基于代谢组学预测乳腺癌新辅助化疗疗效及预后的研究进展

乳腺癌是一种异质性疾病,表现为新辅助化疗(neoadjuvant chemotherapy,NAC)疗效差异大、预后差异大。代谢组学可以对体内外肿瘤细胞受刺激或扰动后的内源性小分子代谢物进行动态、全面和定量的检测。现有的研究表明,通过对肿瘤、体液等多种标本的代谢组学检测,可以对乳腺癌进行代谢分型,可以预测治疗效果,可以预测疾病预后。虽然其存在一定的局限性,但代谢组学仍为一种新的研究肿瘤的良好手段。全文就代谢组学应用于预测乳腺癌NAC疗效及预后的研究进展进行综述。     

晚期乳腺癌的化疗进展

早期乳腺癌患者的无病生存期和总生存期已经有了明显的提高,经合理治疗,90％以上可获长期生存。系统的治疗对晚期转移性乳腺癌患者收效甚微,所以,怎样制定更合理的治疗政策,是近年来许多肿瘤学者的研究焦点和有待攻克的研究难题,更优化的治疗方案已使晚期转移性乳腺癌的有效率从20％-40％提高到60％-80％,完全缓解（CR）率从0提高到15％。在本篇文章中,我们将综述最新的晚期转移性乳腺癌的化疗进展。     

晚期乳腺癌的化疗进展

早期乳腺癌患者的无病生存期和总生存期已经有了明显的提高,经合理治疗,90%以上可获长期生存[1].系统的治疗对晚期转移性乳腺癌患者收效甚微,所以,怎样制定更合理的治疗政策,是近年来许多肿瘤学者的研究焦点和有待攻克的研究难题,更优化的治疗方案已使晚期转移性乳腺癌的有效率从20%-40%提高到60%-80%,完全缓解(CR)率从0提高到15%[2].在本篇文章中,我们将综述最新的晚期转移性乳腺癌的化疗进展.     

药敏指导下的晚期乳腺癌化疗

1982年,我们开始用正常小鼠肾包膜下移植方法(SRC)测定抗癌药物的敏感性。1986年应用临床治疗女性晚期乳腺癌。本文报告22例,年龄37～60岁,,除2例外,先前曾接受过放疗、化疗。22例中,单药治疗14例,联合用药8例。按国际通用标准评定疗效。结果,单药组及联合用药组的有效率分别为64％和87.5％,明显优于常用有效单药及联合化疗方案。     

泰素为主的联合化疗治疗晚期乳腺癌的临床研究

 泰素系植物类抗癌药，其抗癌机理在于它能够促使微管聚合，形成稳定的不具活性的微管聚合物，从而影响肿瘤细胞的有丝分裂，造成细胞死亡。本文简要报告50例晚期或复发的乳腺癌患者行以泰素为主的联合化疗结果如下：     

以长春地辛为主的联合化疗治疗晚期乳腺癌的近期疗效观察

本文以长春地辛 (ＶＤＳ ,商品名 :西艾克 )为主 ,组成联合化疗方案 (ＣＶＴＦ) ,自 1997年 3月～ 1998年 8月治疗晚期乳腺癌 35例 ,报告如下。材料与方法一、临床资料　本组共 35例 ,均为女性 ,年龄 35～ 6 4岁 ,均经病理证实。其中浸润性导管癌 34例 ,单纯癌 1例。35例化疗前     

局部晚期乳腺癌术前化疗的疗效分析

目的：探讨新辅助化疗应用于局部晚期乳腺癌患者的疗效。方法：回顾性分析62例局部晚期乳腺癌患者进行新辅助化疗的临床资料,62例患者手术前均进行TA方案化疗4段,其中吡柔比星50mg/m^2,d1,多西他赛135mg/m^2,d2,3周方案,化疗后白细胞低下者予以对症治疗,手术后的治疗方案依据新辅助化疗疗效及病理结果而定。结果：新辅助化疗有效率为90.3%（56/62）,其中完全缓解6.5%（4/62）,术后随访6个月至60个月,50例存活,其中41例为无病生存,占68.3%,死亡12例。结论：新辅助化疗能使局部晚期乳腺癌原发灶和腋窝淋巴结缩小,肿瘤降期,减少肿瘤的远处转移和复发,改善患者预后,且临床毒副反应可以耐受。     

46例局部晚期乳腺癌的新辅助化疗

目的 观察多西紫杉醇+表阿霉素+环磷酰胺联合(TAC方案)新辅助化疗在局部晚期乳腺癌治疗中的疗效和毒副反应.方法 46例未经治疗的Ⅱb～Ⅲc期的局部晚期乳腺癌(包括炎性乳腺癌)接受TAC方案的新辅助化疗.TAC方案:多西紫杉醇75mg/m2静脉滴注,d1;表阿霉素75 mg/m2静脉注射,d1;环磷酰胺500 mg/m2静脉注射,d1;21 d为1个疗程,共3个疗程.入组患者化疗前均接受肿瘤原发灶空芯针穿刺活检并获得病理组织学确诊.结果 TAC方案新辅助化疗在局部晚期乳腺癌的治疗中总有效率80.4%,其中临床完全缓解15.2%(7/46),临床部分缓解65.2%(30/46),病理完全缓解8.3%(4/46).主要的毒副反应为白细胞减少、脱发和恶心呕吐,发生肺栓塞1例,无败血症和死亡病例.结论 TAC方案新辅助化疗在局部晚期乳腺癌的治疗中疗效显著,耐受性好.     

局部晚期乳腺癌的新辅助化疗

乳腺癌是全身性疾病,新辅助化疗在乳腺癌治疗策略上的转变有着划时代意义。国外报道新辅助化疗治疗Ⅲ期局部晚期乳腺癌(locally advanced breast cancer,LABC)已显示出了比较理想的效果[1],成为LABC治疗的标准方案之一。目前新辅助化疗已被不少大中医院乳腺科采用。我院自2003年1月至2006年10月对36例局部晚期乳腺癌患者进行新辅助化疗,收到了良好的效果,现报告如下。一、资料与方法1.一般资料:2003年1月至2006年10月在我院住院治疗乳腺癌221例,其中局部晚期48例,对其中愿接受新辅助化疗且无化疗禁忌证者36例术前行新辅助化疗。36例均为…     

Psychological factors can predict the response to primary chemotherapy in patients with locally advanced breast cancer

This study evaluated the possible value of psychological variables in predicting clinical and pathological response to primary chemotherapy. 96 women with newly diagnosed large, or locally advanced, breast cancer (T2 > 4 cm, T3, T4, N2 and M0) participated in a prospective, randomised trial to evaluate the effects of relaxation training with guided imagery and L-arginine on response to primary chemotherapy. Before the first of six cycles of primary chemotherapy, women were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Eysenck Personality Questionnaire (EPQ). The primary outcomes were clinical response (evaluated using standard International Union Against Cancer (UICC) criteria) and pathological response (graded by means of a previously published 5-point scale) following primary chemotherapy. Stepwise linear regressions were used to estimate the predictive value of age, menopausal status, clinical nodal status, tumour size at diagnosis, oestrogen receptor status, dietary supplementation (L-arginine versus placebo), personality (EPQ-L scores), mood (HADS scores) and a psychological intervention. HADS depression score was a significant independent predictor of pathological response to chemotherapy. HADS anxiety score was a significant independent predictor of clinical response. Because the original tumour size before chemotherapy (also a significant predictor of clinical and pathological responses) was taken into account in the analyses, the results cannot be explained in terms of psychobiological factors related to tumour size. This study supports the importance of psychological factors as independent predictors of response to primary chemotherapy in patients with breast cancer. If they can be replicated, these findings have major implications for the management of women with breast cancer. Psychological factors need to be assessed and evaluated in future trials of chemotherapy.     

Tumor markers in patients with advanced breast cancer as prognosticators: A preliminary study

Summary A retrospective study was performed on 69 breast cancer patients (stage II, N=18; advanced disease, N=51) in order to assess the prognostic value of circulating prolactin (PRL), CEA, CA 15-3, insulin-like growth factor-1 (IGF-1), and epidermal growth factor (EGF) by RIA/IRMA. These markers were compared with short-term prognosis (two years). Significant difference was observed only for PRL (<20.0 ng/ml vs. >20.0 ng/ml), which provide an independent predictor of short-term prognosis in advanced breast cancer.     

DCE-MRI parameters have potential to predict response of locally advanced breast cancer patients to neoadjuvant chemotherapy and hyperthermia: A pilot study

Combined therapies represent a staple of modern medicine. For women treated with neoadjuvant chemotherapy (NA ChT) for locally advanced breast cancer (LABC), early determination of whether the patient will fail to respond can enable the use of alternative, more beneficial therapies. This is even more desirable when the combined therapy includes hyperthermia (HT), an efficient way to improve drug delivery, however, more costly and time consuming. There is data showing that this goal can be achieved using magnetic resonance imaging (MRI) with contrast agent (CA) enhancement. This work for the first time proposes combining the information extracted from pre-treatment MR imaging into a morpho-physiological tumour score (MPTS) with the hypothesis that this score will increase the prognostic efficacy, compared to each of its MR-derived components: morphological (derived from the shape of the tumour enhancement) and physiological (derived from the CA enhancement variance dynamics parameters). The MPTS was correlated with response as determined by both pathologic residual tumour and MRI imaging, and was shown to have potential to predict response. The MPTS was extracted from pre-treatment MRI parameters, so independent of the combined therapy used.

Purpose: To use a novel morpho-physiological tumour score (MPTS) generated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict response to treatment.

Materials and methods: A protocol was designed to acquire DCE-MRI images of 20 locally advanced breast cancer (LABC) patients treated with neoadjuvant chemotherapy (NA ChT) and hyperthermia (HT). Imaging was done over 30 min following bolus injection of gadopentetate-based contrast agent. Parametric maps were generated by fitting the signal intensity to a double exponential curve and were used to derive a morphological characterisation of the lesions. Enhancement-variance dynamics parameters, wash-in and wash-out parameters (WiP, WoP), were extracted. The morphological characterisation and the WiP and WoP were combined into a MPTS with the intent of achieving better prognostic efficacy. The MPTS was correlated with response to NA therapy as determined by pathological residual tumour and MRI imaging.

Results: The contrast agent in all tumours typically peaked in the first 1–4 min. The tumours’ WiP and WoP varied considerably. The MPTS was highly correlated with whether the patients had a pathological response. This scoring system has a specificity of 78% and a sensitivity of 91% for predicting response to NA chemotherapy. The kappa was 0.69 with a 95% confidence interval of [0.38, 1] and a p-value of 0.002.

Conclusions: This pilot study shows that the MPTS derived using pre-treatment MRI images has the potential to predict response to NA ChT and HT in LABC patients. Further prospective studies are needed to confirm the validity of these results.     

HER-2/Neu overexpression does not predict response to neoadjuvant chemotherapy or prognosticate survival in patients with locally advanced breast cancer

Data about the prognostic and predictive value of HER-2/neu overexpression in patients with locally advanced breast cancer (LABC) treated with primary chemotherapy is limited. Therefore, this retrospective study was performed to examine this issue. Fifty-four consecutive patients with LABC were prospectively managed using a uniform multimodality approach. Response to neoadjuvant chemotherapy and survival were examined against HER-2/neu overexpression as determined by an immunohistochemistry method on formalin-fixed, paraffin-embedded samples of breast cancer using the commercially available, United States Food and Drug Administration-approved kit HercepTest (Dako Corp, Carpinteria, CA). The number of patients in each Hercep Test immunostaining group were as follows; 0 in 12 patients (22%), 1+ in 8 (15%), 2+ in 12 (22%), and 3+ in 22 (41%). None of the clinical variables was significantly associated with HER-2/neu expression. After primary therapy, 22% of patients attained clinical complete response and an additional 70% achieved clinical partial response with an overall response rate of 92% (95% confidence interval: 100% to 79%). There was no significant correlation between clinical response and HercepTest positivity (p=0.85). Of 52 patients with complete pathological data, there was no significant difference in HercepTest status between those who attained complete pathological response (46%) and those who did not (38%) (p=0.74). Moreover, there was no significant difference in disease-free survival (75% vs 84%, [p=0.26]) or overall survival (81% vs 84% [p=0.31]) between those who overexpressed HER-2/neu and those with negative HercepTest, respectively. In patients with LABC, HER-2/neu overexpression determined using HercepTest assay and according to the manufacturer’s approved guidelines failed to demonstrate a predictive or a prognostic role.     

DW-MRI ADC values can predict treatment response in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy

The purpose of this study was to evaluate the importance of diffusion-weighted magnetic resonance imaging (DW-MRI) apparent diffusion coefficient (ADC) values to predict treatment response to neoadjuvant chemotherapy (NCT) in patients with locally advanced breast cancer (LABC). Thirty-two patients with LABC underwent 2–4 cylces of NCT (docetaxel and epirubicin). The DW-MRI scans were performed within one week prior to chemotherapy and after the first course of treatment, respectively. Accordingly, tumor volumes, changes in tumor ADC values, and their degree of correlation were analyzed. The overall response (OR) was observed in 62.5% (95% CI, 45.7–79.3%) of patients after 2 cycles of NCT. The clinical complete response (CR) rate and pathological CR (pCR) rate were 15.6 and 9.4%, respectively. The stable disease (SD) rate was 34.4% (11 patients), and progressive disease (PD) was observed in only one patient (3.1%). After the first cycle of NCT, the ADC values in the CR + PR group significantly increased (P < 0.001). The initial ADC values before chemotherapy in the OR group were significantly lower than those in the SD + PD group (P < 0.001). The initial ADC values and the changes in tumor volume after chemotherapy were negatively correlated (r = −0.58, P = 0.02). The lower the initial tumor ADC value was the more obvious the decrease in tumor volume after chemotherapy. The changes in ADC values of tumors after chemotherapy and the changes in tumor volume were positively correlated (r = 0.96, P < 0.001). After chemotherapy, the greater the change in ADC value, the more the tumor volume was reduced. Using the initial ADC values of breast cancer tumors and the early changes in ADC values after NCT, we may be able to predict tumor response to chemotherapy. Tumors with low initial ADC values may be sensitive to chemotherapy; tumors with significantly increasing ADC values early after chemotherapy may be sensitive to chemotherapy.     

Androgen receptor genotypes predict response to endocrine treatment in breast cancer patients

Background:

The androgen receptor (AR) is frequently expressed in breast cancers. The AR genotype may affect disease-free survival and response to endocrine therapy.

Methods:

In all, 634 women undergoing breast cancer surgery between 2002 and 2008 were followed until 30 June 2010. Six haplotype-tagging single-nucleotide polymorphisms in the AR, and the resulting AR diplotypes, were examined in relation to breast cancer patient characteristics, tumour characteristics, disease-free survival, and response to endocrine treatment.

Results:

Five common AR diplotypes were found. Seventeen rare variants were combined into a composite group. The resulting six AR diplotype groups were clustered into two subgroups, groups A (n=128) and B (n=499), with three diplotypes in each. Patients in group B had larger total breast volume (P=0.024), higher body mass index (BMI) (P=0.050), more axillary lymph node involvement (P_trend=0.020), and higher histological grade (P_trend=0.031). There were 59 breast cancer events in the 569 patients with invasive cancers and no preoperative treatment. Patients in group B also had shorter disease-free survival (P=0.037) than patients in group A. Among patients in group B with oestrogen receptor α positive tumours, tamoxifen (TAM) treatment was associated with longer disease-free survival (P=0.008), while treatment with aromatase inhibitors (AIs) was not (P=0.94). Response to endocrine treatment could not be predicted based on BMI, suggesting that the effect of AR diplotypes went beyond that of a higher BMI.

Conclusion:

A marker for a group of patients who responded to TAM, but not to AIs, was identified. If this finding is confirmed, AR genotyping may provide useful information for selection of endocrine treatment of breast cancer patients.     

Prognostic factors in the initial response to therapy by patients with advanced breast cancer.

Identification of important prognostic factors with respect to the patient's initial response to therapy was made from a set of 25 covariates available on 281 patients with advanced breast cancer. Since the patients studied were all participants in a randomized clinical trial that involved three different treatment regimens (repeated weekly treatment of a combination of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone; intermittent treatment of the same preceding five drugs given in 5-day courses every 4 weeks; or treatment every 3 weeks with adriamycin as a single agent), the effect of these treatments on the selection of important covariates was assessed. Although some evidence indicated that the set of important covariates differed by treatment, the differences were not strong enough to be of practical importance. Non-Caucasian patients did poorly on all regimens with a response rate of only 31% compared to 62% for Caucasian patients. The covariates of major prognostic importance for Caucasians were: disease-free interval, liver involvement, and performance status. Ambulatory patients with long disease-free intervals and no liver involvement had the best prognosis. After adjustments were made for these three covariates, the remaining covariates (such as menopausal status, bone involvement, number of metastatic sites, and duration of metastatic disease) were not significantly related to response. As reported earlier, the treatment effect was significant, even after adjustments were made for the important covariates.