Molecular prediction of the therapeutic response to neoadjuvant chemotherapy in breast cancer

Breast cancer is considered to be relatively sensitive to chemotherapy, and multiple combinations of cytotoxic agents are used as standard therapy. Chemotherapy is applied empirically despite the observation that not all regimens are equally effective across the population of patients. Up to date clinical tests for predicting cancer chemotherapy response are not available, and individual markers have shown little predictive value. A number of microarray studies have demonstrated the use of genomic data, particularly gene expression signatures, as clinical prognostic factors in breast cancer. The identification of patient subpopulations most likely to respond to therapy is a central goal of recent personalized medicine. We have designed experiments to identify gene sets that will predict treatment-specific response in breast cancer. Taken together with our recent trial about the construction of a high-throughput functional screening system for chemo-sensitivity related genes, studies for drug sensitivity will provide rational strategies for establishment of the prediction system with high accuracy, and identification of ideal targets for drug intervention. This article is based on a presentation delivered at Presidential Symposium 1, “Breast cancer: individualized diagnosis for tailored treatment,” held on 29 June 2007 at the 15th Annual Meeting of the Japanese Breast Cancer Society in Yokohama.     

乳腺癌新辅助化疗后腋窝淋巴结病理学完全缓解预测模型的验证与改良研究

背景与目的：新辅助化疗（neoadjuvant chemotherapy,NAC）是局部晚期乳腺癌患者的标准治疗模式,2018年有研究报道了一个多变量预测模型,用于预测临床腋窝淋巴结阳性（clinical lymph node-positive,cN₊）患者NAC后腋淋巴结病理完全缓解（ypN₀）的概率。分析乳腺癌NAC后ypN₀的相关因素,验证Olga Kantor预测模型的临床应用价值。方法：纳入山东大学附属山东省肿瘤医院2014年4月—2018年5月收治的350例临床腋淋巴结阳性NAC后行腋窝淋巴结清扫术（axillary lymph node dissection,ALND）的患者,并进行Olga Kantor预测模型的验证;由于该模型采用术后病理学评估乳腺原发肿瘤反应无助于术前预测ypN₀,因此采用术前影像评价替代术后病理学评估进行改良,分别分析验证模型和改良模型的独立预测因素,计算受试者工作特征（receiver operating characteristic,ROC）曲线的曲线下面积（area under curve,AUC）评估两模型的预测效能。结果：验证模型中年龄、分型分组及病理乳房原发肿瘤反应为ypN0的独立预测指标,改良模型中年龄、分型分组及临床乳房原发肿瘤反应为ypN₀的独立预测指标（P均＜0.05）。验证模型及改良模型的AUC分别为0.788和0.782（P>0.05）。改良模型分数≤3分、4~7分及≥8分患者NAC后ypN₀概率分别为2.5%（1/40）、22.4%（51/228）和68.3%（56/82）。结论：Olga Kantor预测模型可以较为准确地评估cN+患者ypN₀概率,改良模型具有同等的预测效能且更贴合临床实际,有助于NAC后腋窝处理模式的合理选择：得分≤3分推荐直接行ALND,4~7分可选择前哨淋巴结活检（sentinel lymph node biopsy,SLNB）,≥8分推荐行SLNB。     

A simple system for grading the response of breast cancer to neoadjuvant chemotherapy

BackgroundThe response of primary breast cancer to chemotherapy is usually expressed either as a pathological complete remission (pCR) or as ‘no pCR’. A more quantitative measure is called for.Patients and methodsThe ‘neoadjuvant response index’ (NRI) was calculated by adding a breast response score (a number from a five-point scale) to an axillary response score (a number from a three-point scale) and dividing this by the score that would have been obtained in case of a pCR in both breast and axilla. Consequently, the NRI is a number between 0 (representing no response) and 1 (a pCR of both breast and axilla).ResultsThe NRI was calculated in 267 patients who had received neoadjuvant chemotherapy. The average NRI was 0.48 (median 0.40). Forty-one patients (15%) had an NRI of 0; 55 patients (21%) had an NRI of 1 (pCR). ‘Highly endocrine responsive’ tumors responded substantially less than ‘incompletely endocrine responsive’ ones. In triple negatives, an NRI of >0.70 was associated with a better recurrence-free survival than a lower NRI.ConclusionsThe NRI proposed here may be useful to better reflect the efficacy of neoadjuvant systemic regimens than the binary pCR–‘no pCR’ system.     

腋窝淋巴结超声造影预测乳腺癌新辅助化疗的疗效

目的探讨腋窝淋巴结超声造影对浸润型乳腺癌新辅助化疗(NAC)疗效的预测价值.方法对58例Ⅱ、Ⅲ期浸润型乳腺癌患者的腋窝转移性淋巴结于NAC前、后进行超声造影检查,观察造影增强方式并进行时间强度分析,然后与手术病理对照.结果临床评价35例有效,23例化疗无变化.NAC有效组和无变化组两组之间灌注模式差异无统计学意义.到达淋巴结皮质时间化疗前两组间比较差异无统计学意义,化疗后有效组大于化疗无变化组.化疗前的弥散时间两组间差异有统计学意义,化疗后有效组弥散时间降低.以化疗后弥散时间275秒为最佳临界点,预测的敏感性为77%,特异性为90%.达峰时间、峰值强度两组之间差异无统计学意义.结论淋巴结超声造影增强方式对预测新辅助化疗的疗效无明显特异性,但到达淋巴结皮质时间、弥散时间对预测新辅助化疗的有效性有临床价值.     

腋窝淋巴结超声造影预测乳腺癌新辅助化疗的疗效

Objective To explore the predictive value of response to neoadjuvant chemotherapy(NAC)in local advanced breast cancer with contrast-enhanced ultrasound(CEUS)of axillary lymph node.Methods CEUS of metastatic axillary lymph nodes in 58 patients stacng Ⅱ-Ⅲ breast cancer was performed before and after NAC treatment. The enhancement patterns and parameters of time-intensity curve were assessed and compared with the pathology.Results The clinic response evaluation were drug-effective in 35 cases and no change in 23 ones.There Were no significant differences in enhancement patterns between no-change and drugeffective groups.Lymph node cortex arriving time was longer in drug-effective cases than that in no-change ones after NAC,whereas it showed no significant differences before NAC.Statistical significant difierence in enhancement duration(ED)was found between the two groups before NAC,which decreased markedly in drug-effective case8 after NAC.Histopatholngic response could be predicted with a sensitivity of 77% and a specificity of 90% by standardized ED below 275 seconds after NAC.No significant difference was found in time to peak(TP),peak intensity(PI)between the two groups.Conclusion The perfusion pattern of axillary lymph node CEUS after NAC Was insufficient to predict curative effect.But the lymph node cortex arriving time and enhancement duration may be of value in the prediction of clinical response to chemotherapy.     

腋窝淋巴结超声造影预测乳腺癌新辅助化疗的疗效

Objective To explore the predictive value of response to neoadjuvant chemotherapy(NAC)in local advanced breast cancer with contrast-enhanced ultrasound(CEUS)of axillary lymph node.Methods CEUS of metastatic axillary lymph nodes in 58 patients stacng Ⅱ-Ⅲ breast cancer was performed before and after NAC treatment. The enhancement patterns and parameters of time-intensity curve were assessed and compared with the pathology.Results The clinic response evaluation were drug-effective in 35 cases and no change in 23 ones.There Were no significant differences in enhancement patterns between no-change and drugeffective groups.Lymph node cortex arriving time was longer in drug-effective cases than that in no-change ones after NAC,whereas it showed no significant differences before NAC.Statistical significant difierence in enhancement duration(ED)was found between the two groups before NAC,which decreased markedly in drug-effective case8 after NAC.Histopatholngic response could be predicted with a sensitivity of 77% and a specificity of 90% by standardized ED below 275 seconds after NAC.No significant difference was found in time to peak(TP),peak intensity(PI)between the two groups.Conclusion The perfusion pattern of axillary lymph node CEUS after NAC Was insufficient to predict curative effect.But the lymph node cortex arriving time and enhancement duration may be of value in the prediction of clinical response to chemotherapy.     

Pre-treatment haemoglobin levels and the prediction of response to neoadjuvant chemotherapy in breast cancer

AimsA low pre-treatment haemoglobin level has been shown to negatively influence outcome in the treatment of tumours of the cervix, bladder and head and neck by radiotherapy. The purpose of this study was to assess the influence of baseline haemoglobin levels on the response to neoadjuvant chemotherapy for breast cancer.Materials and methodsOne hundred and thirty-nine women receiving neoadjuvant chemotherapy for operable breast tumours (T2–4, N0–1, M0) were accessed from our prospective database. Women were treated between March 1999 and June 2004. The median age was 47 years (range 25–70). Most women were treated with 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy (122/139 patients). Baseline haemoglobin levels were compared for clinical responders (partial or complete) and non-responders (stable or progressive disease) using Student's t test and logistic regression. The analysis was adjusted for nodal status, tumour size, tumour grade and menopausal status.ResultsThe overall response rate was 84.9% (118/139), with a complete clinical response in 24.5% (34/139). Mean haemoglobin levels were 13.3 g/dl in responders and 13.4 g/dl in non-responders (range 7.9–15.8). The distributions of haemoglobin levels were not significantly different when comparing either responders with non-responders or ‘good’ responders with ‘poor’ responders (P = 0.70 and P = 0.32, respectively). If haemoglobin is treated as a binary variable using 12.0 g/dl as the threshold, there is a non-significant trend towards a reduction in the probability of achieving a good response if baseline haemoglobin is below 12.0 g/dl (odds ratio = 0.26, confidence interval = 0.06–1.21; P = 0.086). The rate of complete pathological response was 4.3% (6/139). The mean haemoglobin level in these patients was 14.2 g/dl (range = 12.8–15.7), but the small numbers precluded further analysis.ConclusionsThere is no evidence for an influence of pre-treatment haemoglobin levels on the clinical response to neoadjuvant chemotherapy in breast cancer. It is unlikely that correction of anaemia above that which is warranted clinically will improve outcomes.     

预测乳腺癌新辅助化疗疗效的多基因表达谱研究进展

新辅助治疗是在除外转移的情况下,在局部治疗前(手术或放疗)进行的全身药物治疗.乳腺癌的异质性决定了乳腺癌对药物治疗的敏感性存在较大的差异,用多基因表达谱模型来预测新辅助治疗疗效,为乳腺癌个体化治疗方案的选择提供了新的途径.文章简述预测性多基因表达谱在乳腺癌治疗中的应用.     

新辅助化疗对食管癌围手术期影响的临床研究

目的:探讨新辅助化疗对食管癌围手术期的影响,并对化疗后手术时机进行探讨.方法:将扬州大学附属泰兴市人民医院同一手术组医生施行食管癌切除术的食管癌160例,按时间段分成新辅助化疗组(NC组)和常规手术组(对照组),NC组化疗后1-3天手术,对照组直接常规手术.按照UICC标准进行临床病理分期.比较两组的术前一般情况、手术时间、术中出血量、术后胸管引流量、术后并发症发生率和住院时间.结果:两组病人术前一般情况差异无显著性.NC组术中出血量略多,但无统计学意义 ,两组的手术时间、住院天数等差异无统计学意义,术后引流量、感染、心律失常等并发症发生率不高于对照组.结论:新辅助化疗不增加手术并发症及治疗相关死亡率,化疗后立即手术是可行的.     

Dynamic breast magnetic resonance imaging: pretreatment prediction of tumor response to neoadjuvant chemotherapy

BackgroundDynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may have the potential of predicting response to neoadjuvant chemotherapy for patients with breast cancer. However, most of these studies focused on evaluating hot-spot characteristics. To thoroughly reflect tumor status, the cold spot and heterogeneity characteristics should also be evaluated.Patients and MethodsDCE-MRIs from 60 patients newly diagnosed with primary invasive breast cancer were reviewed. Kinetic parameters (including cold spot, hot spot, and heterogeneity parameters) derived from DCE-MRI data were used to describe cold spot, hot spot, and heterogeneity features. Patients with a pathologic complete response (pCR) or a ductal carcinoma in situ with microinvasion after chemotherapy were categorized into the pCR group. Pretreatment kinetic parameters in the pCR and non-pCR groups were compared by using univariate tests. Binary logistic regression analysis was used to identify the independent predictors for pCR. The best cutoff value of the independent predictor at pretreatment, with which to differentiate between patients who had a pCR and a non-pCR, was calculated by using receiver operating characteristic curve analysis.ResultsAfter chemotherapy, 10 (16.7%) patients were categorized into the pCR group and 50 (83.3%) into non-pCR group. Multivariate analysis showed that pretreatment washout slope at a cold spot (washout^C) was the only significant and independent predictor of pCR (β = 26.128; P = .005). The best pretreatment washout^C cutoff value with which to differentiate between patients who had pCR and those with non-pCR was 0.0277, which yielded a sensitivity of 80.0% (95% CI, 44.4%-97.5%) and a specificity of 74.0% (95% CI, 59.7%-85.4%).ConclusionWashout^C may be used as a predictor for pCR in patients with breast cancer who undergo neoadjuvant chemotherapy.     

影像学预测乳腺癌患者预后及新辅助化疗反应的研究进展

在世界范围内,乳腺癌是女性发病率最高的恶性肿瘤,也是女性因癌症死亡的主要原因。新辅助化疗(Neoadjuvant chemotherapy,NAC)可以降低乳腺癌分期、缩小肿瘤,甚至使病灶达到病理完全缓解(Pathological complete response,pCR),在乳腺癌综合治疗中得到广泛应用。由于患者对治疗的反应各有差异,所以及时准确评估NAC疗效已成为临床医生关注并致力解决的重点。常规影像学检查手段如乳腺钼靶、超声、PET-CT和磁共振成像(MRI)已广泛用于乳腺癌NAC疗效的评估,且每种影像学检查各有优势和不足。本文就常规影像学检查用于预测乳腺癌患者预后及NAC疗效的研究进展进行综述。     

不同生物学标志物对乳腺癌新辅助化疗疗效的预测价值

背景与目的:寻找乳腺癌新辅助化疗疗效预测指标将有助于筛选对化疗敏感的患者,指导个体化治疗.因此,本研究旨在探讨不同生物学标志物对紫杉醇类药物联合蒽环类药物的新辅助化疗方案治疗乳腺癌的疗效预测价值.方法:对160例行4个周期紫杉醇类药物联合蒽环类药物的新辅助化疗方案治疗的乳腺癌患者资料进行回顾性分析.采用免疫组织化学法检测术前肿瘤穿刺标本中雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PgR)、人类表皮生长因子受体2(human epidermal growth factor receptor-2,Her-2)、Topo-Ⅱ和Ki-67蛋白的表达,分析其与临床疗效及病理改变的关系.结果:总临床有效率为85%,其中临床完全缓解为46例(28.8%),部分缓解率为90例(56.3%);病理完全缓解23例.单因素分析发现ER、PgR表达阴性及Her-2过表达均可预测临床完全缓解及病理完全缓解(P＜0.05).多因素分析发现Her-2过表达仍是预测临床完全缓解的独立变量(P=0.011),仅ER阴性为预测病理完全缓解的独立变量(P=0.001).结论:Her-2过表达、ER阴性的患者对紫杉醇类药物联合蒽环类药物的新辅助化疗方案更敏感,可作为该方案的疗效预测参考指标.     

进展期胃癌新辅助化疗的临床研究

目的评价奥沙利铂联合亚叶酸钙/5-氟尿嘧啶(OXA-LV5FU2)新辅助化疗方案治疗进展期胃癌的疗效与毒副作用。方法32例进展期胃癌患者,接受新辅助化疗方案奥沙利铂(OXA)100mg/m2,静脉滴注2h,第1天;亚叶酸钙(LV)200mg/m2,静脉滴注2h后推注5-氟尿嘧啶(5-Fu)400mg/m2,后续5-Fu1g/m2,化疗泵持续48~72h恒速静脉输入,第1、2天。每2~3周为1周期,共3~4个周期。观察新辅助化疗后肿瘤原发病灶的缓解情况及其毒副反应。结果新辅助化疗后32例患者中27例获得手术切除,其中16例获得根治性切除。临床有效率为46.9%,其中完全缓解(CR)3.1%(1例),部分缓解(PR)43.8%(14例),疾病稳定(SD)34.4%(11例),疾病进展(PD)占18.8%(6例)。10例肿瘤TNM分期降低。毒副反应主要为恶心/呕吐、外周感觉神经异常、白细胞减少、脱发、肝功能异常,对症治疗缓解。无化疗相关死亡。结论奥沙利铂联合亚叶酸钙/5-氟尿嘧啶的新辅助化疗方案在进展期胃癌的治疗中近期疗效显著,耐受性良好。     

Prognostic factors for survival after neoadjuvant chemotherapy in operable breast cancer. the role of clinical response

The aim of this retrospective study was to assess predictive factors for clinical response to preoperative chemotherapy and prognostic factors for survival. From 1981 to 1992, 936 patients with T2-T3, N0-N1 breast cancer who received 2-6 months (median 4) of preoperative chemotherapy were selected from the Institute Curie database. Preoperative treatment was followed by surgery and/or radiotherapy. Median follow-up was 8.5 years (range 7-211 months). The objective response rate before surgery and/or radiotherapy was 58.3%. In stepwise multivariate analysis (Cox model), favourable prognostic factors for survival were the absence of pathological axillary lymph node involvement (Relative Risk (RR) 1.54; P=0.0004), low histological tumour grade (RR=1.54; P=0.0017), clinical response to preoperative chemotherapy (RR=1.45, P=0.0013), positive progesterone receptor (PR) status (RR=1.56; P=0.0001), smaller tumour size (RR=1.37; P=0.005) and lack of clinical lymph node involvement (RR=1.42; P=0.007). The association of clinical tumour response with survival is independent of the baseline characteristics of the tumour. Clinical response could be used as a surrogate marker for evaluation of the efficacy of neoadjuvant chemotherapy before assessment of the pathological response.     

Construction of novel immune-related signature for prediction of pathological complete response to neoadjuvant chemotherapy in human breast cancer

BackgroundThe aim of this study was to construct a novel prediction model for the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) using immune-related gene expression data.Patients and methodsDNA microarray data were used to perform a gene expression analysis of tumor samples obtained before NAC from 117 primary breast cancer patients. The samples were randomly divided into the training (n = 58) and the internal validation (n = 59) sets that were used to construct the prediction model for pCR. The model was further validated using an external validation set consisting of 901 patients treated with NAC from six public datasets.ResultsThe training set was used to construct an immune-related 23-gene signature for NAC (IRSN-23) that is capable of classifying the patients as either genomically predicted responders (Gp-R) or non-responders (Gp-NR). IRSN-23 was first validated using an internal validation set, and the results showed that the pCR rate for Gp-R was significantly higher than that obtained for Gp-NR (38 versus 0%, P = 1.04E-04). The model was then tested using an external validation set, and this analysis showed that the pCR rate for Gp-R was also significantly higher (40 versus 11%, P = 4.98E-23). IRSN-23 predicted pCR regardless of the intrinsic subtypes (PAM50) and chemotherapeutic regimens, and a multivariate analysis showed that IRSN-23 was the most important predictor of pCR (odds ratio = 4.6; 95% confidence interval = 2.7–7.7; P = 8.25E-09).ConclusionThe novel prediction model (IRSN-23) constructed with immune-related genes can predict pCR independently of the intrinsic subtypes and chemotherapeutic regimens.     

Impact of biomarker changes during neoadjuvant chemotherapy for clinical response in patients with residual breast cancers

Background

Residual cancer burden or Ki67 expression levels in residual tumors reportedly provided significant prognostic information for a non-pathological complete response subset after neoadjuvant chemotherapy (NAC). However, the significance of Ki67 reduction for clinical response during chemotherapy in each subtype or menopausal status is yet to be determined.

Methods

A total of 183 breast cancers surgically removed after chemotherapy were recruited for this study. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki67 were determined immunohistochemically for semiquantitative measurement and these biomarkers were compared in pre- and post-NAC samples from pathological non-responders (n = 125). Responses to chemotherapy were evaluated both clinically and pathologically.

Results

Ki67 expression levels after NAC (median 5 %, range 0–70 %) were significantly reduced compared with before NAC (25, 1–80 %, P < 0.0001), but only in patients who attained clinical response. This significant suppression of Ki67 in clinical responders was consistently observed in breast cancers from the ER-positive subset, but not the ER-negative subset in the total test set (n = 120). These observations were also made in the validation set (n = 63). Among premenopausal, but not postmenopausal patients, a significant decrease in PgR expression levels was detected in breast cancers of patients who attained clinical response (pre-NAC 50, 0–100 %, post-NAC 5, 0–20 %; P = 0.0003).

Conclusion

The impact of Ki67 suppression on clinical response seems to be restricted to ER-positive breast cancers. Since PgR expression levels of premenopausal ER-positive cancers were significantly reduced in clinical responders, inhibition of estrogen signaling due to chemotherapy-induced amenorrhea may be involved in this association.

     

乳腺癌新辅助化疗的临床研究进展

乳腺癌是全身性疾病,通过手术、放疗、化疗、内分泌等综合治疗可提高疗效。近年乳腺癌新辅助化疗（NCT）引起了肿瘤学界极大的兴趣,一系列的临床研究都希望这一疗法不但能提高保乳,而且能延长总生存期。现就NCT在乳腺癌治疗中的研究进展作一综述。     

Metabolomics approach for predicting response to neoadjuvant chemotherapy for breast cancer

Breast cancer is a clinically heterogeneous disease, which necessitates a variety of treatments and leads to different outcomes. As an example, only some women will benefit from chemotherapy. Identifying patients who will respond to chemotherapy and thereby improve their long-term survival has important implications to treatment protocols and outcomes, while identifying non responders may enable these patients to avail themselves of other investigational approaches or other potentially effective treatments. In this study, serum metabolite profiling was performed to identify potential biomarker candidates that can predict response to neoadjuvant chemotherapy for breast cancer. Metabolic profiles of serum from patients with complete (n = 8), partial (n = 14) and no response (n = 6) to chemotherapy were studied using a combination of nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography–mass spectrometry (LC–MS) and statistical analysis methods. The concentrations of four metabolites, three (threonine, isoleucine, glutamine) from NMR and one (linolenic acid) from LC–MS were significantly different when comparing response to chemotherapy. A prediction model developed by combining NMR and MS derived metabolites correctly identified 80% of the patients whose tumors did not show complete response to chemotherapy. These results show promise for larger studies that could result in more personalized treatment protocols for breast cancer patients.     

Quantitative prediction of tumor response to neoadjuvant chemotherapy in breast cancer: novel marker genes and prediction model using the expression levels

Background  

In breast cancer, the identification of accurate predictors of tumor response to neoadjuvant chemotherapy is of key importance, but none of the critical markers have been validated to date. We attempted to identify potent marker genes genome-wide, and we developed a prediction model for individual response to epirubicin (EPI)/cyclophosphamide (CPM) combination chemotherapy (EC).     

Automated quantification of apoptosis after neoadjuvant chemotherapy for breast cancer: early assessment predicts clinical response.

PURPOSE: A large body of evidence implicates apoptosis in the effects of cancer chemotherapeutic agents on tumor cells in vitro and tumor xenografts in vivo, but the predictive value of apoptosis as an early marker for clinical response in cancer patients remains unclear. EXPERIMENTAL DESIGN: We developed an automated, laser scanning cytometer-based method to quantify the percentage of tumor cells containing DNA fragmentation characteristic of apoptosis in tumor sections. We measured levels of apoptosis in a panel of 15 matched, 18-gauge core breast cancer biopsies obtained before and 48 h after neoadjuvant therapy with docetaxel plus doxorubicin or paclitaxel as part of two prospective clinical trials. RESULTS: The results revealed a strongly significant (P = 0.0023) association between chemotherapy-induced apoptosis and pathological response. CONCLUSIONS: If the results can be validated in a larger patient cohort, the method could be used to "tailor" therapy to optimize benefit in a patient-specific fashion.