Cathepsin-D和nm23在乳腺癌蒽环类新辅助化疗中疗效的预测价值

目的探讨乳腺癌病人肿瘤组织中分子生物学标记物的表达与含蒽环类新辅助化疗有效率的关系。方法检测复旦大学附属肿瘤医院2000年1月至2006年8月173例乳腺癌新辅助化疗病人化疗术前或术后标本中ER、PR、Her-2/neu等15种分子标记物的表达情况,分析这些分子标记物的表达在新辅助化疗中的疗效预测价值。结果nm23或Cathepsin-D阴性病人化疗疗效显著优于阳性病人,多因素回归分析提示Cathepsin-D是独立的新辅助化疗疗效预测指标。结论Cathepsin-D可能作为乳腺癌新辅助化疗(蒽环类)敏感性的独立预测指标。     

乳腺癌ER、PR、p53、Her-2表达与新辅助化疗有效率的关系

目的探讨乳腺癌患者ER、PR、p53、Her-2的表达及其与新辅助化疗有效率的关系。方法采用免疫组化的方法检测178例乳腺癌新辅助化疗患者化疗前ER、PR、p53、Her-2的表达情况,观察新辅助化疗的效果。结果178例乳腺癌新辅助化疗病例中,ER、PR、p53阴性率、Her-2过度表达率分别为33.15、23.60%、60.67%、35.39%。ER(+)组与ER(-)组、PR(+)组与PR(-)组、p53(+)组与p53(-)组化疗有效率差异均有统计学意义(P<0.05),Her-2过度表达组与非过度表达组化疗有效率差异无统计学意义(P>0.05)。结论ER、PR、p53阴性的乳腺癌病人对化疗更敏感,化疗后获益更多,ER、PR、p53可作为乳腺癌新辅助化疗(TE或CET方案)敏感性的预测指标。     

TOPⅡ联合Ki-67和p53表达对局部晚期乳腺癌化疗敏感性的预测分析

目的探讨TOPⅡ联合p53和Ki-67的表达对局部晚期乳腺癌化疗敏感性的预测价值。方法采用免疫组化方法检测90例乳腺癌患者不同分子分型的TOPⅡ、p53和Ki-67的表达状况,比较不同TOPⅡ、p53及Ki-67表达状况患者接受新辅助化疗的疗效差异。结果 Ki-67表达阳性率在HER2过表达型、Basal-like型、腺腔A型和腺腔B型之间的差异具有统计学意义(χ2=38.877,P=0.000),其中HER2过表达型和Basal-like型高于腺腔A型和腺腔B型;TOPⅡ及p53的表达表达阳性率在4种分子分型间的差异无统计学意义(χ2=7.105,P=0.069;χ2=7.105,P=0.069)。TOPⅡ和Ki-67表达阳性者的新辅助化疗疗效优于表达阴性者χ2=18.28,P=0.000;χ2=6.64,P=0.009;而p53的表达状况与新辅助化疗的敏感性无关。结论 HER2过表达型和Basal-like型乳腺癌患者对新辅助化疗敏感,疗效好;TOPⅡ表达阳性并Ki-67表达阳性可作为乳腺癌临床化疗患者敏感性生物学指标。     

乳腺癌新辅助化疗疗效生物学预测指标的研究进展

目的总结乳腺癌新辅助化疗疗效生物学预测指标的研究进展。方法阅读近年来相关文献,对预测乳腺癌行新辅助化疗后疗效的生物学指标进展加以综述。结果既往研究显示,许多生物学指标可能与乳腺癌新辅助化疗疗效相关,如人表皮生长因子受体-2(HER-2)基因、雌激素受体(ER)、孕激素受体(PR)、Ki-67、P53基因、中性粒细胞和淋巴细胞的比值(NLR)、血小板水平、血小板平均体积(MPV)等,但具体预测价值尚未达成一致结论。结论各种因子对乳腺癌新辅助化疗疗效的预测价值尚不确定,需待进一步研究。     

乳腺癌p53，ki-67和bcl-2的表达与新辅助化疗的关系

目的 研究乳腺癌p53,ki-67和bcl-2基因蛋白表达与新辅助化疗临床效果的关系,以寻找指导治疗、判断预后的生物学指标.方法 采用免疫组化SABC法测定118例可手术的乳腺癌标本的p53,ki-67和bcl-2的蛋白表达,并分析其与新辅助化疗疗效的关系.结果 术前辅助化疗有效率为68.6%.p5 3表达阳性,化疗效果差（P＜0.05）;而ki-67阳性表达者有效率明显高于ki-67不表达者（P＜0.05）;bcl-2表达与疗效无明显关系.p53蛋白阳性表达者bcl-2表达下降.p53与ki-67蛋白表达有明显关系.结论 p53和ki-67蛋白表达可作为指导新辅助化疗及预后判断的分子生物学指标.     

Her-2阴性乳腺癌中激素受体、Ki-67、P53的表达与蒽环类新辅助化疗疗效的关系

目的探讨Her-2阴性乳腺癌中激素受体、Ki-67、P53的表达与蒽环类新辅助化疗疗效的关系。方法应用免疫组化法测定78例Her-2阴性乳腺浸润性导管癌蒽环类新辅助化疗前ER、PR、Ki-67、P53的表达。四个周期CEF或AC方案化疗后进行临床及病理疗效评价。结果激素受体双阳或单阳组与激素受体双阴组相比,临床总有效率及术后病理有效率有显著性差异(P0.05);Ki-67阳性组与Ki-67阴性组相比,临床总有效率无显著性差异(P0.05),术后病理有效率有显著性差异(P0.05);P53阳性组与P53阴性组相比,临床总有效率及术后病理有效率均未见显著性差异(P10.05)。结论激素受体阴性、Ki-67阳性对Her-2阴性乳腺癌患者蒽环类新辅助化疗的敏感性较高,激素受体状态、Ki-67可能成为判断Her-2阴性乳腺癌蒽环类新辅助化疗疗效的重要指标。     

TopoⅡ、MRP和GST-π在食管胃交界部腺癌中的表达及与新辅助化疗疗效的关系

目的探讨TopoⅡ、MRP和GST-π5在进展期食管胃交界部腺癌新辅助化疗疗效中的预测价值。方法对72例食管胃交界部腺癌患者行SOX方案新辅助化疗,以RECIST 1.0评价标准评价疗效。用免疫组化方法检测化疗前3种蛋白的表达情况,并分析其与化疗疗效的关系。结果年龄和病理类型与化疗敏感性无关(P0.05)。本组72例患者中新辅助化疗有效率为48.6%,其中5例达病理完全缓解,6例进展。患者肿瘤标本中3种蛋白的表达情况:TopoⅡ、MRP和GSTπ的阳性率分别为73.6%、34.7%和40.3%。TopoⅡ、MRP和GST-π的表达与化疗敏感性无关(P0.05)。结论 TopoⅡ、MRP和GST-π的表达与食管胃交界部腺癌新辅助化疗的疗效无关,尚不能作为预测SOX方案疗效的指标。     

ER、PR、HER-2/neu与乳腺癌新辅助化疗有效率的关系研究

目的探讨乳腺癌患者ER、PR、HER-2/neu的表达及其与新辅助化疗有效率的关系及乳腺癌新辅助化疗敏感性的预测指标。方法采用免疫组化的方法检测160例乳腺癌新辅助化疗病人化疗前后ER、PR、HER-2/neu的表达情况,并评估其与乳腺癌新辅助化疗有效率的关系。结果160例乳腺癌新辅助化疗病例中,ER、PR阴性率、HER-2/neu过度表达率分别为35.63%,24.38%,33.13%,ER( )组与ER(-)组、PR( )组与PR(-)组及HER-2/neu过度表达组与非过度表达组化疗有效率差异均有统计学意义(χ2>3.875,P<0.05);新辅助化疗前后ER、PR的阳性率和HER-2/neu过度表达率的改变无统计学意义。结论ER或PR阴性的乳腺癌病人对化疗更敏感,化疗后获益更多,而HER-2/neu过度表达的病人化疗不敏感,ER、PR和HER-2/neu可作为乳腺癌新辅助化疗敏感性的预测指标;新辅助化疗不改变ER、PR及HER-2/neu的表达水平。     

乳腺癌Ki-67|p53|CerbB-2|ER及PR的表达预测新辅助化疗效果的研究

目的探讨乳腺癌Ki-67,p5 3,CerbB-2,ER,PR的表达与新辅助化疗效果的关系。方法对局部晚期乳腺癌行空心针穿刺活检明确诊断,免疫组化测定肿瘤组织的Ki-67,p5 3,CerbB-2,ER和PR的表达,随后给予紫杉类联合蒽环类的新辅助化疗。结果 3 1例新辅助化疗后总有效率(RR)为8 0.6%,其中完全缓解(CR)2例(6.5%),均为病理完全缓解(pCR),部分缓解(PR)2 3例(74.2%),病稳定(SD)6例(19.4%)。Ki-67,p5 3,CerbB-2,ER及PR的表达与新辅助化疗效果无明显关系,化疗前后免疫指标无明显变化。结论 Ki-67,p5 3,CerbB-2,ER及PR表达不能预测新辅助化疗的疗效。     

胃肠道肿瘤新辅助化疗疗效分析及多药耐药标志物的检测

目的：对胃肠道肿瘤新辅助化疗的疗效进行评价，同时探讨其耐药机理。方法：对20例胃癌及31例大肠癌患者施行新辅助化疗及手术治疗，取术前活检标本进行免疫组化染色，检测其p53、多药耐药蛋白(multidrug resistance-associated protein,MRP)、谷胱甘肽S转移酶(glutathione S transferase，GST)和端粒酶在胃肠道肿瘤组织中的表达，并对术后标本进行常规病理检查以确定其疗效，同时观察术后1个月内并发症的发生率。结果：51例患者中新辅助化疗有效者14例，有效率为27．45％，术后并发症的发生率为15．69％(8／51)．死亡率为1．96％(1／51)。p53、MRP、GST和端粒酶的表达阳性率分别为58．0％、51．0％、66．7％和74．0％；新辅助化疗疗效与患者性别、年龄、淋巴结转移及远处转移无关，与p53及端粒酶的表达相关。结论：胃肠道肿瘤的新辅助化疗是一种安全有效的方法，但在胃肠道肿瘤中原发性耐药较高，其耐药性与p53及端粒酶的表达有关。     

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??Expression of molecular markers predict breast cancer to neoadjuvant anthracycline chemotherapy value CHEN Yi-zuo*, CHEN Can-ming, FEI Fei, et al. *Department of Breast Surgery, Fudan University Shanghai Cancer Center,Shanghai 200032, China
Corresponding author: WU Jiong, E-mail??wujiong1122@vip.sina.com
Abstract Objective To investigate the predictive value of biological markers for responsiveness to anthracyline-based regimen in neoadjuvant systemic therapy for local advanced breast caner. Methods Postoperative paraffin-embedded tumor samples from 420 breast cancer patients admitted between January 2000 and December 2010 in Department of Breast Surgery of Fudan University Shanghai Cancer Center were examined for expression of ER, PR, Her-2/neu and other 15 markers by immunohistochemistry, to analyze the predictive value of the biological markers for response to neoadjuvant chemotherapy. Results Negative p53, cathepsin-D and loss of GSTπwere significantly predictive for an effective response to anthracycline-based neoadjuvant chemotherapy. In multivariate logistic regression analysis, the GSTπand p53 status were found with independent predictive value. Conclusion Loss of GSTπand p53 independently predict the response to anthracycline-based regimen.     

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??Cathepsin-D and nm23 provide the predictive value of response to anthracycline-based neoadjuvant chemotherapy in breast cancer CHEN Yi-zuo*, CHEN Can-ming, FEI Fei, et al. *Department of Breast Surgery?? Cancer Hospital??Fudan University.Department of Oncology, Shanghai Medical College, Fudan University,Shanghai 200032??China Corresponding author: WU Jiong, E-mail: wujiong1122@vip.sina.com Abstract Objective To investigate the predictive value of biological markers for responsiveness to anthracyline-based regimen in neoadjuvant systemic therapy. Methods Post-operative paraffin-embedded tumor samples from 173 breast cancer patients were examined for expression of ER??PR??Her-2/neu??and other 15 markers by immunohistochemistry, to analyze the predictive value of these biological markers for response to neoadjuvant chemotherapy. Results For the primary tumor, the clinical objective response was 66.47%?? 29.48%SD,and 4.05% PD. Pathological complete response was found in 3 cases(1.73%).Negative nm23, and loss of Cathepsin-D were significantly predictive for an effective response to anthracycline-based neoadjuvant chemotherapy. In multivariate logistic regression analysis, only the Cathepsin-D status was found for independent predictive value. Conclusion Loss of Cathepsin-D independently predicts the response to anthracycline-based regimen.     

Biomarkers for breast cancer

Molecular biomarkers for breast cancer are of several types. Risk biomarkers are those associated with increased cancer risk and include mammographic abnormalities, proliferative breast disease with or without atypia, family clustering and inherited germ-line abnormalities. Surrogate endpoint biomarkers are tissue, cellular or molecular alterations that occur between cancer initiation and progression. These biomarkers are utilized as endpoints in short-term chemoprevention trials. Prognostic biomarkers provide information regarding outcome irrespective of therapy, while predictive biomarkers provide information regarding response to therapy. Candidate prognostic biomarkers for breast cancer include elevated proliferation indices such as Ki-67 and proliferating cell nuclear antigen (PCNA); ER and PR overexpression; markers of oncogene overexpression such as c-erbB-2, TGF-a and EGFr; indicators of apoptotic imbalance including overexpression of bcl-2 and an increased bax/bcl-2 ratio; markers of disordered cell signaling such as p53 nuclear protein accumulation; alteration of differentiation signals such as overexpression of c-myc and related proteins; loss of differentiation markers such as TGF-b II receptor and retinoic acid receptor; and alteration of angiogenesis proteins such as VEGF overexpression. As our knowledge regarding molecular biomarkers for breast cancer increases, prognostic indices will be developed that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors.     

Sequencing of hormonal therapy in breast cancer

Hormonal therapy plays an integral role in the management of the majority of women with breast cancer who can be considered to have hormone-dependent breast cancer because of the presence of the molecular predictive markers, estrogen receptor and progesterone receptor. Numerous hormonal agents are available from multiple classes of drugs, including selective estrogen receptor modulators, aromatase inhibitors, progestins, androgens, and luteinizing hormone-releasing hormone analogues. Multiple clinical trials involving these agents have been conducted which permit an evidence-based approach to the development of a sequencing strategy for treatment of women with breast cancer.     

Gene expression profiling of breast cancer patients treated with docetaxel, doxorubicin, and cyclophosphamide within the GEPARTRIO trial: HER-2, but not topoisomerase II alpha and microtubule-associated protein tau, is highly predictive of tumor response

Gene expression analysis in breast cancer patients undergoing neoadjuvant chemotherapy is an interesting tool for identification of gene signatures and new markers to predict tumor response. However, the detection of predictive markers strongly depends on the drugs used in the specific therapeutic setting. There is growing evidence that topoisomerase II-alpha (TOPO IIalpha) is a marker for anthracycline-, and microtubule-associated protein tau (MAPT) for taxane sensitivity. HER-2 has been described as a marker of both anthracycline and taxane sensitivity. We performed gene expression profiling of 50 patients within the GEPARTRIO study, an anthracycline and taxane neoadjuvant chemotherapy trial. Here we investigate the predictive value of TOPO IIalpha, MAPT and HER-2 mRNA expression for pathological complete response (pCR) in this setting. Interestingly, HER-2 gene expression was strongly predictive of pCR (P=0.017) as well as overall response (P=0.037) and clinical complete response (cCR, P=0.050). In contrast, for both TOPO IIalpha and MAPT no correlation with pCR was observed in our sample group.     

The predictive of tumour markers CA 15-3, TPS and CEA in breast cancer recurrence

The predictive values of tumour markers Carcinoma-Associated Antigen CA 15-3, Tissue Polypeptide Specific Antigen (TPS) and Carcinoembryonic Antigen (CEA) in recurrence of breast cancer are unclear. The aim of this study was to examine the predictive value of these markers in our population of 1448 patients with diagnosed breast cancer. Data and mean follow-up of 4.4 years were available on 1082 women of whom 277 had documented recurrence (mean follow up 5.7 years). The recurrence free patients had a mean follow up of 3.9 years. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CA 15-3, TPS and CEA for visceral, bony and locoregional recurrence were calculated. CA 15-3 was the most sensitive marker, 68% for visceral and 69% for bony recurrence. This compared with TPS, 64% and 51% and CEA, 27% and 46% for visceral and bony recurrence respectively. The positive predictive value of CA 15-3 at 47% for visceral and 54% for bony recurrence was greater than that for TPS (visceral 25%, bony 21%) or CEA (visceral 18%, bony 26%). The sensitivity of CA 15-3 and TPS for locoregional recurrence was low at 23% and 17% respectively. A combination of CA 15-3, TPS and CEA failed to increase the sensitivity of CA 15-3 for visceral recurrence. However, a marginally increased sensitivity was recorded for combined CA 15-3 and TPS (70%) and for combined CA 15-3, TPS and CEA (71%) in bony recurrence. The mean lead time effect in visceral recurrence for TPS and CA 15-3 were 8 and 10 months respectively. In patients with bony recurrence the mean lead time effect for TPS and CA 15-3 were 7.5 and 8.25 months. Mean lead time effect was increased to 9 and 11 months for bony and visceral recurrence respectively when CA 15-3 and TPS were combined. CA 15-3 remains the most sensitive tumour marker in breast cancer follow up with a significantly greater positive predictive value when compared to TPS or CEA. Both TPS and CEA failed to complement the sensitivity of CA 15-3 when measured in combination.     

Could biological aggressivity markers of breast cancer alter the therapeutic course? Preliminary results

The aim of this study is to justify an individual therapeutical attitude in breast cancer, related to diversity of breast tumors, aggressiveness grade and metastatic potential. Between January 2000--December 2001, 150 patients were admitted with breast cancer (stage II and III) and underwent surgery in our department. We selected 75 cases in our study. In 51 (68%) cases the first therapeutical method was surgery, in 15 (20%) cases surgery was performed after chemotherapy, in 2 (2.66%) cases after radiotherapy and after chemotherapy and radiotherapy in 7 (9.33%) cases. We evaluated several classical factors and new immunohistochemical markers with an important value for diagnosis, prognosis and therapy: oestrogen and progesterone receptors, c-erb B2, pS2 and p53 proteins, von Willebrand factor. Several factors had a predictive role regarding the response to chemotherapy. These predictive factors will improve the histopathological diagnosis. The oncoproteins and hormonal receptors also will evaluate with more accuracy the metastatic risk and will assure a better therapy decision.     

Profiling the Immune Stromal Interface in Breast Cancer and Its Potential for Clinical Impact

Advances in DNA sequencing technologies, as well as refined bioinformatics methods for interpretation of complex datasets, have provided the opportunity to comprehensively assess gene expression in tumours and their surrounding microenvironment. More recently, these advances have highlighted the interplay between the immune effector mechanisms and breast cancer cell biology, emphasizing the long-recognized link between immunity and cancer. Studying immune-associated genes has not only resulted in further stratification within the broad pathological types of breast cancers, but also provided further biological insights into the complex heterogeneity within breast cancer subgroups. On the basis that anti-cancer therapies can modify the host-tumour interaction, investigators have focused their attention on the predictive value of immune parameters as markers of therapeutic anti-tumour response. We discuss the current status of immune signatures in breast cancer and some of the fundamental limitations that need to be overcome to move these discoveries into clinic.     

Prognostic and Predictive Markers for Treatment Decisions in Early Breast Cancer

Breast cancer clinically represents a heterogeneous disease. Over the last decades, the integration of prognostic and predictive markers in treatment decisions has led to a more individualized and optimized therapy. While prognosis describes the risk of disease recurrence and disease-related death after diagnosis without the influence of therapy, prediction illustrates the probability of efficacy or response of a specific therapeutic measure. The substantial decline in breast cancer mortality seen over the last 20 years is primarily due to the delivery of adjuvant systemic therapy. It is important that clinical decisions are made to minimize overtreatment, under-treatment, and incorrect treatment. Improved understanding of breast cancer biology together with the utilization of classical biomarkers and the identification of new markers or profiles is increasingly defining who should receive cancer therapy and what therapy offers the best efficacy. The molecular targets as the prerequisite for successful concepts of specific therapies like anti-estrogens, antibodies, or small molecules, have therefore high clinical value in regards to prognosis as well as prediction.     

Assessment of the effects of breast cancer on bone and the response to therapy

The skeleton is the most frequent site of metastatic disease in breast cancer and also the site of greatest morbidity. In addition, there is now recognition that accelerated bone loss associated with chemotherapy or hormonal therapy leads to an increased risk of osteoporosis in long-term breast cancer survivors. An improved range of treatment options is available and assessment of skeletal response both to the disease and to therapy is therefore of growing importance. Plain radiographs remain widely used to assess response, but are of limited sensitivity. The isotope bone scan is more sensitive, but lacks specificity. Computerised tomography, magnetic resonance imaging and positron emission tomography all have an increasing role. In treatment-induced osteoporosis, bone mineral density is now readily measured by DEXA scanning. Tumour markers such as CEA, CA 15-3, CA 549 and TPA may have a role in assessing response, but probably in combination rather than individually, using an appropriate quantitative model. Several trials have shown that bone markers, especially markers of bone resorption such as Ntx, Ctx, PYD and DPD, appear to have strong potential as rapid, convenient and inexpensive measures of response. There is also evidence that they may be used as predictive or prognostic indicators. Evidence is accumulating that the reduction of bone resorption markers into the normal range results in substantially reduced morbidity in metastatic breast cancer and that this should be a major target of therapy.