三阴乳腺癌TKR的表达与预后的关系
摘要
目的：研究酪氨酸激酶受体EGFR、IGF-1R和c-met在三阴乳腺癌中的表达状况,探讨其与三阴乳腺癌预后的关系。
方法：收集中南大学湘雅二医院2003年12月-2010年5月诊断为乳腺浸润性导管癌或小叶癌,经手术切除,且免疫组化ER、PR、CerbB-2阴性,资料完整的53例病理标本,所有患者均为女性,年龄33.8-60.1岁(中位年龄44.5岁),其中乳腺癌浸润性导管癌45例,乳腺浸润性小叶癌8例。肿瘤TNM分期为Ⅰ-Ⅲ期患者,其中Ⅰ期12例,Ⅱ期32例,Ⅲ期9例,随访其预后。标本均经10%福尔马林固定,石蜡包埋切片,HE染色,用免疫组织化学方法检测酪氨酸激酶EGFR、IGF-1R和c-met的表达情况(-及+为低表达组,++及+++为高表达组)。应用SPSS13.0统计软件,以Log-rank检验对结果进行统计学分析,比较中位生存时间,P<0.05时认为有统计学意义。
结果：
1、53例三阴乳腺癌组织中,免疫组化结果显示：EGFR的阳性率为37.7%(20/53),其中(-)占62.3%(33/53),(+)占9.4%(5/53),(++)占22.6%(12/53),(+++)占5.7%(3/53)。EGFR低表达者38例,中位生存时间53.2个月,EGFR高表达者15例,中位生存时间42.1个月,两者之间有统计学差异(χ2=5.32,p<0.05)；
2.IGF-1R阳性率为73.6%(39/53),其中(-)占26.4%(14/53),(+)占17.0%(9/53),(++)占26.4%(14/53),(+++)占30.2%(16/53)。IGF-1R低表达者23例,中位生存时间49.9个月,IGF-1R高表达者30例,中位生存时间40.5个月,两者之间有统计学差异(χ2=4.12,p<0.05)；
3.c-met阳性率为83.0%(44/53),其中(-)占17.0%(9/53),(+)占9.4%(5/53),(++)占30.2%(16/53),(+++)占43.4%(23/53)。c-met低表达者14例,中位生存时间51.5个月,c-met高表达者39例,中位生存时间38.2个月,两者之间有统计学差异(χ2=6.25,p<0.05)。
结论：
检测三阴乳腺癌组织中的EGFR.IGF-1 R及c-met的表达情况对判断三阴乳腺癌预后有一定的参考意义。
Objective:To study the expression of PTK receptor EGFR, IGF-1R and c-met in triple-negative breast cancer, and try to find the relationship with survival and prognosis of triple-negative breast cancer.
Methods:53 triple-negative breast cancer (infitrating ductal carcinoma or lobular carcinoma) patients from Second Xiangya Hospital, Central South University since Dec 2003 to May 2010,are all female, age 33.8 to 60.1 (median age 44.5),45 infitrating ductal carcinomas while 8 infiltrating lobular carcinomas. StageⅠtoⅢ(stageⅠ12, stageⅡ32,stageⅢ9),fixed by 10% formalin, sliced after paraffin imbedding, HE staining. The expression of PTK receptor EGFR、IGF-1R and c-met was determined by immunohistochemistry(-and+for the low expression group,++and+++for high expression group). Log-rank test was used to statistical treatment, P<0.05 with statistic significance.
Results: 1、The rate of expression of PTK receptor EGFR in triple-negative breast cancer is 37.7%(20/53), (-) accounted for 62.3%(33/53), (+) accounted for 9.4%(5/53), (++) accounted for 22.6%(12/ 53), (+++) accounted for 5.7%(3/53).The median survival time of 38 patients with low expression of EGFR is 53.2 months, the median survival time of 15 patients with high EGFR expression is 42.1 months. The difference between the two is clear statistic significance(χ2=5.32, p<0.05);
2、The rate of expression of PTK receptor IGF-1R in triple-negative breast cancer is 73.6%(39/53), (-) accounted for 26.4%(14/53), (+) accounted for 17.0%(9/53), (++) accounted for 26.4%(14 /53), (+++) accounted for 30.2%(16/53).The median survival time of 23 patients with low expression of IGF-1R is 49.9 months, the median survival time of 30 patients with high IGF-1R expression is 40.5 months. The difference between the two is clear statistic significance (χ2=4.12,p<0.05);
3、The rate of expression of PTK receptor c-met in triple-negative breast cancer is 83.0%(44/53), (-) accounted for 17.0%(9/53), (+) accounted for 9.4%(5/53), (++) accounted for 30.2%(16/53),(+++)accounted for 43.4%(23/53).The median survival time of 14 patients with low expression of c-met is 51.5 months, the median survival time of 39 patients with high c-met expression is 38.2 months. The difference between the two is clear statistic significance (χ2=6.25, p<0.05).
Conclusion;
EGFR, IGF-1R and c-met expression testing of triple-negative breast cancer tissue may help to prognosis forecast.
方法：收集中南大学湘雅二医院2003年12月-2010年5月诊断为乳腺浸润性导管癌或小叶癌,经手术切除,且免疫组化ER、PR、CerbB-2阴性,资料完整的53例病理标本,所有患者均为女性,年龄33.8-60.1岁(中位年龄44.5岁),其中乳腺癌浸润性导管癌45例,乳腺浸润性小叶癌8例。肿瘤TNM分期为Ⅰ-Ⅲ期患者,其中Ⅰ期12例,Ⅱ期32例,Ⅲ期9例,随访其预后。标本均经10%福尔马林固定,石蜡包埋切片,HE染色,用免疫组织化学方法检测酪氨酸激酶EGFR、IGF-1R和c-met的表达情况(-及+为低表达组,++及+++为高表达组)。应用SPSS13.0统计软件,以Log-rank检验对结果进行统计学分析,比较中位生存时间,P<0.05时认为有统计学意义。
结果：
1、53例三阴乳腺癌组织中,免疫组化结果显示：EGFR的阳性率为37.7%(20/53),其中(-)占62.3%(33/53),(+)占9.4%(5/53),(++)占22.6%(12/53),(+++)占5.7%(3/53)。EGFR低表达者38例,中位生存时间53.2个月,EGFR高表达者15例,中位生存时间42.1个月,两者之间有统计学差异(χ2=5.32,p<0.05)；
2.IGF-1R阳性率为73.6%(39/53),其中(-)占26.4%(14/53),(+)占17.0%(9/53),(++)占26.4%(14/53),(+++)占30.2%(16/53)。IGF-1R低表达者23例,中位生存时间49.9个月,IGF-1R高表达者30例,中位生存时间40.5个月,两者之间有统计学差异(χ2=4.12,p<0.05)；
3.c-met阳性率为83.0%(44/53),其中(-)占17.0%(9/53),(+)占9.4%(5/53),(++)占30.2%(16/53),(+++)占43.4%(23/53)。c-met低表达者14例,中位生存时间51.5个月,c-met高表达者39例,中位生存时间38.2个月,两者之间有统计学差异(χ2=6.25,p<0.05)。
结论：
检测三阴乳腺癌组织中的EGFR.IGF-1 R及c-met的表达情况对判断三阴乳腺癌预后有一定的参考意义。
Objective:To study the expression of PTK receptor EGFR, IGF-1R and c-met in triple-negative breast cancer, and try to find the relationship with survival and prognosis of triple-negative breast cancer.
Methods:53 triple-negative breast cancer (infitrating ductal carcinoma or lobular carcinoma) patients from Second Xiangya Hospital, Central South University since Dec 2003 to May 2010,are all female, age 33.8 to 60.1 (median age 44.5),45 infitrating ductal carcinomas while 8 infiltrating lobular carcinomas. StageⅠtoⅢ(stageⅠ12, stageⅡ32,stageⅢ9),fixed by 10% formalin, sliced after paraffin imbedding, HE staining. The expression of PTK receptor EGFR、IGF-1R and c-met was determined by immunohistochemistry(-and+for the low expression group,++and+++for high expression group). Log-rank test was used to statistical treatment, P<0.05 with statistic significance.
Results: 1、The rate of expression of PTK receptor EGFR in triple-negative breast cancer is 37.7%(20/53), (-) accounted for 62.3%(33/53), (+) accounted for 9.4%(5/53), (++) accounted for 22.6%(12/ 53), (+++) accounted for 5.7%(3/53).The median survival time of 38 patients with low expression of EGFR is 53.2 months, the median survival time of 15 patients with high EGFR expression is 42.1 months. The difference between the two is clear statistic significance(χ2=5.32, p<0.05);
2、The rate of expression of PTK receptor IGF-1R in triple-negative breast cancer is 73.6%(39/53), (-) accounted for 26.4%(14/53), (+) accounted for 17.0%(9/53), (++) accounted for 26.4%(14 /53), (+++) accounted for 30.2%(16/53).The median survival time of 23 patients with low expression of IGF-1R is 49.9 months, the median survival time of 30 patients with high IGF-1R expression is 40.5 months. The difference between the two is clear statistic significance (χ2=4.12,p<0.05);
3、The rate of expression of PTK receptor c-met in triple-negative breast cancer is 83.0%(44/53), (-) accounted for 17.0%(9/53), (+) accounted for 9.4%(5/53), (++) accounted for 30.2%(16/53),(+++)accounted for 43.4%(23/53).The median survival time of 14 patients with low expression of c-met is 51.5 months, the median survival time of 39 patients with high c-met expression is 38.2 months. The difference between the two is clear statistic significance (χ2=6.25, p<0.05).
Conclusion;
EGFR, IGF-1R and c-met expression testing of triple-negative breast cancer tissue may help to prognosis forecast.
引文
[1]Breast cancer in a transitional society over 18 years:trends and present status in shanghai, China. Lei Fan, Ying Zheng, Ke-Da YU et al. Breast cancer research treatment. Online pulished on 2009. DOI 10.1007/s10549-008-0303-z.
[2]HE Dan-dan, WANG Chun-fang, CAO Li-li et al. Cancer Incidence in Minhang District, Shanghai [J]. China Cancer,2010,19(2):108-110.
[3]Perou CM. Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours[J]. Nature,2000,406(6797):747.
[4]Elsheikh SE, Green AR, Rakha EA, et al. Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype[J]. Br J Cancer,2008,99(2):327-334.
[5]Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma [J]. Clin Cancer Res,2004,10(16):5367.
[6]Osborne Ck. Adjurant endocrine Herapy [A]. In:Harris, Lippman, Morrow et al. Edd. Disesses of the breast [M].3rd Ed. USA Lippincott: Williams & Wilkins,2004,90(15):865-891.
[7]LOU Shanxian, WANG Lixia, XU Qingcai. The significance of the expressions of ER、PR and C-erbB-2、EGFR in breast cancer [J]. Journal of practical Oncology,2004,21 (1):15-17.
[8]Xu Binghe. The study progress on molecular target therapy to aim directly at signal transduction pathway of human epidermal growth factor receptors [J].ONCOLOGY PROGRESS; 2007,5 (3):219-224.
[9]Reis-Filho JS, Tutt AN. Triple negative tumours; a critical review. Histopathology,2008,52(1):108-118.
[10]Bauer K R, Brown M, Cress R D, et al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative breast cancer, the so-called triple-negative phenotype:a population-based study from the California cancer Registy [J]. Cancer,2007,109(9):1721-1728.
[11]YUAN Zhong-Yu, WANG Shu-sen, GAO Yan et al. Clinical Characteristics and Prognosis of Triple-negative Breast Cancer:A Report of 305 Cases [J]. Chinese Journal of Cancer,2008,27 (6): 561-565.
[12]Rakha E A, El-Sayed M E, Green A R, et al. Prognostic markers in triple-negative breast cancer[J]. Cancer.2007,109(1):25-32.
[13]Cleator S, Heller W, Coombes RC. Triple-negative breast cancer; therapeutic options[J]. Lancet Oncol,2007,8(3):235-244.
[14]LIN Jian, HU Mei-qi PENG Wei et al. Analysis of clinicopathologic features and prognosis-related factors in triple-negative breast cancer[J]. CHINA ONCOLOGY,2010,20(6):462-465.
[15]Dent R, Trudeau M, Pritchard KI et al. Triple-negative cancer: clinical features and patterns of recurrence [J]. Clin Cancer Res, 2007,13(15):4429-4434.
[16]Ritter CA, Arteaga CL. The epidermal growth factor receptor-tyrosine kinase:a promising therapeutic target in solid tumors[J]. Semin Oneol,2003,30(16):3-11.
[17]Zhen Si-hu, Tan Hai-Dong, Zhan Xin-En et al. Prognostic Significance of Epidermal Growth Factor Receptor Status and DNA Ploidy in Human Breast Cancer [J]. Chinese Journal of Clinical Oncology,1998,25(2):124-127.
[18]张平,许成蓉.胰岛素样生长因子1受体与抗肿瘤治疗[J].现代肿瘤医学,2006,14(3)：360-362.
[19]XU Yan, WANG Guang-shus SUN Wei, et al. Progress in the studies on small molecule IGF-1R inhibitors [J]. Acta Pharmaceutica Sinica,2008, 43(10):979-984.
[20]何文专,尹家俊,王晓波.乳腺癌中c-met蛋白表达的意义[J].中国肿瘤临床与康复,1999,6(6)：55-56.
[21]冯国勋,魏学明,任力等.基底细胞样型乳腺癌病理诊断及治疗预后分析[J].河北医药,2009,31(17)：2197-2200.
[22]Stoppa-Lyonnet D, Ansquer Y, Dreyfus H, et al. Familial invasive breast cancer; worse outcome related to BRCA1 mutations[J]. J Clin Oncol,2000,18(24):4053-4059.
[23]Turner N, Tutt A, Ashworth A. Hallmarks of'BRCAness'in sporadic cancers [J]. Nat Rev Cancer,2004,4(10):814-819.
[24]韩芳芳,赵峰,张银华等. BRCA1、EGFR在乳腺基底细胞样癌中的表达及临床意义[J].新疆医科大学学报,2010,33(4)：397-400.
[25]Torrisi R, Balduzzi A, Ghisini R, et al. Tailored preoperative treatment of locally advanced triple-negative(hormone receptor negative and HER-2 negative) breast cancer with epirubicin, cisplatin, and infusional fluorouracil followed by weekly paclitaxel [J]. Cancer Chemother Pharmacol,2008,62(4):667-672.
[26]Carey LA, Dees EC, Sawyer L, et al. The triple-negative paradox, primary tumor chemosensitivity of breast subtypes [J]. Clin Cancer Res,2007,13(8):2329-2334.
[27]曹轶林,徐李容,屈元娇等.三阴性乳腺癌化疗疗效及预后分析[J].中国癌症防治杂志,2009,1(1)：47-52.
[28]Silva 0, Lopes G, Morgenzstern D, et al. A phase II trial of split, low-dose docetaxel and low-dose capecitabine:a tolerable and efficacious regimen in the first-line treatment of patients with HER-2/neu-negative metastatic breast cancer[J]. Clin Breast Cancer, 2008,8(2):162-167.
[29]刘璎婷,陈瑛,罗清平.蛋白酪氨酸激酶靶向药物研究进展[J].长春理工大学学报(高教版),2009,4(5)：179.
[30]Xu NZ. Oncology(肿瘤学)[M]. Beijing:People's Medical Publishing House,1999.80-96.
[31]彭珧,张怡轩,郑更新.新型蛋白酪氨酸激酶抑制类抗肿瘤药物的研究进展[J].沈阳药科大学学报,2007,24(7)：451.
[32]Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy [J]. Oncogene,2000,19(56):6550-6565.
[33]Fortunato C, Giampaolo T. A novel approach in the treatment of cancer:targeting the epidermal growth factor receptor [J]. Clin Cancer Res,2001,7(10):2958-2970.
[34]郑建涛,林永堃,曾金华等.雌激素受体、表皮生长因子受体在乳腺癌中表达的意义探讨[J].福建医药杂志,1998,20(3)：99-102.
[35]丁秀敏,何振祥,郎义方等.乳腺癌组织中表皮生长因子受体(EGFR)的研究[J].中国肿瘤临床,1995,22(12)：872-875.
[36]冷冬妮,王海,刘英娜等.浸润性乳腺癌中CK5/6、EGFR以及激素受体表达的相关性分析[J].现代肿瘤医学,2010,18(6)：1110-1113.
[37]Tsutsui S, Ohno S, Murakami S, et al. Prognostic value of epidermal growth factor receptor (EGFR) and its relationship to the estrogen receptor status in 1029 patients with breast cancer[J]. Breast Cancer Res Treat.2002,71(1):67-75.
[38]Russell WE, Van Wyk JJ, Pledger WJ, et al. Inhibition of the mitogenic effect of plama by camonoclonal antibody to somatomedin C [J]. Proc Natl Acad sci. USA,1984,81(8):2389-2393.
[39]Resnicoff M, Brugaud JL, Rotman HL, et al. correlation between apoptosis, tumorigeneisis, an levels of insulin like growth factor 1 receptors [J]. cancer Res,1995,55(17):3739-3741.
[40]Webster NJ, Resnik JL, Reichart DB, et. al. Repression of the insulin receptor promoter by the tumor suppressor gene product p53:a possible mechanism for receptor overexpression in breast cancer[J]. Cancer Res,1996,56(12):2781-2788.
[41]Carroll VA, Ashcroft M. Role of hypoxia-inducible factor (HIF)-1 alpha versus HIF-2 alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-1, or loss of von Hippel-Lindau function:implications for targeting the HIF pathway [J]. Cancer Res,2006,66(12):6264-6270.
[42]Baserga R. IGF-I receptor signaling in cell growth and proliferation [A]. In HallMN, RaffM, Thom as G, eds. Cell growth: control of cell size [M]. Cold Spring Harbor Laboratory Press, 2004:235-263.
[43]Carboni JM, Lee AV, Hadsell DL, et al. Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor [J]. Cancer Res,2005,65(9):3781-3787.
[44]HUANG Gui-lin, ZHANG Jian-quan, WU Yi-ping, et al. Influence of Neoadjuvant Chemotherapy on Insulin-Like Growth Factor-1 Receptor Expression of Breast Cancer Patients [J]. Chinese Jorunal of Bases and Clinics In General Surgery,2009,16 (10):834-837.
[45]ZENG Jing, HOU Jing-hui, ZHANG Hui-zhong, et al. Expression of Insulin-like Growth Factor-1 (IGF-1), Insulin-like Growth Factor-1 Receptor (IGF-1R) in Different Grade of Glioma and its Significance [J]. Journal of Oncology,2004,4(6):404-406.
[46]MALONEY EK, MCLAUGHLIN JL, DAGDIGIAN NE, et al. An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation [J]. Cancer Res, 2003,63:5073-5083.
[47]Scotlandi K, Avnet S, Benini S, et al. Expression of an IGF-1 receptor dominant negative mutant induces apoptosis, inhibits tumorigenesis and enhances chemosensitivity in Ewing's sarcoma cells, Int J Cancer,2002; 101(1):11-16.
[48]Scotlandi K, Manara MC, Hattinger CM, et al. Prognostic and therapeutic relevance of HER-2 expression in osteosarcoma and Ewing's sarcoma. Eur J Cancer,2005,41(9):1349-1361.
[49]KONG Min-jian, DONG Ai-qiang, MA Zhi-yuan, et al. Biological behaviors and chemosensitivity of NSCLC A549 cells after IGF-1R gene silencing by targeting RNAi in vitro [J]. Journal of Zhejiang University:Medical Sciences,2008,37(4):373-380.
[50]Gao Xia, Diao Luming, Li Heng, et al. Expression of C-met Protein in Non-small Cell Lung Carcinoma and Its Relationship with Tumor Cell Proliferation and Angiogenesis [J]. Medical Jorumal of Wuhan University,2005,26 (3):273-283.
[51]LIU Tao, ZHANG Xiaoxia WANG Jinguang et al. The Role of Oncogene c-met in tumor Proliferation and Angiogenesis in Breast Cancer [J]. The Journal of Medical Theory and Pratice,2009,22 (10):1178-1180.
[1]Gramdis JR,Sok JC.Signaling through the epidermal growth factor receptor during the development of malignancy [J]. Pharmacal Ther,2004,102(1):37-46
[2]徐兵河,针对人表皮生长因子受体信号传导途径的乳腺癌分子靶向治疗新进展,癌症进展杂志[J].2007,220-221
[3]Mehra R,Burtness B.Antibody therapy for early-stage breast cancer trastuzum ab adjuvant and neoadjuvant trials[J].Expert Opin BiolTher,2006,6(9):951-962
[4]Smith KL,Dang C,Seidman AD.Cardiac dysfunction associatead with trastuzumab [J]. Expert Opin Drug Saf,2006,5(5):619-629
[5]Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressioning metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol,1999,11717(9):2639-2648.
[6]Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumablasa single agentin first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol,2002,20(3):719-726.
[7]徐兵河,乳腺癌分子靶向治疗的临床应用及其评价,中国处方药[J].2005,12(45)：15-18.
[8]Slamon DJ, Ledland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N EnglJ med,2001,344(11):783-792.
[9]Pegram M, Hus S, Lewis G, et al. Inhibitory effects of combinations of HER2/neu antibody and chemotherapeutic agents used of treatment of human breast cancers. Oncogene,1999,18(13):2241-2251.
[10]Tripathy D.Capecitabine in combination with novel targeted agents in the management of metastatic breast cancer underlying rationale and results of clinical trials [J]. Oncologist,2007,12(4):375-389
[11]戚晓军,赵卫红,王怀瑾等,乳腺癌的分子靶向治疗研究进展[J].中国处方药,2008,4(73)：82-87.
[12]Baselga J,Albanell J,Ruiz A,et al.Phase II and lumor pharmacodynamic study of gefitinib in patients with advanced breast cancer[J].J Clin Oncol,2005,23 (23):5323-5333
[13]Ciardiella F,Troiani T,Caputo F,et,al.Phase Ⅱ study of gefitinib in combination with docetaxel as first-line theraph in breast cancer[J].Br J cancer,2006, 94(11):1604-1609
[14]Lacky KE.Lessons from the drug discovery of lapatinib,a dual ErbB1/2 tyrosine kinas inhibitor [J].Curr Top Med Chem,2006,6(5):435-460
[15]Chu I,Blackwell K,Chen S,et al.The dual ErbBl/ErbB2 inhibitor,lapatinib (GW572016),cooperates with tamoxifen to inhibit both cell proliferation and estrogen-dependent gene expression in antiestrogen-resistant breast cancer[J]. Cancer Res,2005,65(1):18-25
[16]Geyer CE,Forster J,Lindquist D et al.Lapatinib plus capecitabine for HER2-positive advanced breast cancer [J].N Engl J Med,2006, 335(26):2733-2743
[17]Baselga J,Cameron D,Miles D,et al.Objective response rate in a Phase II multicenter trial of pertuzumab(P):a HER2 dimerization inhibiting monoclonal antibody,in combination with trastuzumab(T) in patients(Pts) with HER2 positive metastatic breast cancer (MBC) which had progressed during trastuzumb therapy[J] J Clin Oncol,2007,25(suppl):18
[18]Lyseng-Williamson KA,Robinson DM.Spotlight on bevacizumab in advanced colorectal cancer,breast cancer,and non-small cell lung cancer[J].Bio Drugs,2006,20(3):193-195
[19]Lyseng-Williamson KA,Robinson DM.Spotlight on bevacizumab in advanced colorectal cancer,breast cancer,and non-small cell lung cancer[J].Bio Drugs, 2006,20(3):193-195
[20]王金万,孙燕,刘永煜,等。重组人血管内皮抑素联合NP方案治疗晚期NSCLC随机、双盲、对照、多中心Ⅲ期临床研究[J].中国肺癌杂志,2005,8(4)：283-290.
[21]宋士军,贾良.恩度联合卡培他滨治疗晚期乳腺癌的临床观察[J].中国实用医药,2008,3(12)：22-23.
[22]胡晨,陈彬,王越等,生命的化学,2009,29(6)：907-910
[23]王芝艳,林汝仙,王升启,靶向胰岛素样生长因子1型受体与肿瘤治疗的研究进展[J]2005,32(6)：361-362.
[24]Scotlandi K, Avnet S, Benini S, et al. Expression of an IGF-1 receptor dominant negative mutant induces apoptosis, inhibits tumorigenesis and enhances chemosensitivity in Ewing's sarcoma cells, Int J Cancer,2002; 101 (1):11-16.
[25]Scotlandi K, Manara MC, Hattinger CM, et al. Prognostic and therapeutic relevance of HER-2 expression in osteosarcoma and Ewing's sarcoma. Eur J Cancer,2005,41(9):1349-1361.
[26]Sachdev D,Li SL,Hartell JS,et al.A chimeric humanized singlechain antiboby against the type 1 insulin-like growth factor (IGF) receptor renders breast cancer cells refractory to the mitogenic effects of IGF-1[J].Cancer Res,2003, 63(3);627-635.
[27]Sheen-Chen SM,Liu YW, Eng HL,et al, Serum levels of hepatocyte growth factor in patients with breast cancer [J].Cancer Epidemiology Bramarkers& Prevention,2005,14(3):715-717.
[2]HE Dan-dan, WANG Chun-fang, CAO Li-li et al. Cancer Incidence in Minhang District, Shanghai [J]. China Cancer,2010,19(2):108-110.
[3]Perou CM. Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours[J]. Nature,2000,406(6797):747.
[4]Elsheikh SE, Green AR, Rakha EA, et al. Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype[J]. Br J Cancer,2008,99(2):327-334.
[5]Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma [J]. Clin Cancer Res,2004,10(16):5367.
[6]Osborne Ck. Adjurant endocrine Herapy [A]. In:Harris, Lippman, Morrow et al. Edd. Disesses of the breast [M].3rd Ed. USA Lippincott: Williams & Wilkins,2004,90(15):865-891.
[7]LOU Shanxian, WANG Lixia, XU Qingcai. The significance of the expressions of ER、PR and C-erbB-2、EGFR in breast cancer [J]. Journal of practical Oncology,2004,21 (1):15-17.
[8]Xu Binghe. The study progress on molecular target therapy to aim directly at signal transduction pathway of human epidermal growth factor receptors [J].ONCOLOGY PROGRESS; 2007,5 (3):219-224.
[9]Reis-Filho JS, Tutt AN. Triple negative tumours; a critical review. Histopathology,2008,52(1):108-118.
[10]Bauer K R, Brown M, Cress R D, et al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative breast cancer, the so-called triple-negative phenotype:a population-based study from the California cancer Registy [J]. Cancer,2007,109(9):1721-1728.
[11]YUAN Zhong-Yu, WANG Shu-sen, GAO Yan et al. Clinical Characteristics and Prognosis of Triple-negative Breast Cancer:A Report of 305 Cases [J]. Chinese Journal of Cancer,2008,27 (6): 561-565.
[12]Rakha E A, El-Sayed M E, Green A R, et al. Prognostic markers in triple-negative breast cancer[J]. Cancer.2007,109(1):25-32.
[13]Cleator S, Heller W, Coombes RC. Triple-negative breast cancer; therapeutic options[J]. Lancet Oncol,2007,8(3):235-244.
[14]LIN Jian, HU Mei-qi PENG Wei et al. Analysis of clinicopathologic features and prognosis-related factors in triple-negative breast cancer[J]. CHINA ONCOLOGY,2010,20(6):462-465.
[15]Dent R, Trudeau M, Pritchard KI et al. Triple-negative cancer: clinical features and patterns of recurrence [J]. Clin Cancer Res, 2007,13(15):4429-4434.
[16]Ritter CA, Arteaga CL. The epidermal growth factor receptor-tyrosine kinase:a promising therapeutic target in solid tumors[J]. Semin Oneol,2003,30(16):3-11.
[17]Zhen Si-hu, Tan Hai-Dong, Zhan Xin-En et al. Prognostic Significance of Epidermal Growth Factor Receptor Status and DNA Ploidy in Human Breast Cancer [J]. Chinese Journal of Clinical Oncology,1998,25(2):124-127.
[18]张平,许成蓉.胰岛素样生长因子1受体与抗肿瘤治疗[J].现代肿瘤医学,2006,14(3)：360-362.
[19]XU Yan, WANG Guang-shus SUN Wei, et al. Progress in the studies on small molecule IGF-1R inhibitors [J]. Acta Pharmaceutica Sinica,2008, 43(10):979-984.
[20]何文专,尹家俊,王晓波.乳腺癌中c-met蛋白表达的意义[J].中国肿瘤临床与康复,1999,6(6)：55-56.
[21]冯国勋,魏学明,任力等.基底细胞样型乳腺癌病理诊断及治疗预后分析[J].河北医药,2009,31(17)：2197-2200.
[22]Stoppa-Lyonnet D, Ansquer Y, Dreyfus H, et al. Familial invasive breast cancer; worse outcome related to BRCA1 mutations[J]. J Clin Oncol,2000,18(24):4053-4059.
[23]Turner N, Tutt A, Ashworth A. Hallmarks of'BRCAness'in sporadic cancers [J]. Nat Rev Cancer,2004,4(10):814-819.
[24]韩芳芳,赵峰,张银华等. BRCA1、EGFR在乳腺基底细胞样癌中的表达及临床意义[J].新疆医科大学学报,2010,33(4)：397-400.
[25]Torrisi R, Balduzzi A, Ghisini R, et al. Tailored preoperative treatment of locally advanced triple-negative(hormone receptor negative and HER-2 negative) breast cancer with epirubicin, cisplatin, and infusional fluorouracil followed by weekly paclitaxel [J]. Cancer Chemother Pharmacol,2008,62(4):667-672.
[26]Carey LA, Dees EC, Sawyer L, et al. The triple-negative paradox, primary tumor chemosensitivity of breast subtypes [J]. Clin Cancer Res,2007,13(8):2329-2334.
[27]曹轶林,徐李容,屈元娇等.三阴性乳腺癌化疗疗效及预后分析[J].中国癌症防治杂志,2009,1(1)：47-52.
[28]Silva 0, Lopes G, Morgenzstern D, et al. A phase II trial of split, low-dose docetaxel and low-dose capecitabine:a tolerable and efficacious regimen in the first-line treatment of patients with HER-2/neu-negative metastatic breast cancer[J]. Clin Breast Cancer, 2008,8(2):162-167.
[29]刘璎婷,陈瑛,罗清平.蛋白酪氨酸激酶靶向药物研究进展[J].长春理工大学学报(高教版),2009,4(5)：179.
[30]Xu NZ. Oncology(肿瘤学)[M]. Beijing:People's Medical Publishing House,1999.80-96.
[31]彭珧,张怡轩,郑更新.新型蛋白酪氨酸激酶抑制类抗肿瘤药物的研究进展[J].沈阳药科大学学报,2007,24(7)：451.
[32]Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy [J]. Oncogene,2000,19(56):6550-6565.
[33]Fortunato C, Giampaolo T. A novel approach in the treatment of cancer:targeting the epidermal growth factor receptor [J]. Clin Cancer Res,2001,7(10):2958-2970.
[34]郑建涛,林永堃,曾金华等.雌激素受体、表皮生长因子受体在乳腺癌中表达的意义探讨[J].福建医药杂志,1998,20(3)：99-102.
[35]丁秀敏,何振祥,郎义方等.乳腺癌组织中表皮生长因子受体(EGFR)的研究[J].中国肿瘤临床,1995,22(12)：872-875.
[36]冷冬妮,王海,刘英娜等.浸润性乳腺癌中CK5/6、EGFR以及激素受体表达的相关性分析[J].现代肿瘤医学,2010,18(6)：1110-1113.
[37]Tsutsui S, Ohno S, Murakami S, et al. Prognostic value of epidermal growth factor receptor (EGFR) and its relationship to the estrogen receptor status in 1029 patients with breast cancer[J]. Breast Cancer Res Treat.2002,71(1):67-75.
[38]Russell WE, Van Wyk JJ, Pledger WJ, et al. Inhibition of the mitogenic effect of plama by camonoclonal antibody to somatomedin C [J]. Proc Natl Acad sci. USA,1984,81(8):2389-2393.
[39]Resnicoff M, Brugaud JL, Rotman HL, et al. correlation between apoptosis, tumorigeneisis, an levels of insulin like growth factor 1 receptors [J]. cancer Res,1995,55(17):3739-3741.
[40]Webster NJ, Resnik JL, Reichart DB, et. al. Repression of the insulin receptor promoter by the tumor suppressor gene product p53:a possible mechanism for receptor overexpression in breast cancer[J]. Cancer Res,1996,56(12):2781-2788.
[41]Carroll VA, Ashcroft M. Role of hypoxia-inducible factor (HIF)-1 alpha versus HIF-2 alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-1, or loss of von Hippel-Lindau function:implications for targeting the HIF pathway [J]. Cancer Res,2006,66(12):6264-6270.
[42]Baserga R. IGF-I receptor signaling in cell growth and proliferation [A]. In HallMN, RaffM, Thom as G, eds. Cell growth: control of cell size [M]. Cold Spring Harbor Laboratory Press, 2004:235-263.
[43]Carboni JM, Lee AV, Hadsell DL, et al. Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor [J]. Cancer Res,2005,65(9):3781-3787.
[44]HUANG Gui-lin, ZHANG Jian-quan, WU Yi-ping, et al. Influence of Neoadjuvant Chemotherapy on Insulin-Like Growth Factor-1 Receptor Expression of Breast Cancer Patients [J]. Chinese Jorunal of Bases and Clinics In General Surgery,2009,16 (10):834-837.
[45]ZENG Jing, HOU Jing-hui, ZHANG Hui-zhong, et al. Expression of Insulin-like Growth Factor-1 (IGF-1), Insulin-like Growth Factor-1 Receptor (IGF-1R) in Different Grade of Glioma and its Significance [J]. Journal of Oncology,2004,4(6):404-406.
[46]MALONEY EK, MCLAUGHLIN JL, DAGDIGIAN NE, et al. An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation [J]. Cancer Res, 2003,63:5073-5083.
[47]Scotlandi K, Avnet S, Benini S, et al. Expression of an IGF-1 receptor dominant negative mutant induces apoptosis, inhibits tumorigenesis and enhances chemosensitivity in Ewing's sarcoma cells, Int J Cancer,2002; 101(1):11-16.
[48]Scotlandi K, Manara MC, Hattinger CM, et al. Prognostic and therapeutic relevance of HER-2 expression in osteosarcoma and Ewing's sarcoma. Eur J Cancer,2005,41(9):1349-1361.
[49]KONG Min-jian, DONG Ai-qiang, MA Zhi-yuan, et al. Biological behaviors and chemosensitivity of NSCLC A549 cells after IGF-1R gene silencing by targeting RNAi in vitro [J]. Journal of Zhejiang University:Medical Sciences,2008,37(4):373-380.
[50]Gao Xia, Diao Luming, Li Heng, et al. Expression of C-met Protein in Non-small Cell Lung Carcinoma and Its Relationship with Tumor Cell Proliferation and Angiogenesis [J]. Medical Jorumal of Wuhan University,2005,26 (3):273-283.
[51]LIU Tao, ZHANG Xiaoxia WANG Jinguang et al. The Role of Oncogene c-met in tumor Proliferation and Angiogenesis in Breast Cancer [J]. The Journal of Medical Theory and Pratice,2009,22 (10):1178-1180.
[1]Gramdis JR,Sok JC.Signaling through the epidermal growth factor receptor during the development of malignancy [J]. Pharmacal Ther,2004,102(1):37-46
[2]徐兵河,针对人表皮生长因子受体信号传导途径的乳腺癌分子靶向治疗新进展,癌症进展杂志[J].2007,220-221
[3]Mehra R,Burtness B.Antibody therapy for early-stage breast cancer trastuzum ab adjuvant and neoadjuvant trials[J].Expert Opin BiolTher,2006,6(9):951-962
[4]Smith KL,Dang C,Seidman AD.Cardiac dysfunction associatead with trastuzumab [J]. Expert Opin Drug Saf,2006,5(5):619-629
[5]Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressioning metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol,1999,11717(9):2639-2648.
[6]Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumablasa single agentin first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol,2002,20(3):719-726.
[7]徐兵河,乳腺癌分子靶向治疗的临床应用及其评价,中国处方药[J].2005,12(45)：15-18.
[8]Slamon DJ, Ledland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N EnglJ med,2001,344(11):783-792.
[9]Pegram M, Hus S, Lewis G, et al. Inhibitory effects of combinations of HER2/neu antibody and chemotherapeutic agents used of treatment of human breast cancers. Oncogene,1999,18(13):2241-2251.
[10]Tripathy D.Capecitabine in combination with novel targeted agents in the management of metastatic breast cancer underlying rationale and results of clinical trials [J]. Oncologist,2007,12(4):375-389
[11]戚晓军,赵卫红,王怀瑾等,乳腺癌的分子靶向治疗研究进展[J].中国处方药,2008,4(73)：82-87.
[12]Baselga J,Albanell J,Ruiz A,et al.Phase II and lumor pharmacodynamic study of gefitinib in patients with advanced breast cancer[J].J Clin Oncol,2005,23 (23):5323-5333
[13]Ciardiella F,Troiani T,Caputo F,et,al.Phase Ⅱ study of gefitinib in combination with docetaxel as first-line theraph in breast cancer[J].Br J cancer,2006, 94(11):1604-1609
[14]Lacky KE.Lessons from the drug discovery of lapatinib,a dual ErbB1/2 tyrosine kinas inhibitor [J].Curr Top Med Chem,2006,6(5):435-460
[15]Chu I,Blackwell K,Chen S,et al.The dual ErbBl/ErbB2 inhibitor,lapatinib (GW572016),cooperates with tamoxifen to inhibit both cell proliferation and estrogen-dependent gene expression in antiestrogen-resistant breast cancer[J]. Cancer Res,2005,65(1):18-25
[16]Geyer CE,Forster J,Lindquist D et al.Lapatinib plus capecitabine for HER2-positive advanced breast cancer [J].N Engl J Med,2006, 335(26):2733-2743
[17]Baselga J,Cameron D,Miles D,et al.Objective response rate in a Phase II multicenter trial of pertuzumab(P):a HER2 dimerization inhibiting monoclonal antibody,in combination with trastuzumab(T) in patients(Pts) with HER2 positive metastatic breast cancer (MBC) which had progressed during trastuzumb therapy[J] J Clin Oncol,2007,25(suppl):18
[18]Lyseng-Williamson KA,Robinson DM.Spotlight on bevacizumab in advanced colorectal cancer,breast cancer,and non-small cell lung cancer[J].Bio Drugs,2006,20(3):193-195
[19]Lyseng-Williamson KA,Robinson DM.Spotlight on bevacizumab in advanced colorectal cancer,breast cancer,and non-small cell lung cancer[J].Bio Drugs, 2006,20(3):193-195
[20]王金万,孙燕,刘永煜,等。重组人血管内皮抑素联合NP方案治疗晚期NSCLC随机、双盲、对照、多中心Ⅲ期临床研究[J].中国肺癌杂志,2005,8(4)：283-290.
[21]宋士军,贾良.恩度联合卡培他滨治疗晚期乳腺癌的临床观察[J].中国实用医药,2008,3(12)：22-23.
[22]胡晨,陈彬,王越等,生命的化学,2009,29(6)：907-910
[23]王芝艳,林汝仙,王升启,靶向胰岛素样生长因子1型受体与肿瘤治疗的研究进展[J]2005,32(6)：361-362.
[24]Scotlandi K, Avnet S, Benini S, et al. Expression of an IGF-1 receptor dominant negative mutant induces apoptosis, inhibits tumorigenesis and enhances chemosensitivity in Ewing's sarcoma cells, Int J Cancer,2002; 101 (1):11-16.
[25]Scotlandi K, Manara MC, Hattinger CM, et al. Prognostic and therapeutic relevance of HER-2 expression in osteosarcoma and Ewing's sarcoma. Eur J Cancer,2005,41(9):1349-1361.
[26]Sachdev D,Li SL,Hartell JS,et al.A chimeric humanized singlechain antiboby against the type 1 insulin-like growth factor (IGF) receptor renders breast cancer cells refractory to the mitogenic effects of IGF-1[J].Cancer Res,2003, 63(3);627-635.
[27]Sheen-Chen SM,Liu YW, Eng HL,et al, Serum levels of hepatocyte growth factor in patients with breast cancer [J].Cancer Epidemiology Bramarkers& Prevention,2005,14(3):715-717.