乳腺癌免疫治疗:生物标志物、药物及疫苗
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摘要
虽然近年来肿瘤的治疗取得较大进展,乳腺癌依旧是威胁女性健康的主要杀手。近年来,乳腺癌相关的免疫治疗取得较大进展,肿瘤浸润淋巴细胞(TILs)、程序性死亡受体-1(PD-1)及其配体PD-L1、肿瘤突变负荷等肿瘤标志物对乳腺癌免疫治疗具有预测作用,并与乳腺癌的预后相关。免疫检查点抑制剂,例如PD-1/PD-L1及细胞毒性T淋巴细胞抗原4(CTLA-4)抑制剂在乳腺癌中取得极大进展,各期临床试验结果显示不同的效用。肿瘤疫苗的使用为乳腺癌免疫治疗的另一途径,虽然部分疫苗在临床试验中取得较好成效,但绝大多数仍需深入研究,乳腺癌免疫治疗之途仅为开端,依旧需要大量研究。本文简要介绍了乳腺癌免疫治疗相关的生物标志物、免疫检查点抑制剂以及肿瘤疫苗的研究进展。
Despite dramatic advance in cancer therapeutic treatments,breast cancer remains the most common cancer in women. Over the last decade,the development of immunotherapy has led to a paradigm shift in the treatment of breast cancer,especially in some subsets of breast cancer. Depending on the various subtypes of breast cancer,tumor-infiltrating lymphocytes,programmed death-1( PD-1)/PD-L1 and tumor mutation burden are not only predictive of response to immune checkpoint inhibitors,but also prognostic for survival. To this point the main clinical use of immunotherapy in breast cancer is the inhibition of two important immune checkpoints,PD-1 and cytotoxic T-lymphocyte-associated protein 4( CTLA-4). The development was achieved in the monoclonal antibodies used to block those two checkpoints. Recently,evidences from several clinical trials demonstrated that breast cancer could respond to single or combination of immune checkpoint inhibitors with a small population reaping considerable beneficial clinical outcomes. Although part of breast cancer vaccines are used for primary or secondary prevention and some are used for therapeutic,it still needs further research for their clinical significance. Immunotherapy in breast cancer is still on its early age and there is a long way to go. The predictive and prognostic implications of the biomarkers for tumor-infiltrating lymphocytes,PD-1/PD-L1 and tumor mutation burden etc are summarized, and the research progresses of biomarkers,immunosuppressants and tumor vaccines related to immunotherapy for breast cancer were briefly introduced.
Despite dramatic advance in cancer therapeutic treatments,breast cancer remains the most common cancer in women. Over the last decade,the development of immunotherapy has led to a paradigm shift in the treatment of breast cancer,especially in some subsets of breast cancer. Depending on the various subtypes of breast cancer,tumor-infiltrating lymphocytes,programmed death-1( PD-1)/PD-L1 and tumor mutation burden are not only predictive of response to immune checkpoint inhibitors,but also prognostic for survival. To this point the main clinical use of immunotherapy in breast cancer is the inhibition of two important immune checkpoints,PD-1 and cytotoxic T-lymphocyte-associated protein 4( CTLA-4). The development was achieved in the monoclonal antibodies used to block those two checkpoints. Recently,evidences from several clinical trials demonstrated that breast cancer could respond to single or combination of immune checkpoint inhibitors with a small population reaping considerable beneficial clinical outcomes. Although part of breast cancer vaccines are used for primary or secondary prevention and some are used for therapeutic,it still needs further research for their clinical significance. Immunotherapy in breast cancer is still on its early age and there is a long way to go. The predictive and prognostic implications of the biomarkers for tumor-infiltrating lymphocytes,PD-1/PD-L1 and tumor mutation burden etc are summarized, and the research progresses of biomarkers,immunosuppressants and tumor vaccines related to immunotherapy for breast cancer were briefly introduced.
引文
[1] Siegel RL,Miller KD,Jemal A. Cancer Statistics,2017[J].CA Cancer J Clin,2017,67(1):7-30
[2]郑荣寿,孙可欣,张思维,等. 2015年中国恶性肿瘤流行情况分析[J].中华肿瘤杂志(Zheng RS,Sun KX,Zhang SW,et al. Report of cancer epidemiology in China,2015[J]. Chin J Oncol),2019,41(1):19-28
[3] De Santis CE,Ma J,Goding Sauer A,et al. Breast cancer statistics,2017,racial disparity in mortality by state[J]. CA Cancer J Clin,2017,67(6):439-448
[4] Charoentong P,Finotello F,Angelova M,et al. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response checkpoint blockade[J].Cell Rep,2017,18(1):248-262
[5] Alexandrov LB,Nik-Zainal S,Wedge DC,et al. Signatures of mutational processes in human cancer[J]. Nature,2013,500(7463):415-421
[6] Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors[J]. Nature,2012,490(7418):61-70
[7] Salgado R,Denkert C,Campbell C,et al. Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab:A Secondary Analysis of the Neo ALTTO Trial[J]. JAMA Oncol,2015,1(4):448-454
[8] Loi S,Dushyanthen S,Beavis PA,et al. RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer:Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors[J]. Clin Cancer Res,2016,22(6):1499-1509
[9] Schmid P,Cruz C,Braiteh FS,et al. Atezolizumab in metastatic TNBC(m TNBC):Long-term clinical outcomes and biomarker analyses[J]. Cancer Res,2017,77(13 Suppl).DOI:10. 1158/1538-7445.AM2017-2986
[10] Loi S,Adams S,Schmid P,et al. Relationship between tumor infiltrating lymphocyte(TIL)levels and response to pembrolizumab(pembro)in metastatic triple-negative breast cancer(m TNBC):result from KEYNOTE-086[J]. Annals Oncol,2017,28(suppl_5). doi:10. 1093/annonc/mdx440. 005
[11] Savas P,Salgado R,Denkert C,et al. Clinical relevance of host immunity in breast cancer:from TILs to the clinic[J]. Nat Rev Clin Oncol,2016,13(4):228-241
[12] Adams S,Gray RJ,Demaria S,et al. Prognostic value of tumorinfiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials:ECOG 2197and ECOG 1199[J]. J Clin Oncol,2014,32(27):2959-2966
[13] Martinet L,Garrido I,Filleron T,et al. Human solid tumors contain high endothelial venules:association with T-and Blymphocyte infiltration and favorable prognosis in breast cancer[J]. Cancer Res,2011,71(17):5678-5687
[14] Liu S,Foulkes WD,Leung S,et al. Prognostic significance of FOXP3+tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration[J].Breast Cancer Res,2014,16(5):432
[15] Yu X,Zhang Z,Wang Z,et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in breast cancer:a systematic review and meta-analysis[J]. Clin Transl Oncol,2016,18(5):497-506
[16] Tian T,Ruan M,Yang W,et al. Evaluation of the prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers[J]. Oncotarget,2016,7(28):44395-44405
[17] Salgado R,Denkert C,Demaria S,et al. The evaluation of tumor-infiltrating lymphocytes(TILs)in breast cancer:recommendations by an International TILs Working Group 2014[J]. Ann Oncol,2015,26(2):259-271
[18] BuquéA, Bloy N, Aranda F, et al. Trial Watch:Immunomodulatory monoclonal antibodies for oncological indications[J]. Oncoimmunology,2015,4(4):e1008814
[19] Nixon MJ,Balko JM. Biomarkers for assessing the effectiveness of immunotherapy in breast cancer[J]. Biomark Med,2018,12(2):97-100
[20] Zhang M,Sun H,Zhao S,et al. Expression of PD-L1 and prognosis in breast cancer:a meta-analysis[J]. Oncotarget,2017,8(19):31347-31354
[21] Sabatier R,Finetti P, Mamessier E, et al. Prognostic and predictive value of PDL1 expression in breast cancer[J].Oncotarget,2015,6(7):5449-5464
[22] Baptista MZ, Sarian LO, Derchain SF, et al. Prognostic significance of PD-L1 and PD-L2 in breast cancer[J]. Hum Pathol,2016,47(1):78-84
[23] Bae SB,Cho HD,Oh MH,et al. Expression of Programmed Death Receptor Ligand 1 with High Tumor-Infiltrating Lymphocytes Is Associated with Better Prognosis in Breast Cancer[J]. J Breast Cancer,2016,19(3):242-251
[24] Tsang JY,Au WL,Lo KY,et al. PD-L1 expression and tumor infiltrating PD-1+lymphocytes associated with outcome in HER2+breast cancer patients[J]. Breast Cancer Res Treat,2017,162(1):19-30
[25] Carbone DP,Reck M,Paz-Ares L,et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer[J]. N Engl J Med,2017,376(25):2415-2426
[26] Hellmann MD,Ciuleanu TE,Pluzanski A,et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden[J]. N Engl J Med,2018,378(22):2093-2104
[27] Haricharan S,Bainbridge MN,Scheet P,et al. Somatic mutation load of estrogen receptor-positive breast tumors predicts overall survival:an analysis of genome sequence data[J]. Breast Cancer Res Treat,2014,146(1):211-220
[28] Park SE,Park K,Lee E,et al. Clinical implication of tumor mutational burden in patients with HER2-positive refractory metastatic breast cancer[J]. Oncoimmunology, 2018, 7(8):e1466768
[29] Thomas A,Routh ED,Pullikuth A,et al. Tumor mutational burden is a determinant of immune-mediated survival in breast cancer[J]. Oncoimmunology,2018,7(10):e1490854
[30] Nanda R,Chow LQ,Dees EC,et al. Pembrolizumab in Patients with Advanced Triple-Negative Breast Cancer:Phase Ib KEYNOTE-012 Study[J]. J Clin Oncol, 2016, 34(21):2460-2467
[31] Schmid P,Adams S,Rugo HS,et al. Atezolizumab and NabPaclitaxel in Advanced Triple-Negative Breast Cancer[J]. N Engl J Med,2018,379(22):2108-2121
[32] Adams S, Loi S, Toppmeyer D, et al. Pembrolizumab monotherapy for previously untreated,PD-L1-positive,metastatic triple-negative breast cancer:cohort B of the phase II KEYNOTE-086 study[J]. Ann Oncol,2019,30(3):405-411
[33] Rugo HS,Delord JP,Im SA,et al. Preliminary efficacy and safety of pembrolizumab(MK-3475)in patients with PD-L1positive estrogen receptor-positive/HER-2-negative advanced breast cancer enrolled in KEYNOTE-028[J]. Cancer Res,2016,76(4 Suppl):S5-07-S5-07. DOI:10. 1158/1538-7445.SABCS15-S5-07
[34] Loi S,Giobbie-Hurder A,Gombos A,et al. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER-2 positive advanced breast cancer:result PANACEA study. San Antonio Breast cancer symposium,2017,Abstract GS2-06
[35] Emens LA,Cruz C,Eder JP,et al. Long-term clinical outcomes and biomarker analyses of Atezolizumab Therapy for Patients with Metastatic Triple-Negative Breast Cancer:A Phase 1 Study[J].JAMA Oncol,2019,5(1):74-82
[36] Dirix LY,Takacs I,Jerusalem G,et al. Avelumab,an anti-PDL1 antibody, in patients with locally advanced or metastatic breast cancer:a phase 1b JAVELIN Solid Tumor study[J].Breast Cancer Res Treat,2018,167(3):671-686
[37] Domchek SM,Postel-Vinay S,Bang YJ,et al. An open-label,multitumor,phase II basket study of olaparib and durvalumab(MEDIOLA):results in germline BRCA-mutated(g BRCAm)HER2-negative metastatic breast cancer(MBC). San Antonio Breast Cancer Symposium,2017,Abstract PD6–11
[38] Tolaney S. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triplenegative breast cancer. San Antonio Breast Cancer Symposium,2017,Abstract PD6–13
[39] Adams S,Diamond JR,Hamilton,EP,et al. Phase Ib trial of atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer(m TNBC)[J]. J Clin Oncol,2016(34):1009
[40] Page DB,Kim IK,Sanchez K,et al. Safety and effcacy of pembrolizumab(pembro)plus capecitabine(cape)in metastatic triple negative breast cancer(m TNBC)[J]. J Clin Oncol,2018,36(Suppl 15):1033
[41] Santa-Maria CA,Kato T,Park JH,et al. A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer[J]. Oncotarget, 2018, 9(27):18985-18996
[42] Mc Arthur HL,Barker CA,Gucalp A,et al. A single-arm,phase II study assessing the effcacy of pembrolizumab(pembro)plus radiotherapy(RT)in metastatic triple negative breast cancer(m TNBC)[J]. J Clin Oncol,2018,36(5 Suppl):14
[43] Vinayak S,Tolaney SM,Schwartzberg LS,et al. TOPACIO/KEYNOTE-162:niraparib+pembrolizumab in patients(pts)with metastatic triple-negative breast cancer(TNBC),a phase 2trial[J]. J Clin Oncol,2018,36(15 Suppl):1011
[44] Vonderheide RH,LoRusso PM,Khalil M,et al. Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of indu cible costimulator expression on patient T cells[J]. Clin Cancer Res,2010,16(13):3485-3494
[45] Samadi P,Saki S,Dermani FK,et al. Emerging ways to treat breast cancer:will promises be met?[J]. Cell Oncol(Dordr),2018,41(6):605-621
[46] Emens LA. Breast cancer immunobiology driving immunotherapy:vaccines and immune checkpoint blockade[J]. Expert Rev Anticancer Ther,2012,12(12):1597-1611
[47] Holmes JP,Gates JD,Benavides LC,et al. Optimal dose and schedule of an HER2/neu(E75)peptide vaccine to prevent breast cancer recurrence:from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02[J]. Cancer,2008,113(7):1666-1675
[48] Lowenfeld L,Mick R,Datta J,et al. Dendritic Cell Vaccination enhances Immune Responses and Induces Regression of HER2pos DCIS independent of Route:Results of Randomized Selection Design Trail[J]. Clin Cancer Res,2017,23(12):2961-2971
[49] Clifton GT,Peace KM,Holmes JP,et al. Initial safety analysis of a randomized phase II trial of nelipepimut-S+GM-CSF and trastuzumab compared to trastuzumab alone to prevent recurrence in breast cancer patients with HER2 low-expressing tumors[J].Clin Immunol,2019,201:48-54
[50] P Solans B,LD Cerio A,Elizalde A,et al. Assessing the impact of the addition of dendritic cell vaccination to neoadjuvant chemotherapy in breast cancer patients:A model-based character rization approach[J]. Br J Clin Pharmacol, 2019, doi:10. 1111/bcp.13947.[Epub ahead of print]
[2]郑荣寿,孙可欣,张思维,等. 2015年中国恶性肿瘤流行情况分析[J].中华肿瘤杂志(Zheng RS,Sun KX,Zhang SW,et al. Report of cancer epidemiology in China,2015[J]. Chin J Oncol),2019,41(1):19-28
[3] De Santis CE,Ma J,Goding Sauer A,et al. Breast cancer statistics,2017,racial disparity in mortality by state[J]. CA Cancer J Clin,2017,67(6):439-448
[4] Charoentong P,Finotello F,Angelova M,et al. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response checkpoint blockade[J].Cell Rep,2017,18(1):248-262
[5] Alexandrov LB,Nik-Zainal S,Wedge DC,et al. Signatures of mutational processes in human cancer[J]. Nature,2013,500(7463):415-421
[6] Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors[J]. Nature,2012,490(7418):61-70
[7] Salgado R,Denkert C,Campbell C,et al. Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab:A Secondary Analysis of the Neo ALTTO Trial[J]. JAMA Oncol,2015,1(4):448-454
[8] Loi S,Dushyanthen S,Beavis PA,et al. RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer:Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors[J]. Clin Cancer Res,2016,22(6):1499-1509
[9] Schmid P,Cruz C,Braiteh FS,et al. Atezolizumab in metastatic TNBC(m TNBC):Long-term clinical outcomes and biomarker analyses[J]. Cancer Res,2017,77(13 Suppl).DOI:10. 1158/1538-7445.AM2017-2986
[10] Loi S,Adams S,Schmid P,et al. Relationship between tumor infiltrating lymphocyte(TIL)levels and response to pembrolizumab(pembro)in metastatic triple-negative breast cancer(m TNBC):result from KEYNOTE-086[J]. Annals Oncol,2017,28(suppl_5). doi:10. 1093/annonc/mdx440. 005
[11] Savas P,Salgado R,Denkert C,et al. Clinical relevance of host immunity in breast cancer:from TILs to the clinic[J]. Nat Rev Clin Oncol,2016,13(4):228-241
[12] Adams S,Gray RJ,Demaria S,et al. Prognostic value of tumorinfiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials:ECOG 2197and ECOG 1199[J]. J Clin Oncol,2014,32(27):2959-2966
[13] Martinet L,Garrido I,Filleron T,et al. Human solid tumors contain high endothelial venules:association with T-and Blymphocyte infiltration and favorable prognosis in breast cancer[J]. Cancer Res,2011,71(17):5678-5687
[14] Liu S,Foulkes WD,Leung S,et al. Prognostic significance of FOXP3+tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration[J].Breast Cancer Res,2014,16(5):432
[15] Yu X,Zhang Z,Wang Z,et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in breast cancer:a systematic review and meta-analysis[J]. Clin Transl Oncol,2016,18(5):497-506
[16] Tian T,Ruan M,Yang W,et al. Evaluation of the prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers[J]. Oncotarget,2016,7(28):44395-44405
[17] Salgado R,Denkert C,Demaria S,et al. The evaluation of tumor-infiltrating lymphocytes(TILs)in breast cancer:recommendations by an International TILs Working Group 2014[J]. Ann Oncol,2015,26(2):259-271
[18] BuquéA, Bloy N, Aranda F, et al. Trial Watch:Immunomodulatory monoclonal antibodies for oncological indications[J]. Oncoimmunology,2015,4(4):e1008814
[19] Nixon MJ,Balko JM. Biomarkers for assessing the effectiveness of immunotherapy in breast cancer[J]. Biomark Med,2018,12(2):97-100
[20] Zhang M,Sun H,Zhao S,et al. Expression of PD-L1 and prognosis in breast cancer:a meta-analysis[J]. Oncotarget,2017,8(19):31347-31354
[21] Sabatier R,Finetti P, Mamessier E, et al. Prognostic and predictive value of PDL1 expression in breast cancer[J].Oncotarget,2015,6(7):5449-5464
[22] Baptista MZ, Sarian LO, Derchain SF, et al. Prognostic significance of PD-L1 and PD-L2 in breast cancer[J]. Hum Pathol,2016,47(1):78-84
[23] Bae SB,Cho HD,Oh MH,et al. Expression of Programmed Death Receptor Ligand 1 with High Tumor-Infiltrating Lymphocytes Is Associated with Better Prognosis in Breast Cancer[J]. J Breast Cancer,2016,19(3):242-251
[24] Tsang JY,Au WL,Lo KY,et al. PD-L1 expression and tumor infiltrating PD-1+lymphocytes associated with outcome in HER2+breast cancer patients[J]. Breast Cancer Res Treat,2017,162(1):19-30
[25] Carbone DP,Reck M,Paz-Ares L,et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer[J]. N Engl J Med,2017,376(25):2415-2426
[26] Hellmann MD,Ciuleanu TE,Pluzanski A,et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden[J]. N Engl J Med,2018,378(22):2093-2104
[27] Haricharan S,Bainbridge MN,Scheet P,et al. Somatic mutation load of estrogen receptor-positive breast tumors predicts overall survival:an analysis of genome sequence data[J]. Breast Cancer Res Treat,2014,146(1):211-220
[28] Park SE,Park K,Lee E,et al. Clinical implication of tumor mutational burden in patients with HER2-positive refractory metastatic breast cancer[J]. Oncoimmunology, 2018, 7(8):e1466768
[29] Thomas A,Routh ED,Pullikuth A,et al. Tumor mutational burden is a determinant of immune-mediated survival in breast cancer[J]. Oncoimmunology,2018,7(10):e1490854
[30] Nanda R,Chow LQ,Dees EC,et al. Pembrolizumab in Patients with Advanced Triple-Negative Breast Cancer:Phase Ib KEYNOTE-012 Study[J]. J Clin Oncol, 2016, 34(21):2460-2467
[31] Schmid P,Adams S,Rugo HS,et al. Atezolizumab and NabPaclitaxel in Advanced Triple-Negative Breast Cancer[J]. N Engl J Med,2018,379(22):2108-2121
[32] Adams S, Loi S, Toppmeyer D, et al. Pembrolizumab monotherapy for previously untreated,PD-L1-positive,metastatic triple-negative breast cancer:cohort B of the phase II KEYNOTE-086 study[J]. Ann Oncol,2019,30(3):405-411
[33] Rugo HS,Delord JP,Im SA,et al. Preliminary efficacy and safety of pembrolizumab(MK-3475)in patients with PD-L1positive estrogen receptor-positive/HER-2-negative advanced breast cancer enrolled in KEYNOTE-028[J]. Cancer Res,2016,76(4 Suppl):S5-07-S5-07. DOI:10. 1158/1538-7445.SABCS15-S5-07
[34] Loi S,Giobbie-Hurder A,Gombos A,et al. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER-2 positive advanced breast cancer:result PANACEA study. San Antonio Breast cancer symposium,2017,Abstract GS2-06
[35] Emens LA,Cruz C,Eder JP,et al. Long-term clinical outcomes and biomarker analyses of Atezolizumab Therapy for Patients with Metastatic Triple-Negative Breast Cancer:A Phase 1 Study[J].JAMA Oncol,2019,5(1):74-82
[36] Dirix LY,Takacs I,Jerusalem G,et al. Avelumab,an anti-PDL1 antibody, in patients with locally advanced or metastatic breast cancer:a phase 1b JAVELIN Solid Tumor study[J].Breast Cancer Res Treat,2018,167(3):671-686
[37] Domchek SM,Postel-Vinay S,Bang YJ,et al. An open-label,multitumor,phase II basket study of olaparib and durvalumab(MEDIOLA):results in germline BRCA-mutated(g BRCAm)HER2-negative metastatic breast cancer(MBC). San Antonio Breast Cancer Symposium,2017,Abstract PD6–11
[38] Tolaney S. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triplenegative breast cancer. San Antonio Breast Cancer Symposium,2017,Abstract PD6–13
[39] Adams S,Diamond JR,Hamilton,EP,et al. Phase Ib trial of atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer(m TNBC)[J]. J Clin Oncol,2016(34):1009
[40] Page DB,Kim IK,Sanchez K,et al. Safety and effcacy of pembrolizumab(pembro)plus capecitabine(cape)in metastatic triple negative breast cancer(m TNBC)[J]. J Clin Oncol,2018,36(Suppl 15):1033
[41] Santa-Maria CA,Kato T,Park JH,et al. A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer[J]. Oncotarget, 2018, 9(27):18985-18996
[42] Mc Arthur HL,Barker CA,Gucalp A,et al. A single-arm,phase II study assessing the effcacy of pembrolizumab(pembro)plus radiotherapy(RT)in metastatic triple negative breast cancer(m TNBC)[J]. J Clin Oncol,2018,36(5 Suppl):14
[43] Vinayak S,Tolaney SM,Schwartzberg LS,et al. TOPACIO/KEYNOTE-162:niraparib+pembrolizumab in patients(pts)with metastatic triple-negative breast cancer(TNBC),a phase 2trial[J]. J Clin Oncol,2018,36(15 Suppl):1011
[44] Vonderheide RH,LoRusso PM,Khalil M,et al. Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of indu cible costimulator expression on patient T cells[J]. Clin Cancer Res,2010,16(13):3485-3494
[45] Samadi P,Saki S,Dermani FK,et al. Emerging ways to treat breast cancer:will promises be met?[J]. Cell Oncol(Dordr),2018,41(6):605-621
[46] Emens LA. Breast cancer immunobiology driving immunotherapy:vaccines and immune checkpoint blockade[J]. Expert Rev Anticancer Ther,2012,12(12):1597-1611
[47] Holmes JP,Gates JD,Benavides LC,et al. Optimal dose and schedule of an HER2/neu(E75)peptide vaccine to prevent breast cancer recurrence:from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02[J]. Cancer,2008,113(7):1666-1675
[48] Lowenfeld L,Mick R,Datta J,et al. Dendritic Cell Vaccination enhances Immune Responses and Induces Regression of HER2pos DCIS independent of Route:Results of Randomized Selection Design Trail[J]. Clin Cancer Res,2017,23(12):2961-2971
[49] Clifton GT,Peace KM,Holmes JP,et al. Initial safety analysis of a randomized phase II trial of nelipepimut-S+GM-CSF and trastuzumab compared to trastuzumab alone to prevent recurrence in breast cancer patients with HER2 low-expressing tumors[J].Clin Immunol,2019,201:48-54
[50] P Solans B,LD Cerio A,Elizalde A,et al. Assessing the impact of the addition of dendritic cell vaccination to neoadjuvant chemotherapy in breast cancer patients:A model-based character rization approach[J]. Br J Clin Pharmacol, 2019, doi:10. 1111/bcp.13947.[Epub ahead of print]