Predicting Treatment Response of Breast Cancer to Neoadjuvant Chemotherapy Using Ultrasound-Guided Diffuse Optical Tomography

PURPOSE: To prospectively investigate ultrasound-guided diffuse optical tomography (US-guided DOT) in predicting breast cancer response to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Eighty-eight breast cancer patients, with a total of 93 lesions, were included in our study. Pre– and post–last chemotherapy, size and total hemoglobin concentration (THC) of each lesion were measured by conventional US and US-guided DOT 1 day before biopsy (time point t0, THC THC0, SIZE S0) and 1 to 2 days before surgery (time point tL, THCL, SL). The relative changes in THC and SIZE of lesions after the first and last NAC cycles were considered as the variables ΔTHC and ΔSIZE. Receiver operating characteristic curve was performed to calculate ΔTHC and ΔSIZE cutoff values to evaluate pathologic response of 93 breast cancers to NAC, which were then prospectively used to predicate response of 61 breast cancers to NAC. RESULTS: The cutoff values of ΔTHC and ΔSIZE for evaluation of breast cancers NAC treatment response were 23.9% and 42.6%. At ΔTHC 23.9%, the predicted treatment response in 61 breast lesions for the time points t1 to t3 was calculated by area under the curve (AUC), which were AUC₁ 0.534 (P = .6668), AUC₂ 0.604 (P = .1893), and AUC₃ 0.674(P =. 0.027), respectively; for ΔSIZE 42.6%, at time points t1 to t3, AUC₁ 0.505 (P = .9121), AUC₂ 0.645 (P = .0115), and AUC₃ 0.719 (P = .0018). CONCLUSION: US-guided DOT ΔTHC 23.9% and US ΔSIZE 42.6% can be used for the response evaluation and earlier prediction of the pathological response after three rounds of chemotherapy.     

Analyzing Spatial Heterogeneity in DCE- and DW-MRI Parametric Maps to Optimize Prediction of Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer

The purpose of this study is to investigate the ability of multivariate analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted MRI (DW-MRI) parametric maps, obtained early in the course of therapy, to predict which patients will achieve pathologic complete response (pCR) at the time of surgery. Thirty-three patients underwent DCE-MRI (to estimate K^trans, v_e, k_ep, and v_p) and DW-MRI [to estimate the apparent diffusion coefficient (ADC)] at baseline (t₁) and after the first cycle of neoadjuvant chemotherapy (t₂). Four analyses were performed and evaluated using receiver-operating characteristic (ROC) analysis to test their ability to predict pCR. First, a region of interest (ROI) level analysis input the mean K^trans, v_e, k_ep, v_p, and ADC into the logistic model. Second, a voxel-based analysis was performed in which a longitudinal registration algorithm aligned serial parameters to a common space for each patient. The voxels with an increase in k_ep, K^trans, and v_p or a decrease in ADC or v_e were then detected and input into the regression model. In the third analysis, both the ROI and voxel level data were included in the regression model. In the fourth analysis, the ROI and voxel level data were combined with selected clinical data in the regression model. The overfitting-corrected area under the ROC curve (AUC) with 95% confidence intervals (CIs) was then calculated to evaluate the performance of the four analyses. The combination of k_ep, ADC ROI, and voxel level data achieved the best AUC (95% CI) of 0.87 (0.77–0.98).     

Parameterizing the Logistic Model of Tumor Growth by DW-MRI and DCE-MRI Data to Predict Treatment Response and Changes in Breast Cancer Cellularity during Neoadjuvant Chemotherapy

Diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging (MRI) data of 28 patients were obtained pretreatment, after one cycle, and after completion of all cycles of neoadjuvant chemotherapy (NAC). For each patient at each time point, the tumor cell number was estimated using the apparent diffusion coefficient and the extravascular extracellular (v_e) and plasma volume (v_p) fractions. The proliferation/death rate was obtained using the number of tumor cells from the first two time points in conjunction with the logistic model of tumor growth, which was then used to predict tumor cellularity at the conclusion of NAC. The Pearson correlation coefficient between the predicted and the experimental number of tumor cells measured at the end of NAC was 0.81 (P = .0043). The proliferation rate estimated after the first cycle of therapy was able to separate patients who went on to achieve pathologic complete response from those who did not (P = .021) with a sensitivity and specificity of 82.4% and 72.7%, respectively. These data provide preliminary results indicating that incorporating readily available quantitative MRI data into a simple model of tumor growth can lead to potentially clinically relevant information for predicting an individual patient's response to NAC.     

Evaluation of Neoadjuvant Chemotherapy Response in Women with Locally Advanced Breast Cancer Using Ultrasound Elastography

PURPOSE: Ultrasound elastography is a new imaging technique that can be used to assess tissue stiffness. The aim of this study was to investigate the potential of ultrasound elastography for monitoring treatment response of locally advanced breast cancer patients undergoing neoadjuvant therapy. METHODS: Fifteen women receiving neoadjuvant chemotherapy had the affected breast scanned before, 1, 4, and 8 weeks following therapy initiation, and then before surgery. Changes in elastographic parameters related to tissue biomechanical properties were then determined and compared to clinical and pathologic tumor response after mastectomy. RESULTS: Patients who responded to therapy demonstrated a significant decrease (P < .05) in strain ratios and strain differences 4 weeks after treatment initiation compared to non-responding patients. Mean strain ratio and mean strain difference for responders was 81 ± 3% and 1 ± 17% for static regions of interest (ROIs) and 81 ± 3% and 6 ± 18% for dynamic ROIs, respectively. In contrast, these parameters were 102±2%, 110±17%, 101±4%, and 109±30% for non-responding patients, respectively. Strain ratio using static ROIs was found to be the best predictor of treatment response, with 100% sensitivity and 100% specificity obtained 4 weeks after starting treatment. CONCLUSIONS: These results suggest that ultrasound elastography can be potentially used as an early predictor of tumor therapy response in breast cancer patients.     

新辅助化疗配合手术治疗中晚期乳腺癌的临床效果分析

目的:观察新辅助化疗配合手术治疗中晚期乳腺癌的临床效果,为临床研究提供参考。方法:选取我院2009年5月-2011年4月收治的中晚期乳腺癌患者107例,根据治疗方法的不同,将患者分为新辅助化疗组和对照组。新辅助化疗组采取术前辅助化疗,而对照组术前不接受化疗。观察新辅助化疗组患者的近期临床疗效、毒副反应发生率;比较两组患者的手术时间、术中出血量等;术后随访三年,记录两组患者的肿瘤局部复发率及远处转移率。结果:新辅助化疗组患者治疗的总有效率为79.66%,毒副反应的发生率为33.89%;新辅助化疗组的平均手术时间、术中出血量均低于对照组,差异具有统计学意义(P0.05)。新辅助化疗组患者的局部复发率为5.08%,远处转移率为6.78%;对照组患者局部复发率为12.50%,远处转移率为18.75%。新辅助化疗组患者的肿瘤复发转移率低于对照组,差异具有统计学意义(P0.05)。结论:在中晚期乳腺癌的临床治疗中,术前对患者实施新辅助化疗具有明显的效果,患者近期疗效良好,毒副反应可耐受,且手术后的复发转移率相对较低,值得推广应用。     

Exploratory Cost-Effectiveness Analysis of Response-Guided Neoadjuvant Chemotherapy for Hormone Positive Breast Cancer Patients

PurposeGuiding response to neoadjuvant chemotherapy (guided-NACT) allows for an adaptative treatment approach likely to improve breast cancer survival. In this study, our primary aim is to explore the expected cost-effectiveness of guided-NACT using as a case study the first randomized controlled trial that demonstrated effectiveness (GeparTrio trial).ResultsOur exploratory CEA predicted that guided-NACT as proposed by the GeparTrio, costs additional €110, but results in 0.014 QALYs gained per patient. This scenario of guided-NACT was considered cost-effective at any willingness to pay per additional QALY. At the prevailing Dutch willingness to pay threshold (€80.000/QALY) cost-effectiveness was expected with 78% certainty.ConclusionThis exploratory CEA indicated that guided-NACT (as proposed by the GeparTrio trial) is likely cost-effective in treating HR+ EBC women. While prospective validation of the GeparTrio findings is advisable from a clinical perspective, early CEAs can be used to prioritize further research from a broader health economic perspective, by identifying which parameters contribute most to current decision uncertainty. Furthermore, their use can be extended to explore the expected cost-effectiveness of alternative guided-NACT scenarios that combine the use of promising imaging techniques together with personalized treatments.     

乳腺癌新辅助化疗的研究进展

乳腺癌是一种女性最常见的恶性肿瘤,近年来我国乳腺癌的发病率呈逐年上升趋势。研究证实,新辅助化疗不仅可使不能手术的晚期乳腺癌患者获得手术机会,而且也增加了部分患者的保乳概率,但是约20%的乳腺癌患者不能从新辅助化疗中获益,并影响后续治疗效果。因此,制定合理的、个体化的新辅助化疗方案对于提高乳腺癌患者的生存质量和改善其预后尤为重要。目前,研究已发现的NCT相关的预测因子主要包块肿瘤类型、分子分型、ER、PR、Ki67等,而HER2、TOP2A、P53、PRAP单独作为预测因子的还存在争议。本文主要对乳腺癌新辅助化疗的现状、各种预测因子的作用及其不足之处进行了综述。     

Background Parenchymal Enhancement of the Contralateral Normal Breast: Association with Tumor Response in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

PURPOSE: This study investigated the association between background parenchymal enhancement (BPE) and pathologic response to neoadjuvant chemotherapy (NAC). METHODS: A total of 46 patients diagnosed with invasive breast cancer were analyzed. Each patient had three magnetic resonance imaging (MRI) studies, one pre-treatment and two follow-up (F/U) MRI studies. BPE was measured as the averaged enhancement of the whole fibroglandular tissues. The pre-treatment BPE and the changes in the F/U MRI were compared between patients achieving pathologic complete response (pCR) versus those not. Subgroup analyses based on age, estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2) status of their cancers were also performed. RESULTS: The pre-treatment BPE was higher in the pCR group than that in the non-pCR group. Compared to baseline, BPE at F/U-1 was significantly decreased in the pCR group but not in the non-pCR group. In subgroup analysis based on age, these results were seen only in the younger group (< 55 years old), not in the older group (≥ 55 years old). Older patients had a significantly lower pre-treatment BPE than younger patients. In analysis based on molecular biomarkers, a significantly decreased BPE at F/U-1 was only found in the ER-negative pCR group but not in the non-pCR, nor in the ER-positive groups. CONCLUSIONS: A higher pre-treatment BPE showing a significant decrease early after starting NAC was related to pCR in pre/peri-menopausal patients.     

乳腺癌新辅助化疗疗效评价体系

目前新辅助化疗已广泛应用于乳腺癌的治疗,可降低肿瘤分期,提高手术切除率和增加保乳手术的机会。恰当的新辅助化疗疗效评价不仅可以指导患者治疗方案和预测预后,还可对不同药物的疗效提供可靠的评估。目前新辅助化疗评估主要采用临床检查如触诊、超声、钼靶X线、计算机断层显像、磁共振成像及病理学检查确定肿瘤体积变化,可分为临床评估和病理学评估。两者均有多种体系标准,未形成统一公认的标准。临床试验中采用较多的标准有WHO和RECIST等临床评价标准以及MP标准和JBCS标准等病理学评价标准。本文就乳腺癌新辅助化疗疗效评估体系进行总结。     

A Systematic Evaluation of Multi-Gene Predictors for the Pathological Response of Breast Cancer Patients to Chemotherapy

Previous studies have reported conflicting assessments of the ability of cell line-derived multi-gene predictors (MGPs) to forecast patient clinical outcomes in cancer patients, thereby warranting an investigation into their suitability for this task. Here, 42 breast cancer cell lines were evaluated by chemoresponse tests after treatment with either TFAC or FEC, two widely used standard combination chemotherapies for breast cancer. We used two different training cell line sets and two independent prediction methods, superPC and COXEN, to develop cell line-based MGPs, which were then validated in five patient cohorts treated with these chemotherapies. This evaluation yielded high prediction performances by these MGPs, regardless of the training set, chemotherapy, or prediction method. The MGPs were also able to predict patient clinical outcomes for the subgroup of estrogen receptor (ER)-negative patients, which has proven difficult in the past. These results demonstrated a potential of using an in vitro-based chemoresponse data as a model system in creating MGPs for stratifying patients’ therapeutic responses. Clinical utility and applications of these MGPs will need to be carefully examined with relevant clinical outcome measurements and constraints in practical use.     

Neutrophil Gelatinase-Associated Lipocalin (NGAL) Predicts Response to Neoadjuvant Chemotherapy and Clinical Outcome in Primary Human Breast Cancer

In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC.     

Utilization of Neoadjuvant Chemotherapy Varies in the Treatment of Women with Invasive Breast Cancer

Background

Treatment with neoadjuvant chemotherapy (NAC) has made it possible for some women to be successfully treated with breast conservation therapy (BCT ) who were initially considered ineligible. Factors related to current practice patterns of NAC use are important to understand particularly as the surgical treatment of invasive breast cancer has changed. The goal of this study was to determine variations in neoadjuvant chemotherapy use in a large multi-center national database of patients with breast cancer.

Methods

We evaluated NAC use in patients with initially operable invasive breast cancer and potential impact on breast conservation rates. Records of 2871 women ages 18-years and older diagnosed with 2907 invasive breast cancers from January 2003 to December 2008 at four institutions across the United States were examined using the Breast Cancer Surgical Outcomes (BRCASO) database. Main outcome measures included NAC use and association with pre-operatively identified clinical factors, surgical approach (partial mastectomy [PM] or total mastectomy [TM]), and BCT failure (initial PM followed by subsequent TM).

Results

Overall, NAC utilization was 3.8%l. Factors associated with NAC use included younger age, pre-operatively known positive nodal status, and increasing clinical tumor size. NAC use and BCT failure rates increased with clinical tumor size, and there was significant variation in NAC use across institutions. Initial TM frequency approached initial PM frequency for tumors >30-40mm; BCT failure rate was 22.7% for tumors >40mm. Only 2.7% of patients undergoing initial PM and 7.2% undergoing initial TM received NAC.

Conclusions

NAC use in this study was infrequent and varied among institutions. Infrequent NAC use in patients suggests that NAC may be underutilized in eligible patients desiring breast conservation.     

Effect of Imaging Parameter Thresholds on MRI Prediction of Neoadjuvant Chemotherapy Response in Breast Cancer Subtypes

The purpose of this study is to evaluate the predictive performance of magnetic resonance imaging (MRI) markers in breast cancer patients by subtype. Sixty-four patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy were enrolled in this study. Each patient received a dynamic contrast-enhanced (DCE-MRI) at baseline, after 1 cycle of chemotherapy and before surgery. Functional tumor volume (FTV), the imaging marker measured by DCE-MRI, was computed at various thresholds of percent enhancement (PE_t) and signal-enhancement ratio (SER_t). Final FTV before surgery and percent changes of FTVs at the early and final treatment time points were used to predict patients’ recurrence-free survival. The full cohort and each subtype defined by the status of hormone receptor and human epidermal growth factor receptor 2 (HR+/HER2-, HER2+, triple negative) were analyzed. Predictions were evaluated using the Cox proportional hazard model when PE_t changed from 30% to 200% in steps of 10% and SER_t changed from 0 to 2 in steps of 0.2. Predictions with high hazard ratios and low p-values were considered as strong. Different profiles of FTV as predictors for recurrence-free survival were observed in each breast cancer subtype and strong associations with survival were observed at different PE_t/SER_t combinations that resulted in different FTVs. Findings from this retrospective study suggest that the predictive performance of imaging markers based on FTV may be improved with enhancement thresholds being optimized separately for clinically-relevant subtypes defined by HR and HER2 receptor expression.     

Association of Pretreatment Anemia with Pathological Response and Survival of Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: A Population-Based Study

Background

Anemia related to adjuvant chemotherapy might predict compromised survival in patients with breast cancer. The present population-based study was to investigate the correlation of pretreatment anemia with pathological response and long-term prognosis of breast cancer patients receiving neoadjuvant chemotherapy (NCT).

Methods

From 1999 to 2011, a total of 655 patients with operable or locally advanced breast cancer who underwent NCT before definitive surgery were reviewed. The patients were subdivided into anemic (baseline hemoglobin (Hb)<12.0g/dL) and non-anemic (Hb≥12.0g/dL) groups. Comparison was made between anemic and non-anemic groups concerning the rate of pathological complete response (pCR), relapse-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS). Logistic and Cox regression models were utilized to determine the predictive value of pretreatment anemia in outcomes of patients undergoing NCT.

Results

166 women (25.3%) were anemic before treatment. Patients in the anemic group were less likely to achieve pCR in NCT than their non-anemic counterparts (odds ratio (OR) 0.428, 95% confidence interval (CI) 0.198–0.927, p = 0.031). Patients with baseline anemia displayed inferior 10-year RFS (59.1% vs 66.0%, p = 0.022 by log-rank), OS (75.3% vs 90.9%, p<0.001) and CSS (82.4% vs 94.4%, p<0.001) compared with those without. After adjustment for confounders, pretreatment anemia was demonstrated to correlate with elevated risk of relapse (hazard ratio (HR) 1.453, 95% CI 1.077–1.962, p = 0.015), cancer-specific mortality (HR 2.961, 95% CI 1.679–5.222, p<0.001) and all-cause mortality (HR 2.873, 95% CI 1.757–4.699, p<0.001).

Conclusions

Pretreatment anemia was associated with worse pathological response to NCT as well as survival status in breast cancer. Further studies are warranted to identify optimal interventions and improve the prognosis of this subgroup.     

药学干预对乳腺癌患者辅助化疗期间恶心呕吐和生活质量影响的研究

目的:探讨药学干预对乳腺癌患者辅助化疗期间恶心呕吐和生活质量的影响。方法:采用前瞻性队列研究,共入组87例乳腺癌术后患者。在接受辅助化疗前随机分为干预组(n=44)和对照组(n=43),干预组患者在接受化疗和常规支持治疗的同时,针对化疗引起的恶心呕吐由临床药师对患者进行咨询并指导用药,优化对症治疗方案,对照组仅接受化疗和常规支持治疗。比较两组患者对止吐药物的完全反应率、恶心严重程度、呕吐频次和生活质量。结果:化疗的前3个周期两组对止吐药物的完全缓解率分别为37.2%和63.6%,46.5%和75.0%,44.2%和72.7%,干预组完全缓解率明显高于对照组(P=0.014,P=0.006,P=0.007)。干预组的急性和迟发性恶心较对照组轻(P=0.023,P=0.045),急性和迟发性呕吐频率较对照组明显减少(P=0.006,P=0.034)。生活质量测评显示干预组患者的总健康状况较对照组升高(P=0.028),恶心、呕吐和食欲丧失的症状评分较对照组降低(P=0.025,P=0.045)。结论:临床药师对乳腺癌患者辅助化疗期间进行药学干预可明显减轻患者恶心、呕吐的副反应,并可改善生活质量。临床药师参与乳腺癌患者辅助化疗期间的对症治疗值得在临床广泛推广。     

香菇多糖联合TA方案化疗治疗晚期乳腺癌的临床观察

目的:观察香菇多糖联合TA方案(紫杉醇、阿霉素)治疗晚期乳腺癌患者的近期疗效及毒副反应。方法:将确诊为Ⅳ期的52例乳腺癌患者随机分为对照组及治疗组,两组均采用TA方案化疗,治疗组加用香菇多糖,观察两组近期疗效及毒副反应,计算和比较两组治疗前后的CD4+/CD8+值。结果:治疗组及对照组的治疗总有效率分别为67.86%、62.50%,其差异无统计学意义(P>0.05);两组的生活质量(Karnofsky评分)改善率分别为71.43%和41.67%,治疗组显著高于对照组,差异有统计学意义(P<0.05)。两组治疗后CD4+及CD8+细胞绝对计数均较治疗前下降,差异有统计学意义(P<0.05)。治疗组CD4+/CD8+值上升,但与治疗前比较差异无统计学意义(P>0.05),对照组CD4+/CD8+值较治疗前下降,差异无统计学意义(P>0.05);两组治疗后CD4+/CD8+值差异有统计学意义(P<0.05)。治疗组毒副反应较对照组明显减轻(P<0.05)。结论:香菇多糖联合TA化疗方案能有效改善晚期乳腺癌患者的生存质量、调节免疫力并减轻毒副反应。     

Magnetic Resonance Metabolic Profiling of Breast Cancer Tissue Obtained with Core Needle Biopsy for Predicting Pathologic Response to Neoadjuvant Chemotherapy

The purpose of this study was to determine whether metabolic profiling of core needle biopsy (CNB) samples using high-resolution magic angle spinning (HR-MAS) magnetic resonance spectroscopy (MRS) could be used for predicting pathologic response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer. After institutional review board approval and informed consent were obtained, CNB tissue samples were collected from 37 malignant lesions in 37 patients before NAC treatment. The metabolic profiling of CNB samples were performed by HR-MAS MRS. Metabolic profiles were compared according to pathologic response to NAC using the Mann-Whitney test. Multivariate analysis was performed with orthogonal projections to latent structure-discriminant analysis (OPLS-DA). Various metabolites including choline-containing compounds were identified and quantified by HR-MAS MRS in all 37 breast cancer tissue samples obtained by CNB. In univariate analysis, the metabolite concentrations and metabolic ratios of CNB samples obtained with HR-MAS MRS were not significantly different between different pathologic response groups. However, there was a trend of lower levels of phosphocholine/creatine ratio and choline-containing metabolite concentrations in the pathologic complete response group compared to the non-pathologic complete response group. In multivariate analysis, the OPLS-DA models built with HR-MAS MR metabolic profiles showed visible discrimination between the pathologic response groups. This study showed OPLS-DA multivariate analysis using metabolic profiles of pretreatment CNB samples assessed by HR- MAS MRS may be used to predict pathologic response before NAC, although we did not identify the metabolite showing statistical significance in univariate analysis. Therefore, our preliminary results raise the necessity of further study on HR-MAS MR metabolic profiling of CNB samples for a large number of cancers.