Disease-free Survival In Breast Cancer Patients Research Articles

Abstract P3-07-21: Non-alcoholic fatty liver disease induced by selective estrogen receptor modulators is a protective factor for breast cancer survival

Abstract Purpose: Non-alcoholic fatty liver disease (NAFLD) induced by selective estrogen receptor modulators (SERMs) treatment may be related to treatment efficacy for the antagonism of circulating estrogens. We conducted a retrospective study to investigate the relationship between survival outcomes and NAFLD in breast cancer patients treated with tamoxifen or toremifene. Patients and methods: 785 eligible patients received tamoxifen or toremifene in Sun Yat-sen university cancer center from January 2005 to December 2009 were included in our study. All patients have at less one abdominal ultrasonography measurement at baseline and every year's follow-up. Patients who diagnosed NAFLD by ultrasonography during three-year's follow-up were classified into NAFLD cohort, others were classified into no-NAFLD cohort. Univariate and multivariate Cox regression was utilized to analyse the relationship between NAFLD and disease-free survival (DFS) and overall survival (OS). Results:158 patients had reported NAFLD in the first 3 years' follow-up. Patients who developed NAFLD had better DFS and OS than those not developing NAFLD. The 5-years DFS was 91.56% and 85.01% at NAFLD and no-NAFLD cohort (univariate hazard ratio [HR]: 0.59 [95%CI 0.37-0.96], P=0.034), respectively. The 5-years OS was 96.64% and 93.31% at NAFLD and no-NAFLD cohort (univariate HR: 0.39 [95%CI 0.16-0.99], P=0.047), respectively. Multivariate analysis revealed that NAFLD is an independent prognostic factor on DFS in breast cancer patients with SERMs treated. Women treated with SERMs experienced NAFLD in the first three-year's follow-up had a reduced risk of DFS of 42% (multivariate HR: 0.58; [95%CI 0.36-0.95], P=0.032) compared with patients without NAFLD. Conclusion: NAFLD induced by SERMs seems to be associated with better survival outcomes and may therefore be helpful in predicting treatment responses in breast cancer patients treated with SERMs. Citation Format: Wang S, Zheng Q, Nie M, Xu F, Xia W, Yuan Z, Peng R, An X, Qin T, Qin G. Non-alcoholic fatty liver disease induced by selective estrogen receptor modulators is a protective factor for breast cancer survival. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-21.

Novel Molecular Markers for Breast Cancer.

The use of molecular biomarkers assures that breast cancer (BC) patients receive optimal treatment. Established biomarkers, such as estrogen receptor, progesterone receptor, HER2, and Ki67, have been playing significant roles in the subcategorization of BC to predict the prognosis and decide the specific therapy to each patient. Antihormonal therapy using 4-hydroxytamoxifen or aromatase inhibitors have been employed in patients whose tumor cells express hormone receptors, while monoclonal antibody to HER2 has been administered to HER2-positive BCs. Although new therapeutic agents have been developed in the past few decades, many patients still die of the disease due to relapse; thus, novel molecular markers that predict therapeutic failure and those that can be targets for specific therapy are expected. We have chosen four of such molecules by reviewing recent publications, which are cyclin E, B-Myb, Twist, and DMP1β. The oncogenicity of these molecules has been demonstrated in vivo and/or in vitro through studies using transgenic mice or siRNAs, and their expressions have been shown to be associated with shortened overall or disease-free survival of BC patients. The former three molecules have been shown to accelerate epithelial–mesenchymal transition that is often associated with cancer stem cell-ness and metastasis; all these four can be novel therapeutic targets as well. Thus, large prospective studies employing immunohistochemistry will be needed to establish the predictive values of these molecules in patients with BC.

Elevated preoperative neutrophil-to-lymphocyte ratio predicts poor disease-free survival in Chinese women with breast cancer.

Inflammation and tumor immune microenviroment are critical factors for prognosis in numerous cancers. The aim of this study was to determine the prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR) in breast cancer. We performed a retrospective analysis of 487 patients diagnosed with primary breast cancer at Shanghai Ruijin hospital from January 2009 to December 2010. Hematological parameters before surgery, clinicopathological data, and survival status were obtained. Survival analysis was used to evaluate the prognostic value of NLR. The optimal cutoff value was determined as 1.93 for NLR and the median follow-up time was 55.0months. On univariate analysis, patients with high NLR (>1.93) had worse 5-year disease-free survival (DFS) compared to those with low NLR (77.9 vs 88.0%, p = 0.002). Regarding overall survival, there was no significant difference between patients with high NLR and low NLR, with 5-year overall survival of 90.8 and 91.7% (p = 0.707). In triple-negative breast cancer, patients with high NLR was associated with worse 5-year DFS compared with patients with low NLR (63.4 vs 84.9%, p = 0.040). Mutivariate analysis revealed that NLR was an independent prognostic factor for DFS in breast cancer (HR = 1.867, 95% confidence interval; (95%CI) = 1.155-3.017, p = 0.011). Preoperative NLR is an independent predictor of DFS in breast cancer patients, especially in triple-negative subtype. Further studies are required to validate the prognostic value of NLR before clinical application.

High casein kinase 1 epsilon levels are correlated with better prognosis in subsets of patients with breast cancer.

Reliable biological markers that predict breast cancer (BC) outcomes after multidisciplinary therapy have not been fully elucidated. We investigated the association between casein kinase 1 epsilon (CK1ε) and the risk of recurrence in patients with BC. Using 168 available tumor samples from patients with BC treated with surgery +/- chemo(radio)therapy, we scored the CK1ε expression as high (≥ 1.5) or low (<1.5) using an immunohistochemical method. Kaplan-Meier analysis was performed to assess the risk of relapse, and Cox proportional hazards analyses were utilized to evaluate the effect of CK1ε expression on this risk. The median age at diagnosis was 60 years (range 35-96). A total of 58% of the patients underwent breast conservation surgery, while 42% underwent mastectomy. Adjuvant chemotherapy and radiation therapy were administered in 101 (60%) and 137 cases (82%), respectively. Relapse was observed in 24 patients (14%). Multivariate analysis found high expression of CK1ε to be associated with a statistically significant higher disease-free survival (DFS) in BC patients with wild-type p53 (Hazard ratio [HR] = 0.33; 95% CI, 0.12-0.91; P = 0.018) or poor histological differentiation ([HR] = 0.34; 95% CI, 0.12-0.94; P = 0.039) or in those without adjuvant chemotherapy ([HR] = 0.11; 95% CI, 0.01-0.97; P = 0.006). Our data indicate that CK1ε expression is associated with DFS in BC patients with wild-type p53 or poor histological differentiation or in those without adjuvant chemotherapy and thus may serve as a predictor of recurrence in these subsets of patients.

Combined expression of ezrin and E-cadherin is associated with lymph node metastasis and poor prognosis in breast cancer.

Ezrin and E-cadherin have been known to play a role in tumor metastasis. However, the association between the expression of ezrin and E-cadherin in breast cancer patients remains unclear. In the present study, we investigated the expression of ezrin and E-cadherin in 275 breast cancer and 80 control patients with benign hyperplasia, using tissue microarray-based immunohistochemistry (IHC). Ezrin expression was higher, while that of E-cadherin was lower in breast cancer than in control samples. Ezrin expression was negatively correlated with E-cadherin expression in a subpopulation of breast cancer patients with a high expression of ezrin [ezrin(high)] and a low expression of E-cadherin [E-cad(low)]. The cytoplasmic expression of E-cadherin [E-cad(c)] occurred significantly more frequently in ezrin(high) breast cancer than in ezrin(low) breast cancer. The expression level of ezrin was significantly higher in breast cancer with E-cad(c) than that with a membrane expression of E-cadherin [E-cad(m)]. Ezrin(high) or E-cad(low) expression was more associated with lymph node metastasis, and shorter overall survival (OS) and disease-free survival (DFS) in breast cancer patients. E-cad(c) was more associated with lymph node metastasis and shorter OS and DFS compared with E-cad(m). The combined expression of ezrin(high) and E-cad(low) or ezrin(high) and ezrin(c) was more associated with lymph node metastasis and poor prognosis. In addition, the multivariate Cox regression analysis revealed that lymph node metastasis and ezrin(high) expression were independent prognostic factors for shorter OS and DFS in breast cancer patients. The results of the present study suggested that ezrin promotes breast cancer metastasis via the regulation of E-cadherin expression.

Effect of body mass index on disease-free and overall survival in Chinese women with breast cancer

Obesity has been shown to be an indicator of poor prognosis for patients with primary breast cancer. The aim of this study was to clarify the effect of obesity on Chinese women with breast cancer. This is a retrospective analysis of 1699 breast cancer patients. We evaluated the effect of body mass index (BMI) on disease-free survival (DFS) and overall survival (OS) in these patients. BMI was obtained before surgery. Obesity was defined as a BMI ≥ 24. Kaplan-Meier analysis and Log rank test were employed to perform survival analysis. The impact of different characteristics on survival was assessed by using Cox proportional-hazards regression model. In total 635 (37.4%) patients were obese, while 1 064 (62.6%) were non-obese. Comparing the tumor characteristics in the two groups, the BMI ≥ 24 group showed a higher rate of older age (P < 0.001), postmenopausal status (P < 0.001), increased risk of lymph node metastasis (P = 0.001) and less chances of accepting breast conservation surgery (P = 0.012). The median follow-up time was 16 months, and the estimated 16-months DFS was 98.1% for non-obese and 95.0% for obese patients (P = 0.007), the estimated 16-months OS was 99.4% for non-obese and 98.4% for obese patients (P = 0.004). The multivariate analysis indicated that obesity is an independent prognostic factor for OS and DFS in breast cancer patients. Our findings suggest that obesity is associated with a poorer outcome in Chinese female patients with breast cancer.

Number of negative lymph nodes is associated with disease-free survival in patients with breast cancer.

BackgroundThe aim of this study was to evaluate the prognostic value of the number of negative lymph nodes (NLNs) in breast cancer patients after mastectomy.Methods2,455 breast cancer patients who received a mastectomy between January 1998 and December 2007 were retrospectively reviewed. The prognostic impact of the number of NLNs with respect to disease-free survival (DFS) was analyzed.ResultsThe median follow-up time was 62.0 months, and the 5-year and 10-year DFS was 87.1% and 74.3%, respectively. The DFS of patients with >10 NLNs was significantly higher than that of patents with ≤10 NLNs, and the 5-year DFS rates were 87.5% and 69.5%, respectively (P < 0.001). Univariate Cox analysis showed that the NLN count (continuous variable) was a prognostic factor of DFS (hazard ratio [HR] = 0.913, 95% confidence interval [CI]: 0.896-0.930, P < 0.001). In multivariate Cox analysis, patients with a higher number of NLNs had a better DFS (HR = 0.977, 95% CI: 0.958-0.997, P = 0.022). Subgroup analysis showed that the NLN count had a prognostic value in patients at different pT stages and pN positive patients (log-rank P < 0.001). However, it had no prognostic value in pN0 patients (log-rank P = 0.684).ConclusionsThe number of NLNs is an independent prognostic factor of DFS in breast cancer patients after mastectomy, and patients with a higher number of NLNs have a better DFS.

Potential Prognostic Value of Histone Deacetylase 6 and Acetylated Heat-Shock Protein 90 in Early-Stage Breast Cancer.

PurposeHistone deacetylase 6 (HDAC6) is an enzyme that deacetylates heat-shock protein 90 (HSP90). Many studies have investigated the role of HDAC6 and HSP90 in tumorigenesis and in the prognosis of cancer patients. This study aimed to evaluate the prognostic value of HDAC6 and acetylated HSP90 (acetyl-HSP90) in a cohort of breast cancer patients.MethodsImmunohistochemical analysis of 314 surgical specimens obtained from patients with invasive breast cancer was carried out to assess standard pathologic factors and the expression of HDAC6 and acetyl-HSP90. Statistical analyses were performed to determine the association between HDAC6, acetyl-HSP90, and conventional clinicopathological factors, and the prognostic values of these factors were evaluated.ResultsHDAC6 expression did not show any correlation with other clinicopathological factors, but acetyl-HSP90 was significantly correlated with histologic grade (p=0.001) and the Ki-67 index (p=0.015). HDAC6 and acetyl-HSP90 expression were significantly associated with each other (p=0.047). Although HDAC6 was not prognostic for disease-free survival (DFS), some patients with high expression of HDAC6 experienced recurrence 5 years after diagnosis, while there was no recurrent disease after 5 years in those with low expression. Acetyl-HSP90 was significantly associated with the DFS of all patients (p=0.016) and with high HDAC6 expression (p=0.017), but not with low expression.ConclusionExpression of HDAC6 and acetyl-HSP90 are correlated. HDAC6 is proposed to be a possible predictive marker of late recurrence, and acetyl-HSP90 has prognostic value in predicting the DFS of breast cancer patients.

Impact of Acetylsalicylic Acid on the Clinicopathological Characteristics and Prognosis of Patients with Invasive Breast Cancer

Background: The impact of acetylsalicylic acid (ASA) on the clinicopathological characteristics of breast cancer has not yet been elucidated in detail; we therefore aimed to investigate the effects of ASA on the clinicopathological characteristics of patients with breast cancer. Patients and Methods: Patients diagnosed with breast cancer were retrospectively analyzed. Breast cancer patients who were taking ASA at the time of breast cancer diagnosis were enrolled as ASA users (n = 84); matching patients with the same age who were not taking ASA were included as control group (n = 890). Results: The median age was 56 (range 34-82) years in both groups. ASA users had a significantly lower incidence of grade II-III tumors compared to non-users (P = 0.02). The other clinicopathological characteristics and treatment histories were similar in both groups. In patients using ASA, the disease-free survival (DFS) rate was 97.3%, 89.4%, and 79.9% and in non-users it was 94.1%, 81.8%, and 70.9% in the 1rst, 3rd, and 5th year, respectively (P = 0.01). In aspirin users, the overall survival rate was 95.0%, 90.6%, and 87.6% and in non-users it was 98.1%, 91.2%, and 85.5% in the 1rst, 3rd, and 5th year, respectively (P = 0.50). Conclusion: Using ASA at the time of breast cancer diagnosis was associated with significantly improved DFS in breast cancer patients.

CYP2D6 polymorphisms influence tamoxifen treatment outcomes in breast cancer patients: a meta-analysis

To evaluate whether breast cancer (BC) patients with CYP2D6 gene variation have different clinical tamoxifen (TAM) treatment outcomes to those with normal function of CYP2D6. Systematic searches of the PubMed up to February 21, 2013, were retrieved. The study end points were disease-free survival (DFS) and overall survival (OS). Fixed or random-effects meta-analytical models were used to calculate summary hazard ratio (HR) and corresponding 95% confidence intervals (CIs). Meta-regression, Galbraith plots, subgroup analysis, and sensitivity analysis were also performed. A total of 11,701 BC patients from 20 trials were included. Compared with reduced CYP2D6 function, normal function was associated with a trend toward improved DFS (HR=1.37, 95% CI 1.12-1.69, P=0.002) and OS (HR=1.25, 95% CI 1.03-1.50, P=0.021). We found significant heterogeneity between studies. When the analysis was stratified into subgroups, significantly worse DFS was found in the groups of intermediate metabolizer versus extensive metabolizer (HR=1.65, 95% CI 1.04-2.64, P=0.035), Asian population (HR=3.29, 95% CI 1.64-6.63, P=0.001), 5years TAM treatment duration (HR=1.59; 95% CI 1.14-2.22, P=0.006), concomitant chemotherapy (HR=1.35, 95% CI 1.04-1.76, P=0.025), and TAM alone (HR=1.44, 95% CI 1.44-2.06, P=0.045). With respect to OS, no significant association was demonstrated in stratified analyses. We concluded that CYP2D6 polymorphisms may influence tamoxifen treatment outcomes of DFS in BC patients.

The Importance of Multifocal/Multicentric Tumor on the Disease-Free Survival of Breast Cancer Patients

Multifocal/multicentric breast cancers have been comprehensively studied and their outcomes have been compared with unifocal tumors. We evaluated the impact of multifocality and multicentricity on the disease-free survival (DFS) and overall survival of breast cancer patients and tried to analyze the correlation between multifocality/multicentricity (M/M) and other prognostic factors. Between 1994 and 2009, we analyzed retrospectively 697 breast cancer patients. Multicentric and multifocal breast cancer were defined as the presence of 2 or more invasive tumor foci within the different quadrants of the same breast or within a same quadrant of the breast, respectively. M/M and other prognostic factors were evaluated using univariate and multivariate analyses. Multifocal/multicentric tumors were seen in 107 (15.4%) of the 697 breast cancer patients. pT and pN stage were related with the presence of multifocal/multicentric tumors. As tumor size increased and the number of axillary lymph nodes metastasis increased, the incidence of M/M increased significantly (P=0.003 vs. P=0.02, respectively). Overall, the median DFS time of patients with multifocal/multicentric tumors was significantly worse than that of the unifocal tumors (55 vs. 137 mo, P<0.001). Multivariate analysis showed that the presence of M/M was the most important prognostic factor for DFS (P=0.001, hazard ratio (HR): 0.33; 95% confidence interval (CI), 0.18-0.58), as were pN stage and extracapsular extension of the tumor (P=0.01, HR: 1.74; 95% CI, 1.13-2.69) (P=0.03, HR: 1.9; 95% CI, 1.04-3.47, respectively). M/M were not also statistically significant prognostic factors in breast cancer for overall survival (P=0.06). M/M imparts an unfavorable prognosis on the DFS of breast cancer patients in comparison to unifocal tumors and the presence of multifocal/multicentric tumors were associated with advanced pT and pN stages.

Increased expression of fibroblastic growth factor receptor 2 is correlated with poor prognosis in patients with breast cancer

Although there is growing evidence supporting the hypothesis that fibroblast growth factor receptor 2 (FGFR2) is one of the few candidate genes linked with breast cancer susceptibility, the precise role of FGFR2 protein expression in breast cancer is still unknown. Our study examines FGFR2 protein expression in breast cancer and determines its associations with clinicopathological features and survival. Specimens from 125 invasive ductal carcinoma grade 2 (IDC2) breast cancer patients were investigated by immunohistochemistry for FGFR2 protein expression. Associations between the expression of FGFR2 and various clinicopathological features as well as survival status were studied. Cytoplasmic and nuclear FGFR2 were expressed in 64.8% and 56.8% of breast cancer patients, respectively. Cytoplasmic FGFR2 expression was significantly associated with tumor size and TNM stage. Furthermore, patients with high expression levels of cytoplasmic and nuclear FGFR2 showed much lower overall survival (OS) and disease-free survival (DFS) rates than those patients with low FGFR2 expression. Cytoplasmic FGFR2 expression and lymph node metastasis were independent prognostic factors for both DFS and OS by multivariate analysis. High FGFR2 expression is correlated with poor OS and DFS in breast cancer patients. It could be a biomarker for poor prognosis.

Developing and comparing two different prognostic indexes for predicting disease-free survival of nonmetastatic breast cancer patients

To determine 2 different prognostic indexes (PI) for the differentiation of subgroups of nonmetastatic breast cancer patients with the Cox regression analysis and survival tree (ST) methods and the additional usage of the Kaplan-Meier estimates to investigate the predictive power of these methods. Materials and methods: Prognostic factors data were collected for 410 patients. The Cox regression analysis examines the relationship of the survival distribution and covariates. The ST method is a tree-structured survival analysis based on a recursive partitioning algorithm. In this study, Harrell's concordance indexes of models for training and test sets were computed. Furthermore, survival curves were estimated by the Kaplan-Meier method. Disease-free survival (DFS) was calculated from the time of initial diagnosis (initiation of the first treatment) to the first recurrence of disease. Results: After a median follow-up of 48 months, 100 (24.4%) patients have had at least 1 of the DFS events. In Cox regression analysis, we proposed the simple PI, which is a sum of axillary nodal and HER2/neu status. In the ST method, we identified 3 variables: HER2/neu, axillary nodal, and estrogen receptor status. The axillary nodal status was the most important determining factor for recurrence. Conclusion: We found that the PI of the ST and Cox regression methods had similar performance levels in predicting DFS, and the error rates of the models were close to each other in the training and test sets. Furthermore, we determined that the axillary nodal status and HER2/neu were the most important determining factors for prediction of DFS in breast cancer patients.

Gene polymorphisms in cyclophosphamide metabolism pathway,treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer.

There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a SWOG (Southwest Oncology Group) trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematologic toxicity and disease-free survival (DFS). Germline DNA was available from 458 women who were at high risk of relapse and was randomized to CAF (CP, intravenous doxorubicin, and 5-fluorouracil) versus CMF (CP, intravenous methotrexate, and 5-fluorouracil) ± tamoxifen, and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy. Odds ratios for grade 3 and 4 hematologic toxicity in the treated group and hazard ratios for DFS associated with selected functional polymorphisms in CYP2B6CYP3A4GSTA1 and GSTP1 were estimated by logistic regression and Cox proportional hazard regression. Compared with women with AA genotypes, those with at least 1 GSTP1 variant G allele had reduced risk of grade 3 and 4 neutropenia [odds ratios (OR) = 0.63, 95% CI = 0.41-0.97] and leucopenia (OR = 0.59, 95% CI = 0.39-0.89). No other associations between single nucleotide polymorphisms and toxicity or survival were found in the treated or untreated group. Known genetic variants in genes involved in CP pharmacokinetics may not have major effects on DFS in breast cancer patients. The lower risk of developing high-grade hematologic toxicity among women with variant GSTP1 alleles suggests that genetic markers in combination with clinical factors may be useful in defining a subgroup of women who are less susceptible to adverse hematologic toxicities with CP-containing therapies.

Pharmacogenetics of tamoxifen in relation to disease-free survival in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial.

510 Background: Retrospective studies on the relationship between CYP2D6 genotype and tamoxifen efficacy show conflicting results (Dezentje et al., Clin Cancer Res 2009:15;15-21). Negative studies have been criticized because of heterogeneous populations, lack of controlling for possible confounders and of systematic documentation of treatment adherence and outcome measures. Well documented studies on homogeneous populations with a more comprehensive pathway approach are imperative. Methods: 747 Dutch patients who were randomized to receive tamoxifen followed by exemestane after 2.5 to 3 years within the TEAM Trial were genotyped for 29 germline genetic variants in 12 candidate genes encoding enzymes that are involved in the metabolic and pharmacodynamic pathway of tamoxifen. These variants were related to disease free survival (DFS) during tamoxifen use (censored at the time of switch to exemestane). A multivariable Cox regression was used to adjust for clinically relevant factors. Results: The clinical characteristics of the genotyped patients were similar to the entire Dutch TEAM cohort randomized to tamoxifen (n = 1,379). DFS was associated with UGT2B15*2 [Vt/Vt + Wt/Vt vs. Wt/Wt: HR = 0.51 (0.27-0.95); p = 0.034] and the estrogen receptor-1 polymorphism ESR1 PvuII [gene-dose effect: HR = 1.72 (1.10-2.69); p = 0.017]. In the univariable analysis CYP2C19*2 was associated with DFS [Vt/Vt vs Wt/Vt + Wt/Wt: HR = 3.85 (1.64-9.05); p = 0.002]. However, this association lost significance when adjusted for the ESR1 PvuII polymorphism. No association was found between the CYP2D6 genotypes and DFS. Conclusions: This translational study suggests that common and therefore relevant polymorphisms in UGT2B15 and the estrogen receptor-1 impact DFS in breast cancer patients treated with adjuvant tamoxifen. The previously reported association between CYP2D6 genotype and tamoxifen efficacy was not confirmed in our study. No significant financial relationships to disclose.

Clinical significance of pAKT and CD44v6 overexpression with breast cancer

CD44v6 contributes to apoptosis resistance and metastasis via upregulated activity of the PI3K/AKT pathway. The purpose of this study was to investigate the expression patterns and predictive value of phosphorylated AKT (pAKT) and CD44v6 in breast cancer tissues. Expression of pAkt and CD44v6 protein was detected using immunohistochemistry in breast cancer tissues and lymph node tissues in 98 patients. The correlation between the expression of pAkt, CD44v6 and other disease-related characteristics was investigated. The prognostic value of pAKT and CD44v6 overexpression for overall survival (OS) and disease free survival (DFS) was determined. 37 cases (37.8%) were observed as positive for pAkt expression, and 38 cases (38.8%) for CD44V6 overexpression. Staining was positive for pAKT in 20 of 38 (52.6%) CD44v6(+) and 17 of 60 (28.3%) CD44v6(-) (P = 0.016). A progressively increased trend of CD44v6 overexpression was observed from node(-) primary breast cancer tissues to node(+) primary cancer tissues to node(+) lymph tissues (P = 0.000). In univariate analysis lymph node status, pAKT and CD44V6 were significantly associated with a decreased OS and DFS. Multivariate analysis revealed that CD44v6 status was associated with a reduced OS (P = 0.003), and pAKT and CD44v6 with a shorter DFS (P = 0.012 and 0.016, respectively). Our data suggested that there had an intensive relationship between pAKT and CD44v6 expression in breast cancer tissues. The overexpression of CD44v6 was an independent prognostic marker for predicting OS and DFS of breast cancer patients.

P27Kip1 expression and its prognostic implication in breast carcinoma: a meta-analysis

To evaluate the relationship between p27Kip1 low expression in breast cancer and its prognostic implication in breast carcinoma patients. Methods All data that were associated with the study of the relationship between p27Kip1 and the prognosis for breast cancer was pooled from Cochrane library, PubMed, Embase and Medlinebase. The outcome was measured using the risk ratio (RR). Data pooling was performed by RevMan 4. 2. Results 6457 patients from 20 studies were included in this meta-analysis. RR estimate of overall survival (OS) for patients with low level p27Kip1 was 2.07 [1.66,2.60] (P<0.01). For disease free survival (DFS), the pooled RR was 1.27 [1.10,1.47] (P<0.05). The combined RR estimate of relapse free survival (RFS) for patients with low level of p27Kip1 was 1.49 [0.92, 2.42] (P >0.05). In patients with lymph node negative breast carcinoma, the combined RR for OS and RFS were 1.98 [1.34,2.91] (P <0.01) and 1.28 [0.45,3.65] (P > 0.05), respectively. Among the patients with lymph node positive breast carcinoma, the combined RR for OS and RFS was 1.92 [1.31, 2.82] (P=0.0009) and 1.35 [0.96,1.89] (P>0.05) respectively. Conclusions Low level of p27Kip1 appears to be an independent prognostic factor to OS and DFS of breast cancer patients but not to RFS. Additional studies with large patient number and widely accepted practical methods are required to derive the precise prognostic significance of p27Kip1 expression in breast cancer patients.

Randomized phase II trial evaluating the efficacy of adding sequential half body irradiation (SHBI) to adjuvant chemotherapy in high-risk breast cancer patients with &gt;10 positive lymph nodes

627 Background: Adjuvant sequential half body irradiation (SHBI) is both interesting as well as scientifically sound approach with proven efficacy in many tumors. Methods: Patients with node positive (≥10) breast cancer were randomized in this phase II trial to receive either 6 cycles of adjuvant cyclophosphamide 500 mg/m2, 5FU 500 mg/m2 and epirubicin 100 mg/m2 followed by postoperative local irradiation (Arm A) versus the same adjuvant treatment plus consolidation SHBI staring 3 weeks after end of adjuvant treatment with upper half 750cGy /5 fractions /1week then one month gap followed by the lower half for the same dose (Arm B) Results: Between November 1999 and November 2000 a total of 70 patients who met the eligibility criteria were enrolled. Arm A (n=35) and arm B (n=35) were almost comparable with the respect to different prognostic factors. There was significant improvement in the disease free survival (DFS) at 5 years in arm B. The DFS was 65±8% in arm B while it was 33±8% in arm A (log-rank test: P =0.0036). In subset analysis the difference is apparent in subgroups of patients with less potential metastatic burden, which are T2 cases and ER positive cases. The DFS at 5 years was 83% in arm B and it was 35% in arm A (P=0.0008) in T2 cases. In the subgroup of patients with ER positive tumors (n=51), the DFS at 4 years was 58% in arm B and it was 25% in arm A (P=0.0072). The complications of the addition of SHBI were mild (grades 2 and 3) and mainly gastrointestinal (vomiting, diarrhea and colic). In both arms of the study there were no life-threatening complications or treatment-related mortality. Conclusions: SHBI was found to be a well-tolerated consolidation regimen with acceptable side effects and it showed significant improvement of the DFS in breast cancer patients with ≥ 10 positive lymph nodes especially in the relative cases with good prognosis (T2-ER positive). This makes it worthy of testing in a phase III trial. No significant financial relationships to disclose.

Prognostic relevance of uPAR-del4/5 and TIMP-3 mRNA expression levels in breast cancer

Recently, two components of important protease systems in cancer, i.e., the urokinase plasminogen activator receptor (uPAR) mRNA splice variant uPAR-del4/5 and the tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), were independently reported to be of prognostic value in breast cancer. In the present study, we have evaluated the impact of both these factors on disease-free survival (DFS) in 205 breast cancer patients by assessing mRNA expression in tumour tissue by quantitative PCR. High uPAR-del4/5 mRNA expression was associated with shorter DFS in breast cancer patients ( P = 0.0363), whereas high TIMP-3 mRNA levels were associated with a good prognosis ( P = 0.0049). Furthermore, by combining uPAR-del4/5 with TIMP-3 values, we demonstrate that breast cancer patients with high uPAR-del4/5 and low TIMP-3 mRNA levels had a highly significantly shorter DFS in comparison to those patients with low uPAR-del4/5 and high TIMP-3 mRNA expression ( P < 0.0001). These patients had a more than 6-fold higher risk for disease recurrence or death in multivariate analysis. Therefore, considering the prognostic impact of two proteolytic factors stemming from complementary protease systems may improve the prediction of disease recurrence in breast cancer.