全基因表达谱芯片用于筛选乳腺癌新辅助化疗疗效预测因子的研究
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摘要
背景：新辅助化疗已经成为局部晚期乳腺癌的一种标准治疗模式,然而临床试验中发现10-35%的乳腺癌病人对新辅助化疗不敏感。因此,新辅助化疗预测因子的研究有助于选择可能从新辅助化疗中获益的病人进行术前化疗,并避免对化疗无效的病人进行不必要的术前化疗。很多大型临床试验结果表明：激素受体阳性的病人化疗不敏感,而对内分泌治疗较敏感,然而临床实践中化疗仍是激素阳性的重要辅助治疗手段,副作用大,疗效却不肯定。
目的：利用基因芯片技术筛选出能预测化疗疗效的ER相关基因,通过研究其与新辅助化疗疗效的关系,探索激素受体在化疗疗效的预测作用机理,弥补ER作为单因素预测作用的不足,从而提高预测新辅助化疗疗效的准确性。
方法：化疗前的肿瘤组织取自110例局部晚期乳腺癌患者。所有的患者均行新辅助化疗,即紫杉醇+卡铂的化疗方案,4疗程后接受手术治疗。按照RECIST标准及病理学检查结果进行疗效评估并以此分为pCR±PR±SD以及PD。第一批55例患者作为实验组,采用Human Genome GeneChip Plus U133 2.0 Array (Affymetrix)芯片检测乳腺癌组织中的基因表达谱；用Significance Analysis of Microarrays (SAM)筛选pCR组与非pCR组之间的差异表达基因；运用层次聚类(Hierachical Clustering Analysis)行聚类分析并对全组病例行预测分析；利用基因注解工具Gene Ontology及DAVID 2008 Functional Annotation Bioinformatics Microarray Analysis行功能富集化分析。对筛选所获得的与ER相关的分子标志物作实时定量PCR的验证。另外一批55例患者作为独立验证队例,采用免疫组化方法进一步研究ER及其相关因子在新辅助化疗疗效中的预测价值。
结果：在55例实验组患者中,有16例化疗前癌组织因提取的RNA量不够并有8例未通过芯片质控,因此有31例患者进入候选基因筛查的实验组,86例患者的pCR率为19.7%,其中实验组为6例。用分类比较分析筛选出化疗6例pCR组与25例非pCR组之间显著差异表达的基因共231个(Fold Change>2.0),用层次聚类分析方法能较准确区分pCR组与非pCR组的差异表达基因,预测功能富集化分析发现差异表达基因主要同免疫相关的通路、DNA和蛋白质聚合、跨膜转运蛋白信号通路、PARP通路以及ER相关通路等相关。当Fold Change>3.0时,pCR组与非pCR组之间的差异表达基因为20个,其中GATA3、TFF1、TFF3均与ER相关。实时定量PCR方法验证了GATA3与TFFl的表达结果与芯片结果相一致。在另外一批拥有55例独立验证队例中,采用免疫组化的方法研究ER相关因子与pCR的关系,单因素分析结果显示：ER、PR、GATA3、TFF1以及TFF3的状态与pCR存在统计学意义上相关关系(Pearson卡方检验,P<0.001,P=0.013,P=0.001,P<0.001,P<0.001),对这5个指标进行Spearman相关分析,发现他们之间均存在着显著相关性(P<0.05),采用logistics多因素回归分析结果显示：ER可作为pCR的独立预测指标(P=0.016)。进一步分析ER联合相关因子在预测新辅助化疗疗效的价值,我们发现5个与ER通路活性相关的指标(ER、PR、GATA3、TFF1、TFF3)均为阴性时,pCR率达到80%(4／5),相反,9位PD/SD的患者中有7位患者该5项指标均为阳性。
结论：全基因表达谱芯片能较准确区分化疗pCR与非pCR之间的基因差异,基因芯片技术在探索新辅助化疗疗效预测因子上有较高应用价值,有望发现新的预测因子及其通路,真正实现个体化治疗。ER通路活性较单独ER指标在预测新辅助化疗疗效上的价值高,即ER通路活性低的患者pCR率高,而ER通路活性高的患者pCR率低。ER阴性不代表ER通路活性低,可能由ER变异引起,检测ER相关因子有助于更全面了解ER通路的活性。
Background:Neoadjuvant chemotherapy was widely used as a standard procedure in patients with locally advanced breast cancer. About 10-35% breast cancer patients were resistant to neoadjuvant chemotherapy.The research of neoadjuvant chemotherapy predictive markers can help selecting the patients who might benefit from neoadjuvant chemotherapy, and keep those patients who are resistant to chemotherapy from unnessary preoperative treatment. Many large clinical trails showed patients with hormone responsive diseases are resistant to chemotherapy, while sensitive to endocrine therapy. In clinical practice, however, chemotherapy is still an important adjuvant treatment strategy for hormonal receptor positive patients, accompanying with harmful side effects.
Objective:The aim of this study was to explore the gene expression related with ER of locally advanced breast cancer and to identify novel biomarkers that can be used for characterization and prediction of response to neoadjuvant chemotherapy using microarray gene expression profiling.
Methods:Pretherapeutic tumorous tissues were obtained from 110 patients with locally advanced breast cancer. All patients received preoperative chemotherapy by the regimen of paclitaxel and carboplatin. Standardized surgery was performed after an interval of approximately 4 cycles. The response to chemotherapy was evaluated according to RECIST standards.In the 55 training cases, gene expression profiling of breast cancer were obtained by Human Genome Gene Chip Plus U133 2.0 Array. By using Significance Analysis of Microarrays (SAM), a set of discriminating genes was identified between pCR versus residul disease.Hierachical Clustering Analysis was applied to predict the response of the breast cancer. Gene Ontology and DAVID 2008 Functional Annotation Bioinformatics Microarray Analysis tools were used to gene functional category clustering analysis. As ER related biomarkers, the GATA3、TFF1 and TFF3 were performed further analysis in the validation set by IHC.
Results:In the training set, the yield of total RNA was insufficient to assay in 16 patients and eight chips failed the quality check (QC) process. Therefore, gene expression profiles from 31 samples were available for this study. The overall pCR rate in the 86 patients was 19.7%(n=17,6 cases of pCR in training set and 11 pCR in validation set).6 patients as pCR and 25 patients as non-pCR showed significant different expression levels for 231 genes (Fold Change>2.0) by Significance Analysis of Microarrays (SAM).The list of differential expreesion genes included humoral immune response, protein-DNA complex assembly, transmembrane receptor protein tyrosine kinase signaling pathway, PARP signaling pathway and response to hormone stimulus. Setting fold change>3 resulted in 20 differentially expressed genes, among these 20 genes, TFF1,ESR1,GATA3,TFF3 were found as ER-related genes. In the further study by Real-time PCR, TFF1 and GATA3 showed significant higher expression in patients with non-pCR (P<0.05), which is consistent with the results of microarray analysis.In the 55 independent validation cases, in univariate analysis including clinical variables and ER-related genes, ER, PR, GATA3,TFF1 and TFF3 were all significantly associated with pCR (Pearson x 2,P<0.001,P=0.013, P<0.001,P<0.001, P<0.001).Only ER (P=0.016) remained significant in a logistic regression model.In spearman analysis, these 5 ER-related genes were significantly correlated with each other (P<0.05).To further analyse the predictive value of ER combined with ER-related genes, we found that the pCR rates was as high as.80% (4/5)when these 5 factors were all negative. In contrast, these 5 factors are all positive were found in 7 of 9 PD/SD patients.
Conclusions:The present study suggested the possibility that microarray gene expression profiling may be usefμl in predicting response of locally advanced breast cancer to neoadjuvant chemotherapy and helpful in individualized therapy. ER related genes(ER pathway) may provide more predictive value of response to neoadjuvant chemotherapy than ER status alone. To test ER related factors can help comprehensively understanding the activity of ER pathway.
目的：利用基因芯片技术筛选出能预测化疗疗效的ER相关基因,通过研究其与新辅助化疗疗效的关系,探索激素受体在化疗疗效的预测作用机理,弥补ER作为单因素预测作用的不足,从而提高预测新辅助化疗疗效的准确性。
方法：化疗前的肿瘤组织取自110例局部晚期乳腺癌患者。所有的患者均行新辅助化疗,即紫杉醇+卡铂的化疗方案,4疗程后接受手术治疗。按照RECIST标准及病理学检查结果进行疗效评估并以此分为pCR±PR±SD以及PD。第一批55例患者作为实验组,采用Human Genome GeneChip Plus U133 2.0 Array (Affymetrix)芯片检测乳腺癌组织中的基因表达谱；用Significance Analysis of Microarrays (SAM)筛选pCR组与非pCR组之间的差异表达基因；运用层次聚类(Hierachical Clustering Analysis)行聚类分析并对全组病例行预测分析；利用基因注解工具Gene Ontology及DAVID 2008 Functional Annotation Bioinformatics Microarray Analysis行功能富集化分析。对筛选所获得的与ER相关的分子标志物作实时定量PCR的验证。另外一批55例患者作为独立验证队例,采用免疫组化方法进一步研究ER及其相关因子在新辅助化疗疗效中的预测价值。
结果：在55例实验组患者中,有16例化疗前癌组织因提取的RNA量不够并有8例未通过芯片质控,因此有31例患者进入候选基因筛查的实验组,86例患者的pCR率为19.7%,其中实验组为6例。用分类比较分析筛选出化疗6例pCR组与25例非pCR组之间显著差异表达的基因共231个(Fold Change>2.0),用层次聚类分析方法能较准确区分pCR组与非pCR组的差异表达基因,预测功能富集化分析发现差异表达基因主要同免疫相关的通路、DNA和蛋白质聚合、跨膜转运蛋白信号通路、PARP通路以及ER相关通路等相关。当Fold Change>3.0时,pCR组与非pCR组之间的差异表达基因为20个,其中GATA3、TFF1、TFF3均与ER相关。实时定量PCR方法验证了GATA3与TFFl的表达结果与芯片结果相一致。在另外一批拥有55例独立验证队例中,采用免疫组化的方法研究ER相关因子与pCR的关系,单因素分析结果显示：ER、PR、GATA3、TFF1以及TFF3的状态与pCR存在统计学意义上相关关系(Pearson卡方检验,P<0.001,P=0.013,P=0.001,P<0.001,P<0.001),对这5个指标进行Spearman相关分析,发现他们之间均存在着显著相关性(P<0.05),采用logistics多因素回归分析结果显示：ER可作为pCR的独立预测指标(P=0.016)。进一步分析ER联合相关因子在预测新辅助化疗疗效的价值,我们发现5个与ER通路活性相关的指标(ER、PR、GATA3、TFF1、TFF3)均为阴性时,pCR率达到80%(4／5),相反,9位PD/SD的患者中有7位患者该5项指标均为阳性。
结论：全基因表达谱芯片能较准确区分化疗pCR与非pCR之间的基因差异,基因芯片技术在探索新辅助化疗疗效预测因子上有较高应用价值,有望发现新的预测因子及其通路,真正实现个体化治疗。ER通路活性较单独ER指标在预测新辅助化疗疗效上的价值高,即ER通路活性低的患者pCR率高,而ER通路活性高的患者pCR率低。ER阴性不代表ER通路活性低,可能由ER变异引起,检测ER相关因子有助于更全面了解ER通路的活性。
Background:Neoadjuvant chemotherapy was widely used as a standard procedure in patients with locally advanced breast cancer. About 10-35% breast cancer patients were resistant to neoadjuvant chemotherapy.The research of neoadjuvant chemotherapy predictive markers can help selecting the patients who might benefit from neoadjuvant chemotherapy, and keep those patients who are resistant to chemotherapy from unnessary preoperative treatment. Many large clinical trails showed patients with hormone responsive diseases are resistant to chemotherapy, while sensitive to endocrine therapy. In clinical practice, however, chemotherapy is still an important adjuvant treatment strategy for hormonal receptor positive patients, accompanying with harmful side effects.
Objective:The aim of this study was to explore the gene expression related with ER of locally advanced breast cancer and to identify novel biomarkers that can be used for characterization and prediction of response to neoadjuvant chemotherapy using microarray gene expression profiling.
Methods:Pretherapeutic tumorous tissues were obtained from 110 patients with locally advanced breast cancer. All patients received preoperative chemotherapy by the regimen of paclitaxel and carboplatin. Standardized surgery was performed after an interval of approximately 4 cycles. The response to chemotherapy was evaluated according to RECIST standards.In the 55 training cases, gene expression profiling of breast cancer were obtained by Human Genome Gene Chip Plus U133 2.0 Array. By using Significance Analysis of Microarrays (SAM), a set of discriminating genes was identified between pCR versus residul disease.Hierachical Clustering Analysis was applied to predict the response of the breast cancer. Gene Ontology and DAVID 2008 Functional Annotation Bioinformatics Microarray Analysis tools were used to gene functional category clustering analysis. As ER related biomarkers, the GATA3、TFF1 and TFF3 were performed further analysis in the validation set by IHC.
Results:In the training set, the yield of total RNA was insufficient to assay in 16 patients and eight chips failed the quality check (QC) process. Therefore, gene expression profiles from 31 samples were available for this study. The overall pCR rate in the 86 patients was 19.7%(n=17,6 cases of pCR in training set and 11 pCR in validation set).6 patients as pCR and 25 patients as non-pCR showed significant different expression levels for 231 genes (Fold Change>2.0) by Significance Analysis of Microarrays (SAM).The list of differential expreesion genes included humoral immune response, protein-DNA complex assembly, transmembrane receptor protein tyrosine kinase signaling pathway, PARP signaling pathway and response to hormone stimulus. Setting fold change>3 resulted in 20 differentially expressed genes, among these 20 genes, TFF1,ESR1,GATA3,TFF3 were found as ER-related genes. In the further study by Real-time PCR, TFF1 and GATA3 showed significant higher expression in patients with non-pCR (P<0.05), which is consistent with the results of microarray analysis.In the 55 independent validation cases, in univariate analysis including clinical variables and ER-related genes, ER, PR, GATA3,TFF1 and TFF3 were all significantly associated with pCR (Pearson x 2,P<0.001,P=0.013, P<0.001,P<0.001, P<0.001).Only ER (P=0.016) remained significant in a logistic regression model.In spearman analysis, these 5 ER-related genes were significantly correlated with each other (P<0.05).To further analyse the predictive value of ER combined with ER-related genes, we found that the pCR rates was as high as.80% (4/5)when these 5 factors were all negative. In contrast, these 5 factors are all positive were found in 7 of 9 PD/SD patients.
Conclusions:The present study suggested the possibility that microarray gene expression profiling may be usefμl in predicting response of locally advanced breast cancer to neoadjuvant chemotherapy and helpful in individualized therapy. ER related genes(ER pathway) may provide more predictive value of response to neoadjuvant chemotherapy than ER status alone. To test ER related factors can help comprehensively understanding the activity of ER pathway.
引文
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[1]Mauri D, Pavlidis N, Ioannidis JP.Neoadjuvant versus Adjuvant Systemic Treatment in Breast Cancer:A Meta-Analysis.J Natl Cancer Inst.2005, 97(3):188-194.
[2]Chang JC, Wooten EC, Tsimelzon A, et al.Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet, 2003,362(9381):362-369.
[3]Kaufmann P, Dauphine CE, Vargas MP, et al.Success of neoadjuvant chemotherapy in conversion of mastectomy to breast conservation surgery. Am Surg. 2006,72(10):935-938.
[4]Fernandez-Sanchez M, Gamboa-Dominguez A, Uribe N, et al.Clinical and pathological predictors of response to neoadjuvant anthracycline chemotherapy in locally advanced breast cancer. Med Oncol.2006,23(2):171-183.
[5]Jacquillat C, Weil M, Baillet F, et al.Results of neoadjuvant chemotherapy and radiation therapy in the breast conserving treatment of 250 patients with all stages of infiltrative breast cancer. Cancer.1990,66(1):119-129.
[6]Cristofanili M, Gonzalez-Angμlo A, Sneige N, et al.Invasive lobular carcinoma classic type:response to primary chemotherapy and survival outcomes. J Clin Oncol.2005,23(1):41-48.
[7]Mathieu MC,Rouzier R, Llombart-Cussac A, et al.The poor responsiveness of infiltrating lobμlar breast carcinomas to neoadjuvant chemotherapy can be explained by their biological profile.Eur J Cancer.2004,40(3):342-351.
[8]Hanrahan EO, Hennessy BT, Valero V.Neoadjuvant systemic therapy for breast cancer:an overview and review of recent clinical trials. Expert Opin Pharmacother.2005,6(9):1477-1491.
[9]Prisack HB,Karreman C,Modlich O, et al.Predictive biological markers for response of invasive breast cancer to anthracycline/cyclophosphamide-based primary (radio-) chemotherapy.Anticancer Res.2005,25(6C):4615-4621.
[10]Guarneri V, Broglio K, Kau SW, et al.Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors.J Clin Oncol.2006,24(7):1037-1044.
[11]Gianni L, Baselga J, Eiermann W, et al.Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clin Cancer Res.2005, 11(24 Pt 1):8715-8721.
[12]von Minckwitz G, Raab G, Caputo A, et al.Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every
14 days as preoperative treatment in operable breast cancer:The GEPARDUO study of the German Breast Group.J Clin Oncol.2005,23(12):2676-2685.
[13]Rody A, Karn T, Ahr A, et al. Gene expression profiling of breast cancer patients treated with docetaxel,doxorubicin, and cyclophosphamide within the GEPARTRIO trial:HER2, but not topoisomerase II alpha and microtubμle-associated protein tau, is highly predictive of tumor response.Breast.2007,16(1):86-93.
[14]Petit T, Borel C, Ghnassia J-P, et al.Chemotherapy response of breast cancer depends on HER2 status and anthracycline dose intensity in the neoadjuvant setting. Clin Cancer Res.2001,7(6):1577-1581.
[15]Martin-Richard M, Munoz M, Albanell J, et al.Serial topoisomerase II expression in primary breast cancer and response to neoadjuvant anthracycline-based chemotherapy. Oncology.2004,66(5):388-394
[16]Nakopoulou L, Lazaris AC,Kavantzas N, et al.DNA topoisomerase Ⅱ-a immunoreactivity as a marker of aggressiveness in invasive breast cancer. Pathobiology.2000,68(3):137-143.
[17]Sullivan DM, Latham MD, Ross WE.Proliferation dependent topoisomerase Ⅱ content as a determinant of antineoplastic drug action in human, mouse, and Chinese hamster ovary cells.Cancer Res.1987,47(15):3973-3979.
[18]Chang J, Powles TJ, Allred DC,et.al.Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. J Clin Oncol.1999, 17(10):3058-3063.
[19]Petit T, Wilt M, Velten M, et al.Comparative value of tumour grade, hormonal receptors, Ki-67, HER2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer 2004,40(2):205-211.
[20]Burcombe RJ, Makris A, Richman PI, et al.Evaluation of ER, PgR, HER2 and Ki-67 as predictors of response to neoadjuvant anthracycline chemotherapy for operable breast cancer. Br J Cancer.2005,92(1):147-155.
[21]Faneyte IF,Schrama JG, Peterse JL, et al.Breast cancer response to neoadjuvant chemotherapy:predictive markers and relation with outcome. Br J Cancer.2003, 88(3):406-412.
[22]Sjostrom J. Predictive factors for response to chemotherapy in advanced breast cancer. Acta Oncol.2002,41(4):334-345.
[23]Colleoni M, Orvieto E, Nole F, et al.Prediction of response to primary chemotherapy for operable breast cancer. Eur J Cancer.1999,35(4):574-579.
[24]Ellis PA, Smith IE, Salter J, et al.Preoperative chemotherapy induces apoptosis in early breast cancer. Lancet.1997,349(9055):849-856
[25]Rozan S,Vincent-Salomon A, Zafrani B, et al.No significant predictive value of c-erbB-2 or p53 expression regarding sensitivity to primary chemotherapy or radiotherapy in breast cancer. Int J Cancer.1998,79(1):27-33.
[26]Bonetti A, Zaninelli M, Leone R, et al.bcl-2 but not p53 expression is associated with resistance to chemotherapy in advanced breast cancer. Clin Cancer Res.1998, 4(10):2331-2336.
[27]MacGrogan G, Mauriac L, Durand M, et al.Primary chemotherapy in breast invasive carcinoma:predictive value of the immunohistochemical detection of hormonal receptors, p53,c-erbB-2, MiB1,pS2 and GST pi.Bri J Cancer.1996, 74(9):1458-1465.
[28]Ogston KN,Miller ID, Schofield AC, et al.Can patients'likelihood of benefiting from primary chemotherapy for breast cancer be predicted before commencement of treatment? Breast Cancer Res Treat.2004,86(2):181-189.
[29]Buchholz TA,Garg AK, Chakravarti N, et al.The nuclear transcription kappa B/bcl-2 pathway correlates with pathological complete response to doxorubicin-based chemotherapy in human breast cancer. Clin Cancer Res.2005,11(23):8398-8402.
[30]Kariya S,Ogawa Y, Nishioka A, et al.Relationship between hormonal receptors, HER2, p53 protein, Bcl-2,and MIB-1 status and the antitumor effects of neoadjuvant anthracycline-based chemotherapy in invasive breast cancer patients.Radiati Med.2005,23(3):189-194.
[31]Daidone MG, Veneroni S, Benini E, et al.Biological markers as indicators of response to primary and adjuvant chemotherapy in breast cancer. Int J Cancer.1999, 84(6):580-586.
[32]Colleoni M, Orvieto E, Nole F, et al.Prediction of response to primary chemotherapy for operable breast cancer. Eur J Cancer.1999,35(4):574-579.
[33]Meisamy S,Bolan PJ, Baker EH, et al.Neoadjuvant chemotherapy of locally advanced breast cancer:predicting response with in vivo(1)H MR spectroscopy-a pilot study at 4T. Radiology.2004,233(2):424-431.
[34]Tiling R, Linke R, Untch M, et al.18F-FDG PET and 99mTc-sestamibi scintimammography for monitoring breast cancer response to neoadjuvant chemotherapy:a comparative study. Eur J Nucl Med.2001,28(6):711-720.
[35]Ayers M,Symmans WF,Stec J,et al.Gene expression profiles predict complete pathologic response to neoadjuvent paclitaxel and fluomuracil,doxombicin,and cyclophosphamide chemotherapy in breast csncer.J aill Oneol.2004,22(12): 2284-2293.
[36]Bonnefoi H, Potti A, Delorenzi M,et al.Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy:a substudy of the EORTC 10994/BIG 00-01 clinical trial.Lancet Oncol.2007,8(12):1071-1078.
[37]Hess KR, Anderson K, Symmans WF et.al.Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol.2006,24(26):4236-4244.
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[7]Gianni L, Baselga J, Eiermann W, et al.Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clinical Cancer Res.2005,11(24 Pt 1):8715-8721.
[8]von Minckwitz G, Raab G, Caputo A, et al. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer:The GEPARDUO study of the German Breast Group. J Clin Oncol.2005,23(12):2676-2685.
[9]Ayers M, Symrnans WF, Stec J, et al.Gene expression profiles predict complete pathologic response to neoadjuvent paclitaxel and fluomuracil, doxombicin,and cyclophosphamide chemotherapy in breast csncer.J aill Oneol.2004,22(12):2284-2293.
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[11]Hess KR, Anderson K, Symmans WF, et al.Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer.J Clin Oncol.2006, 24(26):4236-4244.
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[1]Mauri D, Pavlidis N, Ioannidis JP.Neoadjuvant versus Adjuvant Systemic Treatment in Breast Cancer:A Meta-Analysis.J Natl Cancer Inst.2005, 97(3):188-194.
[2]Chang JC, Wooten EC, Tsimelzon A, et al.Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet, 2003,362(9381):362-369.
[3]Kaufmann P, Dauphine CE, Vargas MP, et al.Success of neoadjuvant chemotherapy in conversion of mastectomy to breast conservation surgery. Am Surg. 2006,72(10):935-938.
[4]Fernandez-Sanchez M, Gamboa-Dominguez A, Uribe N, et al.Clinical and pathological predictors of response to neoadjuvant anthracycline chemotherapy in locally advanced breast cancer. Med Oncol.2006,23(2):171-183.
[5]Jacquillat C, Weil M, Baillet F, et al.Results of neoadjuvant chemotherapy and radiation therapy in the breast conserving treatment of 250 patients with all stages of infiltrative breast cancer. Cancer.1990,66(1):119-129.
[6]Cristofanili M, Gonzalez-Angμlo A, Sneige N, et al.Invasive lobular carcinoma classic type:response to primary chemotherapy and survival outcomes. J Clin Oncol.2005,23(1):41-48.
[7]Mathieu MC,Rouzier R, Llombart-Cussac A, et al.The poor responsiveness of infiltrating lobμlar breast carcinomas to neoadjuvant chemotherapy can be explained by their biological profile.Eur J Cancer.2004,40(3):342-351.
[8]Hanrahan EO, Hennessy BT, Valero V.Neoadjuvant systemic therapy for breast cancer:an overview and review of recent clinical trials. Expert Opin Pharmacother.2005,6(9):1477-1491.
[9]Prisack HB,Karreman C,Modlich O, et al.Predictive biological markers for response of invasive breast cancer to anthracycline/cyclophosphamide-based primary (radio-) chemotherapy.Anticancer Res.2005,25(6C):4615-4621.
[10]Guarneri V, Broglio K, Kau SW, et al.Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors.J Clin Oncol.2006,24(7):1037-1044.
[11]Gianni L, Baselga J, Eiermann W, et al.Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clin Cancer Res.2005, 11(24 Pt 1):8715-8721.
[12]von Minckwitz G, Raab G, Caputo A, et al.Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every
14 days as preoperative treatment in operable breast cancer:The GEPARDUO study of the German Breast Group.J Clin Oncol.2005,23(12):2676-2685.
[13]Rody A, Karn T, Ahr A, et al. Gene expression profiling of breast cancer patients treated with docetaxel,doxorubicin, and cyclophosphamide within the GEPARTRIO trial:HER2, but not topoisomerase II alpha and microtubμle-associated protein tau, is highly predictive of tumor response.Breast.2007,16(1):86-93.
[14]Petit T, Borel C, Ghnassia J-P, et al.Chemotherapy response of breast cancer depends on HER2 status and anthracycline dose intensity in the neoadjuvant setting. Clin Cancer Res.2001,7(6):1577-1581.
[15]Martin-Richard M, Munoz M, Albanell J, et al.Serial topoisomerase II expression in primary breast cancer and response to neoadjuvant anthracycline-based chemotherapy. Oncology.2004,66(5):388-394
[16]Nakopoulou L, Lazaris AC,Kavantzas N, et al.DNA topoisomerase Ⅱ-a immunoreactivity as a marker of aggressiveness in invasive breast cancer. Pathobiology.2000,68(3):137-143.
[17]Sullivan DM, Latham MD, Ross WE.Proliferation dependent topoisomerase Ⅱ content as a determinant of antineoplastic drug action in human, mouse, and Chinese hamster ovary cells.Cancer Res.1987,47(15):3973-3979.
[18]Chang J, Powles TJ, Allred DC,et.al.Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. J Clin Oncol.1999, 17(10):3058-3063.
[19]Petit T, Wilt M, Velten M, et al.Comparative value of tumour grade, hormonal receptors, Ki-67, HER2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer 2004,40(2):205-211.
[20]Burcombe RJ, Makris A, Richman PI, et al.Evaluation of ER, PgR, HER2 and Ki-67 as predictors of response to neoadjuvant anthracycline chemotherapy for operable breast cancer. Br J Cancer.2005,92(1):147-155.
[21]Faneyte IF,Schrama JG, Peterse JL, et al.Breast cancer response to neoadjuvant chemotherapy:predictive markers and relation with outcome. Br J Cancer.2003, 88(3):406-412.
[22]Sjostrom J. Predictive factors for response to chemotherapy in advanced breast cancer. Acta Oncol.2002,41(4):334-345.
[23]Colleoni M, Orvieto E, Nole F, et al.Prediction of response to primary chemotherapy for operable breast cancer. Eur J Cancer.1999,35(4):574-579.
[24]Ellis PA, Smith IE, Salter J, et al.Preoperative chemotherapy induces apoptosis in early breast cancer. Lancet.1997,349(9055):849-856
[25]Rozan S,Vincent-Salomon A, Zafrani B, et al.No significant predictive value of c-erbB-2 or p53 expression regarding sensitivity to primary chemotherapy or radiotherapy in breast cancer. Int J Cancer.1998,79(1):27-33.
[26]Bonetti A, Zaninelli M, Leone R, et al.bcl-2 but not p53 expression is associated with resistance to chemotherapy in advanced breast cancer. Clin Cancer Res.1998, 4(10):2331-2336.
[27]MacGrogan G, Mauriac L, Durand M, et al.Primary chemotherapy in breast invasive carcinoma:predictive value of the immunohistochemical detection of hormonal receptors, p53,c-erbB-2, MiB1,pS2 and GST pi.Bri J Cancer.1996, 74(9):1458-1465.
[28]Ogston KN,Miller ID, Schofield AC, et al.Can patients'likelihood of benefiting from primary chemotherapy for breast cancer be predicted before commencement of treatment? Breast Cancer Res Treat.2004,86(2):181-189.
[29]Buchholz TA,Garg AK, Chakravarti N, et al.The nuclear transcription kappa B/bcl-2 pathway correlates with pathological complete response to doxorubicin-based chemotherapy in human breast cancer. Clin Cancer Res.2005,11(23):8398-8402.
[30]Kariya S,Ogawa Y, Nishioka A, et al.Relationship between hormonal receptors, HER2, p53 protein, Bcl-2,and MIB-1 status and the antitumor effects of neoadjuvant anthracycline-based chemotherapy in invasive breast cancer patients.Radiati Med.2005,23(3):189-194.
[31]Daidone MG, Veneroni S, Benini E, et al.Biological markers as indicators of response to primary and adjuvant chemotherapy in breast cancer. Int J Cancer.1999, 84(6):580-586.
[32]Colleoni M, Orvieto E, Nole F, et al.Prediction of response to primary chemotherapy for operable breast cancer. Eur J Cancer.1999,35(4):574-579.
[33]Meisamy S,Bolan PJ, Baker EH, et al.Neoadjuvant chemotherapy of locally advanced breast cancer:predicting response with in vivo(1)H MR spectroscopy-a pilot study at 4T. Radiology.2004,233(2):424-431.
[34]Tiling R, Linke R, Untch M, et al.18F-FDG PET and 99mTc-sestamibi scintimammography for monitoring breast cancer response to neoadjuvant chemotherapy:a comparative study. Eur J Nucl Med.2001,28(6):711-720.
[35]Ayers M,Symmans WF,Stec J,et al.Gene expression profiles predict complete pathologic response to neoadjuvent paclitaxel and fluomuracil,doxombicin,and cyclophosphamide chemotherapy in breast csncer.J aill Oneol.2004,22(12): 2284-2293.
[36]Bonnefoi H, Potti A, Delorenzi M,et al.Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy:a substudy of the EORTC 10994/BIG 00-01 clinical trial.Lancet Oncol.2007,8(12):1071-1078.
[37]Hess KR, Anderson K, Symmans WF et.al.Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol.2006,24(26):4236-4244.