375(18):1738-1748.
[19]GOETZ M P,TOI M,CAMPONE M,et al.MONARCH3:Abemaciclib as initial therapy for advanced breast cancer[J].J Clin Oncol,2017,35(32):3638-3646.
[20]CRISTOFANILLI M,TURNER N C,BONDARENKO I,et al.Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive,HER2-negative metastatic breast cancer that progressed on previous endocrine therapy(PALOMA-3):final analysis of the multicentre,double-blind,phase 3 randomised controlled trial[J].Lancet Oncol,2016,17(4):425-439.
[21]SLEDGE G W,TOI M,NEVEN P,et al.MONARCH 2:Abemaciclib in combination with fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy[J].J Clin Oncol,2017,35(25):2875-2884.
[22]SLAMON D J,NEVEN P,CHIA S,et al.PhaseⅢrandomized study of ribociclib and fulvestrant in hormone receptor-positive,human epidermal growth factor receptor2-negative advanced breast cancer:MONALEESA-3[J].J Clin Oncol,2018,36(24):2465-2472.
[23]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 GINECOstudy[J].J Clin Oncol,2012,30(22):2718-2724.
[24]ROYCE M,BACHELOT T,VILLANUEVA C,et al.Everolimus plus endocrine therapy for postmenopausal women with estrogen receptor-positive,human epidermal growth factor receptor 2-negative advanced breast cancer:A Clinical Trial[J].JAMA Oncol,2018,4(7):977-984.
[25]KORNBLUM N,ZHAO F M,MANOLA J,et al.Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptorpositive,human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy:Results of PrE0102[J].J Clin Oncol,2018,36(16):1556-1563.
[26]WILSON F R,VARU A,MITRA D,et al.Systematic review and network meta-analysis comparing palbociclib with chemotherapy agents for the treatment of postmenopausal women with HR-positive and HER2-negative advanced/metastatic breast cancer[J].Breast Cancer Res Treat,2017,166(1):167-177.
[27]KLOKE O,KLAASSEN U,OBERHOFF C,et al.Maintenance treatment with medroxyprogesterone acetate in patients with advanced breast cancer responding to chemotherapy:results of a randomized trial.Essen Breast Cancer Study Group[J].Breast Cancer Res Treat,1999,55(1):51-59.
[28]LIM S,LEE S,HAN J,et al.Prolonged clinical benefit from the maintenance hormone therapy in patients with metastatic breast cancer[J].Breast,2013,22(6):1205-1209.
[29]DUFRESNE A,PIVOT X,TOURNIGAND C,et al.Maintenance hormonal treatment improves progression free survival after a first line chemotherapy in patients with metastatic breast cancer[J].Int J Med Sci,2008,5(2):100-105.
[30]BERTELLI G,GARRONE O,BERTOLOTTI L,et al.Maintenance hormone therapy with letrozole after first-line chemotherapy for advanced breast cancer[J].Oncology,2005,68(4-6):364-370.
[31]ALBA E,RUIZ-BORREGO M,MARGELM,et al.Maintenance treatment with pegylated liposomal doxorubicin versus observation following induction chemotherapy for metastatic breast cancer:GEICAM 2001-01study[J].Breast Cancer Res Treat,2010,122(1):169-176.
[32]PARK Y H,JUNG K H,IM S A,et al.PhaseⅢ,multicenter,randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as firstline chemotherapy:KCSG-BR07-02[J].J Clin Oncol,2013,31(14):1732-1739.
[33]SI W,ZHU YY,LI Y,et al.Capecitabine maintenance therapy in patients with recurrent or metastatic breast cancer[J].Braz J Med Biol Res,2013,46(12):1074-1081.
[34]DONG G L,JIA Y,WANG X R,et al.The comparison of maintenance treatment with capecitabine(CMT)and nonmaintenance treatment with capecitabine(non-CMT)in patients with metastatic breast cancer[J].Int J Clin Exp Med,2015,8(5):8283-8287.
[35]SURMELI Z G,VAROL U,CAKAR B,et al.Capecitabine maintenance therapy following docetaxel/capecitabine combination treatment in patients with metastatic breast cancer[J].Oncol Lett,2015,10(4):2598-2602.
[36]赵韬,邵清,张汀荣,等.希罗达在转移性乳腺癌维持治疗中的疗效观察[J].实用临床医药杂志,2011,15(7):88-90.
[37]CHEN X L,DU F,HONG R X,et al.Hormonal therapy might be a better choice as maintenance treatment than capecitabine after response to first-line capecitabine-based combination chemotherapy for patients with hormone receptorpositive and HER2-negative,metastatic breast cancer[J].Chin J Cancer,2016,35:39.
[38]LIANG X,YAN Y,WANG L N,et al.First-line chemotherapy with docetaxel plus capecitabine followed by capecitabine or hormone maintenance therapy for the treatment of metastatic breast cancer patients[J].Oncol Lett,2015,9(2):987-993.
[39]齐帆.晚期乳腺癌维持治疗的优化及循环肿瘤DNA在临床应用的探索性研究[D].北京:中国人民解放军军事医学科学院,2015.