Detection of breast cancer cells in the peripheral blood is positively correlated with estrogen-receptor status and predicts for poor prognosis

We investigated whether detection of cytokeratin-positive (CK+) cells in the peripheral blood (PB) of breast cancer patients before chemotherapy could be a prognostic factor. Blood from a total of 92 breast cancer patients was evaluated for the presence of CK+ cells. Blood samples were collected before chemotherapy. Patients entered in the study included: neoadjuvant (n = 25), adjuvant (n = 42) and metastatic (n = 25). Blood samples (10 ml) were centrifuged using a double density-gradient to recovering the mononuclear cell (MNC) and granulocyte cell (GC) fractions. Subsequently, positive immunomagnetic cell separation was carried out to isolating CK+ cells. The enriched cell fraction was cytocentrifuged and then immunocytochemically labeled using an anti-cytokeratin antibody. Our results indicated that breast tumor cells sediment with both MNC and GC fractions. We therefore recommend examination of both fractions in all enrichment protocols. CK+ cells in PB were identified in 57 of 92 (62%) patients when MNC and GC fractions were assessed (range = 1-61 cells, median = 8). No CK+ cells were detected in blood samples of 16 healthy donors. There were significant differences in the presence of CK+ cells according to estrogen receptor expression (p = 0.049), and lymph node status (p = 0.033), but not to the age, menopausal status, type of patient (neoadjuvant, adjuvant or metastatic), TNM stage, histological type, progesterone receptor expression, c-erbB2 expression, p53 expression or Ki67 expression. Regarding the relationship between tumor size (T) and the presence of CK+ cells, a borderline significant trend was observed (p = 0.07). The median follow-up of the patients was 21 months and statistical analysis (Kaplan-Meier analysis) showed that using the method we present, the detection of CK+ cells in PB before starting the chemotherapy in breast cancer patients was significantly correlated with both progression-free survival (p = 0.058) and overall survival (p = 0.003). In conclusion, the present study suggests that detection of CK+ cells in PB before chemotherapy might identify breast cancer patients with poor prognosis.     

新辅助化疗前后乳腺癌患者外周血细胞角蛋白19表达变化及其临床意义

目的探讨细胞角蛋白（CK）19在乳腺癌新辅助化疗前后表达的变化及其临床意义。方法采用实时定量RT-PCR技术检测86例乳腺癌患者新辅助化疗前后外周血CK19 mRNA的表达变化,将30例乳腺良性疾病患者和20例健康体检志愿者作为对照。对非正态分布或方差不齐的数据采用Wilcoxon非参数秩和检验,用中位数±百分位数之差[M（Q_R）]表示,计数资料组间采用χ~2检验。结果新辅助化疗前乳腺癌患者外周血中CK19 mRNA阳性表达率为32.56%（28/86）,与腋窝淋巴结转移、临床分期有关（分别P〈0.001）;而新辅助化疗后阳性表达率为13.95%（12/86）,化疗前后CK19mRNA表达差异具有统计学意义（P=0.004）;新辅助化疗后CK19 mRNA阳性表达的患者中,57.14%（16/28）获得临床完全缓解成部分缓解,低于CK19 mRNA阴性患者的93.10%（54/58）,差异有统计学意义（P〈0.001）,这提示CK19 mNRA表达水平变化可能与新辅助化疗疗效有关。结论 CK19可作为新辅助化疗疗效判定的早期预测指标之一。     

Clinical significance of angiogenic factors in breast cancer

Growth, progression, and metastasis of breast cancer, as well as of most of the other tumors, are angiogenesis-dependent processes.Several pro-angiogenic growth factors and endogenous inhibitors of angiogenesis have been identified and sequenced, and experimental studies suggest that angiogenic activity of a tumor may result from down-regulation of inhibitors of angiogenesis or up-regulation of endothelial growth factors. The mechanisms leading to the alteration of the balance between positive and negative modulators of angiogenesis are only partially known.We are at the beginning of research to identify the more active angiogenic factors in human breast cancer, and little information is presently available on their clinical significance. Preliminary results suggest that among the known angiogenic peptides, both vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor / thymidine phosphorylase (PD-ECGF/TP) have promising prognostic and, perhaps, predictive value.No data are available on the clinical value of co-determination of positive and negative regulators of angiogenesis to look at the angiogenic balance of each single tumor. Only a few studies have assessed the role of endogenous inhibitors of angiogenesis in human breast cancer, with results available only on thrombospondin-1 and -2 (TSP-1, -2).Finally, the determination of some integrins such as 6 and v3 and of some other endothelial-adhesion molecules seems to be of potential prognostic value.Recognizing which are the more biologically active positive and negative angiogenic factors is the key for the identification not only of new prognostic markers but also of targets for antiangiogenic therapy in human breast cancer.     

早期乳腺癌患者术后放化疗后不同基因分型的预后分析

目的:评估早期乳腺癌患者术后不同基因分型放疗后的预后分析。方法:搜集我院2003年-2009年210例早期乳腺癌患者(TNM分期中II期患者,淋巴结转移数目3个以上和/或肿块直径大于5cm),回顾性分析其免疫组化信息及临床病理学资料,210例病人均进行了术后放疗,中位随访59个月(7-132个月),针对不同分型(luminal A、luminal B、HER-2和basal)分析疾病复发(disease recurrences,DR),局部和远处转移以及对侧乳腺癌(contralateral breast cancer,CBC)的发生。所有资料均用SPSS 17.0软件进行分析。结果:中位随访59个月,90%(189/210)病人存活。8年OS和DSS分别为94%(197/210)和96%(201/210)。DR发生率(P=0.004)和CBC发生率(P=0.003)在四种分型中具有统计学意义。HER-2和基底细胞型比luminal A和B型病人更容易复发(P<0.05),而基底细胞型比非基底细胞型更容易发生对侧乳腺癌(P<0.01)。结论:HER-2阳性型和基底细胞型比导管A型和导管B型更容易复发,而基底细胞型乳腺癌更容易发生对侧乳腺癌,基底细胞型预测对侧乳腺癌转移情况具有重要的意义。     

Circulating interleukin-6 predicts survival in patients with metastatic breast cancer

Interleukin-6 (IL-6) is a multifunctional cytokine produced by macrophages, T cells, B cells, endothelial cells and tumour cells. Interleukin-6 is able to promote tumour growth by upregulating anti-apoptotic and angiogenic proteins in tumour cells. In murine models it has been demonstrated that antibodies against IL-6 diminish tumour growth. Several reports have highlighted the prognostic importance of IL-6 in e.g., prostate and colon cancer. We addressed prospectively the prognostic significance of serum IL-6 (sIL-6), measured at diagnosis of metastasis, in 96 unselected and consecutive patients with progressive metastatic breast cancer before the initiation of systemic therapy. The median sIL-6 value for the breast cancer population was 6.6 +/- 2.1 pg/ml. Patients with 2 or more metastatic sites had higher sIL-6 values compared to those with only 1 metastatic site (respectively 8.15 +/- 1.7 pg/ml and 3.06 +/- 6.6 pg/ml; p < 0.001). Patients with liver metastasis (8.3 +/- 2.4 pg/ml), with pleural effusions (10.65 +/- 9.9 pg/ml) and with dominant visceral disease (8.15 +/- 3.3 pg/ml) had significantly higher values compared to those without liver metastases (4.5 +/- 3.4 pg/ml; p = 0.001), without pleural effusions (5.45 +/- 1.5 pg/ml; p = 0.0077) and with dominant bone disease (4.5 +/- 1.4 pg/ml; p = 0.007) respectively. No correlation between sIL-6 and age, menopausal status, performance status, tumour grade, body-mass index, histology and hormone receptor status was found. Multivariate analysis showed that high levels of serum IL-6 have independent prognostic value. We conclude that circulating IL-6 is associated with worse survival in patients with metastatic breast cancer and is correlated with the extent of disease.     

Peripheral blood circulating cytokeratin-19 mRNA-positive cells after the completion of adjuvant chemotherapy in patients with operable breast cancer.

BACKGROUND: The purpose of this study was to evaluate the prognostic significance of the molecular detection of cytokeratin 19 (CK-19) mRNA-positive cells in the peripheral blood of women with operable breast cancer after the completion of adjuvant chemotherapy. PATIENTS AND METHODS: Blood from 161 patients with stage I and II breast cancer, obtained after the completion of adjuvant chemotherapy, was tested by nested RT-PCR for CK-19 mRNA detection. Using univariate and multivariate analyses possible interactions with other prognostic factors and association of CK-19 mRNA detection with risk of relapse, disease-free interval (DFI) and overall survival were investigated. RESULTS: After completion of adjuvant chemotherapy, 27.3% of patients had peripheral blood CK-19 mRNA-positive cells; there was no association of this finding with any other prognostic factors or the type of chemotherapy regimen used. For patients with less than four involved axillary lymph nodes the risk of relapse was 3.81 [95% confidence interval (CI) 1.06-13.71] times higher, and the DFI was significantly reduced (P = 0.028) if CK-19 mRNA-positive cells were detectable in the blood after the completion of adjuvant chemotherapy. In contrast, for patients with four or more involved lymph nodes, the presence of CK-19 mRNA-positive cells after adjuvant chemotherapy did not significantly affect the risk of relapse or DFI. Furthermore, the risk of relapse was higher (hazards ratio 3.70; 95% CI 1.09-13.89) and the DFI was reduced (P = 0.022) for patients with detectable CK-19 mRNA-positive cells following adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as compared with epirubicin, cyclophosphamide and 5-fluorouracil (FEC) or sequential taxotere-epirubicin and cyclophosphamide (T/EC) chemotherapy. CONCLUSIONS: The detection of CK-19 mRNA-positive cells in the peripheral blood after adjuvant chemotherapy may be of clinical relevance for patients with early breast cancer and less than four involved axillary lymph nodes.     

Prognosis of early breast cancer by immunohistochemistry defined intrinsic sub‐types in patients treated with adjuvant chemotherapy in the NEAT/BR9601 trial

Breast cancer can be classified into molecular sub‐types that have distinct survival patterns. We evaluated the prognostic significance of breast cancer sub‐types in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing cyclophosphamide, methotrexate and fluorouracil (CMF) with ECMF (epirubicin and CMF). Furthermore, we evaluated whether the sub‐types were predictive of the added benefit of epirubicin in these trials. Tumour tissue microarrays were stained and scored for ER, PR, HER2, EGFR and CK5/6. These were used to classify the tumours into six intrinsic sub‐types. We used Cox regression to compare overall survival (OS), breast cancer‐specific survival (BCSS) and relapse‐free survival (RFS) in the different sub‐groups. We also compared the effect of ECMF with CMF by sub‐group. Immunohistochemistry data were available for 1,725 cases of whom 805 were luminal 1‐basal negative. Median follow‐up time was 7 years. The luminal 1‐basal negative tumours were associated with the best prognosis in five years after surgery and the HER2‐like tumours were associated with the poorest prognosis. There was little evidence for significant heterogeneity of this effect by tumour sub‐type (OS p = 0.40, BCSS p = 0.53 RFS p = 0.50) – the largest additional benefit of epirubicin was in women with tumours of the 5‐negative phenotype (OS HR = 0.39 95% CI: 0.21–0.73) and the smallest was in Luminal 1‐basal negative tumours (OS HR = 0.86 95% CI: 0.64–1.16). We confirmed that breast cancer sub‐types show distinct behaviour with differences in short‐ and long‐term survival. The benefit of ECMF over CMF was statistically similar in all disease sub‐types.     

Differential effect of adjuvant taxane-based and taxane-free chemotherapy regimens on the CK-19 mRNA-positive circulating tumour cells in patients with early breast cancer

Background:

To determine the effect of adjuvant taxane-free and taxane-based chemotherapy regimens on the elimination of circulating tumour cells (CTCs) in patients with early breast cancer.

Methods:

The presence of CK-19 mRNA-positive CTCs in the peripheral blood was evaluated before and after chemotherapy, using a real-time RT–PCR assay, in a historical comparison of two cohorts of women with stage I–III breast cancer treated with adjuvant taxane-free (N=211; FE₇₅C or E₇₅C) and taxane-based (N=334; T/E₇₅C or T/E₇₅) chemotherapy.

Results:

Taxane-based chemotherapy resulted in a higher incidence of CTCs'' elimination than taxane-free regimens since 49.7% (74 of 149) and 33.0% (29 of 88) of patients with detectable CTCs before chemotherapy, respectively, turned negative post-chemotherapy (P=0.015). Patients treated with taxane-free regimens had a significantly lower disease-free survival (DFS) (P=0.035) than patients treated with taxane-based regimens; this difference was observed in patients with but not without detectable CTCs before chemotherapy (P=0.018 and P=0.481, respectively). The incidence of deaths was significantly higher in the taxane-free cohort of patients with but not without detectable CTCs before chemotherapy compared with that of the taxane-based cohort (P=0.002). Multivariate analysis revealed that the chemotherapy regimen was significantly associated with prolonged DFS (HR: 2.00; 95% CI=1.20–3.34).

Conclusion:

Elimination of CK-19 mRNA-positive CTCs during adjuvant chemotherapy seems to be an efficacy indicator of treatment and is associated with a favourable clinical outcome of patients with detectable CTCs before chemotherapy.     

Prospective evaluation of cognitive function in patients with early breast cancer receiving adjuvant chemotherapy

Aim: To assess cognitive function prospectively in women with early breast cancer before, during and after the administration of adjuvant chemotherapy. Methods: Between May 2000 and November 2001, 35 assessable patients were entered into the study. Thirty‐one received oral cyclophosphamide, methotrexate and 5‐fluorouracil (CMF) and four received epirubicin and cyclophosphamide followed by CMF ((cyclophosphamide, methotrexate and 5‐fluorouracil)). Testing consisted of the completion of a battery of neuropsychological and psychological inventories and was performed prior to chemotherapy and repeated after 3 (n = 31) and 6 months (n = 30) of chemotherapy and also 6 months after the completion of chemotherapy (n = 27). Results: Prior to chemotherapy a proportion of the patients already exhibited some evidence of impairment of cognitive function. However, on completion of chemotherapy, the neuropsychological scores for short‐term verbal memory and verbal learning were significantly lower than prior to, or 6 months after chemotherapy. In all other domains, cognitive function either remained constant or even appeared to improve. Symptom scales showed that fatigue, nausea and vomiting, constipation and diarrhea were worst half way through the chemotherapy. Quality of life scales indicated that functioning was best after completion of chemotherapy. Conclusion: Patients with early breast cancer may have impaired cognitive function before chemotherapy. Although transient deteriorations in verbal memory and verbal learning were observed on completion of chemotherapy, overall, cognitive function did not decline. It is likely that practice effects influenced our findings.     

Amenorrhea induced by adjuvant chemotherapy in early breast cancer patients: prognostic role and clinical implications

Background: The role of amenorrhea induced by chemotherapyin premenopausal women with early breast cancer isvery controversial. Analyses by various authors of theeffect of drug-induced amenorrhea (DIA) on treatment outcomehave yielded conflicting results. In order to gaininsight into the role of DIA, we reviewedall published data addressing the issue of DIAas a prognostic factor. Methods: Computerised and manualsearches were conducted of relevant studies published from1966 to 1995. Results: Thirteen studies involving 3929patients were selected. In two papers, the prognosticrole of DIA was analysed in three andtwo different groups of patients, respectively. Overall, 16groups of patients were evaluated. With 12 groups,a higher disease free survival was observed inpatients developing DIA compared to those who didnot. This difference was statistically significant in eightgroups. Data on overall survival, reported in onlyfive studies, indicated that it was always improvedin patients who became amenorrheic. Conclusions: Available dataon the role of DIA support its importanceas a favorable prognostic factor for early breastcancer patients. However, due to the possible biasesof this type of evaluation, this result shouldbe interpreted with caution.     

Time to initiation of adjuvant chemotherapy in patients with rapidly proliferating early breast cancer

AimTo evaluate the optimal time interval from definitive surgery to commencing chemotherapy in early breast cancer (EBC).Patients and methodsThe relationship between time to initiation of adjuvant chemotherapy (TTC), calculated in weeks, and disease-free (DFS) or overall survival (OS), was assessed in 921 EBC patients with rapidly proliferating tumours (thymidine labelling index >3% or G3 or Ki67 >20%), randomised in a phase III clinical trial (NCT01031030) to receive chemotherapy with or without anthracyclines (epirubicin → cyclophosphamide, methotrexate and fluorouracil (CMF) versus CMF → epirubicin versus CMF). DFS, OS and 95% confidence intervals (95% confidence interval (CI)) were calculated by the Kaplan–Meier method. Multivariate Cox analysis was performed in relation with nodal involvement, oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status, Ki67 value, type of adjuvant chemotherapy, menopausal status and tumour size.ResultsAt a median follow-up of 105 months (range 2–188), a prolonged TTC resulted in a significant increase in the risk of relapse: hazard ratio (HR) 1.15 (95% CI 1.02–1.30, p = 0.019). Using a backward elimination procedure, TTC, tumour size and nodal involvement remained significantly associated with DFS. A time-dependent receiver-operating characteristic (ROC) curve analysis was subsequently utilised to evaluate the best cut-off for TTC, identifying 7 weeks as the best threshold for longer OS (p = 0.043): 8-year OS 88% (95% CI 85–90) for patients with a TTC <7 weeks and 78% (95% CI 68–87) for the other group.ConclusionsOur results confirm that a shorter TTC may reduce relapses and possibly also improve clinical outcome in patients with highly proliferating EBC.     

Influence of circulating c-erbB-2 serum protein on response to adjuvant chemotherapy in node-positive breast cancer patients

This retrospective case control study investigated the therametricvalue of the circulating c-erbB-2 gene product (Her-2,NEU) as (1) an eligibility criterion for highdoses of chemotherapy and (2) response to standardadjuvant chemotherapy in node-positive breast cancer patients. Preoperativec-erbB-2 levels were measured in 211 locally advanced(> 3 nodes positive), pre- and perimenopausal breastcancer patients to determine if circulating levels ofthe gene product can assist in the determinationof appropriate therapeutic options.152 of 211 breast cancer patients received post-operativelya combination chemotherapy including the anthracycline analog mitoxantrone,while 59 patients were treated with conventional CMFtherapy. Using 120 fmol/ml as a cut-off level,elevated c-erbB-2 values were found in 26 (12.3%)patients with locally advanced breast cancer. In univariateanalysis significant survival differences were detected when c-erbB-2positive patients were compared with c-erbB-2 negative patients.However, no significant survival differences were detected, whenc-erbB-2 positive patients were compared according to regimenof adjuvant treatment.In multivariate analysis c-erbB-2 was an independent prognosticfactor for predicting disease-free survival, but not foroverall survival. High levels of c-erbB-2 were associatedwith low estrogen and progesterone receptor concentrations ofthe tumor cytosol. There was no correlation betweenelevated c-erbB-2 values and age, tumor size ordegree of nodal involvement. c-erbB-2 was a betterpredictor of risk of recurrence than extent ofnodal involvement or hormone receptor status.     

High preoperative plasma TIMP-1 is prognostic for early relapse in primary breast carcinoma

TIMP-1 is a natural inhibitor of extracellular matrix degrading enzymes called matrix metalloproteinases. In addition to its capacity to inhibit matrix degradation, TIMP-1 has been shown to promote cell growth and inhibit apoptosis. The expression of TIMP-1 in tumor tissue, as well as in circulating blood, has therefore been shown to associate with worsened survival in several malignancies. In our study, a prospective series of 213 patients with primary breast carcinoma was assessed. Circulating pre- and postoperative TIMP-1 levels were assayed using enzyme-linked immunosorbent assay analysis. It was shown that high preoperative plasma TIMP-1 was a powerful predictor of systemic early relapse in breast carcinoma, with HR 8.1 (95% CI 1.8-37.6) (p = 0.007) as a log-transformed continuous variable in Cox regression univariate analysis. It was shown to be independent of, and superior to, nodal status as a prognostic variable in multivariate analysis, and not associated with any known prognostic clinicopathological parameters. Kaplan-Meier analysis showed that the patients belonging to the highest quartile of circulating TIMP-1 levels had a worsened recurrence-free survival of 79% compared to 94% RFS among patients in the lower quartiles (p = 0.016). The postoperative levels of circulating plasma TIMP-1 were not found to be prognostic for relapse. In conclusion, preoperative plasma TIMP-1 was found to be a powerful prognostic factor for early systemic relapse in primary breast carcinoma.     

40例乳腺癌新辅助化疗的疗效观察

目的评价含紫杉类或葸环类药物在乳腺癌术前化疗中的疗效及副作用。方法2005年7月～2007年11月在我院治疗的40例Ⅰ～Ⅲ期原发乳腺癌患者,采用含紫杉类（TP或TE／TEC方案）或葸环类（EC／FEC方案）联合方案,术前化疗2～4个周期,33例患者接受手术,术后完成规定化疗,应用B超结合触诊判断临床疗效,观察近期疗效及毒副作用,应用x^2检验及单因素分析判定相关因素与疗效的关系。结果化疗前后中位肿瘤最大径分别为3．5厘米和2．0厘米（P=0．01）,临床有效率82．5％（33／40）,其中cCR7．5％（3／40）、cPR75％（30／40）、cSD15％（6／40）、cPD2．5％（1／40）。手术治疗33例,术后pCR9．1％（3／33）,tpCR6．1％（2／33）。这些病例中,不同肿瘤大小、受体状况、CerbB-2表达、不同分化程度以及化疗方案之间的肿瘤缓解率并无统计学差异。化疗毒副作用主要为脱发、骨髓抑制、消化道反应、口腔溃疡及外周神经毒性,心脏毒性主要表现为心律增快、心电图改变,肝功损害少见。结论紫杉类及蒽环类药物联合方案用于浸润性乳腺癌的术前化疗,可有效控制肿瘤,毒副作用可耐受。     

Progesterone receptor activity and relapse-free survival in patients with primary breast cancer: The role of adjuvant chemotherapy

The prognostic significance of progesterone receptor activity (PgR) with regard to the estimated relapse-free survival (RFS) was studied in 350 one-center patients with primary breast cancer. All receptor assays were performed in one laboratory; PgR levels >10 fmol/mg protein were considered positive. Univariate as well as multivariate statistical analyses were used to examine the prognostic significance of several variables. Eighty-nine of the 350 patients received adjuvant CMF chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil). The median observation period was 69 months (range 12–125 months).In the group of 261 patients who did not receive adjuvant CMF, the PgR-status lacked prognostic significance; only the lymph node status significantly affected the RFS (p<0.00001). In contrast, in the CMF-treated group of patients, the PgR-status was the most powerful predictor of recurrence (p<0.0001). The menopausal and the lymph-node status increased the predictive value of PgR (p<0.001). Premenopausal CMF-treated patients with PgR⁺ tumors had a significantly longer RFS than those with PgR^– tumors (p<0.02). The present data urge the need for a reappraisal of the prognostic significance of PgR and of the mechanism of action of adjuvant chemotherapy in primary breast cancer.     

A highly specific real-time RT-PCR method for the quantitative determination of CK-19 mRNA positive cells in peripheral blood of patients with operable breast cancer

The aim of the present study was to decrease the incidence of false positives and to better characterize marginally cytokeratin-19 (CK-19) mRNA positive peripheral blood samples from patients with early stage breast cancer. A new set of highly specific primers for CK-19, which avoids amplification of contaminating genomic DNA, was designed and evaluated to improve the specificity and sensitivity of the previously described methodology. The primers were specifically designed to avoid amplification of contaminating genomic DNA and CK-19 pseudogenes. The breast cancer cell line MCF-7 was used as positive control for the development and analytical evaluation of the assay, while peripheral blood samples from 62 healthy female individuals and 160 patients with early breast cancer were used for the evaluation of the sensitivity and specificity of the new primer pair. The novel designed primer pair was highly sensitive, as it detects up to 1 MCF-7 cell, and specific as none of the healthy individuals had detectable CK-19 mRNA positive cells in their peripheral blood. CK-19 mRNA positive cells were detected in 33 out of 160 (20.6%) patients with early breast cancer. Results obtained by the proposed optimized real-time RT-PCR protocol correlated well with those obtained in the same samples by our previously reported quantitative real-time RT-PCR [concordance in 198/222 (89.2%), p = 0.0022, McNemar test]. The improved method eliminates the incidence of false positives and is highly sensitive and specific. The method could be used in a clinical setting in the near future for continuous monitoring and quantification of circulating epithelial cells in the peripheral blood of patients with operable breast cancer, provided that a quite larger number of clinical samples with a known follow-up will be analyzed.     

Osteoblastic metastatic disease as a therapeutic response to adjuvant chemotherapy in breast cancer

Included in this study were 43 breast cancer patients treated with adjuvant chemotherapy who presented metastasis only in bone. Forty-two percent had metastasis during chemotherapy, and 58% had metastasis after the completion of chemotherapy. In 66% of the patients, the lesions were osteolytic. Twenty-nine percent had osteoblastic lesions, and 5% had mixed lesions. Of the patients with osteoblastic metastatic disease, five showed asymptomatic, osteoblastic disease; this response was considered to be a healing response to chemotherapy. These five patients were continued on the same therapy. The median duration of this response to the adjuvant chemotherapy was 29 months (range 6 to 62+). In one patient, osteoblastic disease gradually faded, and skeletal radiographs reverted to normal.     

Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer

Circulating endothelial cells (CECs) as well as bone-marrow-derived endothelial precursor cells (EPC) play an important role in neovascularisation and tumour growth. To study the impact of neoadjuvant chemotherapy on the amounts of CEC and their precursor cells, mature CEC and their progenitors were quantified by flow cytometry in peripheral blood of breast cancer patients during anthracycline and/or taxane based neoadjuvant chemotherapy and subsequent surgery in comparison to age-matched healthy controls. Cell numbers were tested for correlation with serum levels of angiopoietin-2, erythropoietin, endostatin, endoglin, VEGF and sVCAM-1 as well as clinical and pathological features of breast cancer disease. Circulating endothelial cells were significantly elevated in breast cancer patients and decreased during chemotherapy, whereas EPC (CD34+/VEGFR-2+) as well as their progenitor cell population CD133+/CD34+ and the population of CD34+ stem cells increased. Concomitantly with the increase of progenitor cells an increase of VEGF, erythropoietin and angiopoietin-2 was observed. These data suggest that chemotherapy can only reduce the amounts of mature CEC, probably reflecting detached cells from tumour vessels, whereas the EPC and their progenitors are mobilised by chemotherapy. Since this mobilisation of EPC may contribute to tumour neovascularisation an early antiangiogenic therapy in combination with chemotherapy could be beneficial for the success of cancer therapy.