Prognostic value of cytosolic thymidine kinase activity as a marker of proliferation in breast cancer

Thymidine kinase (TK) is involved in DNA synthesis by the salvage pathway. In this study, thymidine kinase (TK) was determined in routinely prepared cytosols of primary tumors from 290 breast-cancer patients. Enzyme activity was measured using a radioenzymatic method optimized for detection of the fetal isoenzyme. High levels of TK (≥ 126 mU/mg protein) were positively associated with histological grade in both pre/peri-and post-menopausal patients. In pre/peri-menopausal patients, high concentrations of TK were also found more frequently in progesterone receptor (PgR)-negative tumors than in PgR-positive samples. In post-menopausal patients, high levels of TK were associated with large tumor size, estrogen receptor (ER) negativity and PgR negativity. In univariate analysis, high levels of TK were strongly associated with shorter overall survival in both pre/peri- (p = 0.001) and post-menopausal patients (p = 0.02). Pre/peri-menopausal patients whose tumors had high levels of TK also had an increased risk of relapse (p = 0.001). In multivariate analysis (including treatment protocol, patient age, lymph-node involvement, tumor size, histological grade, ER and PgR status), TK status was found to be an independent prognostic factor for recurrence-free survival in pre/peri-menopausal patients with a weight similar to that of PgR status. In post-menopausal patients, TK was the only factor selected for overall survival. © 1995 Wiley-Liss, Inc.     

Prognostic value of lymph node ratio in node-positive breast cancer in Egyptian patients

BackgroundBreast cancer in Egypt is the most common cancer among women and is the leading cause of cancer mortality. Traditionally, axillary lymph node involvement is considered among the most important prognostic factors in breast cancer. Nonetheless, accumulating evidence suggests that axillary lymph node ratio should be considered as an alternative to classical pN classification.Materials and methodsWe performed a retrospective analysis of patients with operable node-positive breast cancer, to investigate the prognostic significance of axillary lymph node ratio.ResultsFive-hundred patients were considered eligible for the analysis. Median follow-up was 35 months (95% CI 32–37 months), the median disease-free survival (DFS) was 49 months (95% CI, 46.4–52.2 months). The classification of patients based on pN staging system failed to prognosticate DFS in the multivariate analysis. Conversely, grade 3 tumors, and the intermediate (>0.20 to ⩽0.65) and high (>0.65) LNR were the only variables that were independently associated with adverse DFS. The overall survival (OS) in this series was 69 months (95% CI 60–77).ConclusionThe analysis of outcome of patients with early breast cancer in Egypt identified the adverse prognostic effects of high tumor grade, ER negativity and intermediate and high LNR on DFS. If the utility of the LNR is validated in other studies, it may replace the use of absolute number of axillary lymph nodes.     

Prognostic significance of PAI-1 and uPA in cytosolic extracts obtained from node-positive breast cancer patients

Cancer cell invasion is accomplished by the concertedaction of several extracellular proteolytic enzyme systems, oneof which is the urokinase plasminogen activation system.The different components of this system, e.g. urokinaseplasminogen activator (uPA), its receptor uPAR, as wellas its main inhibitor plasminogen activator inhibitor type1 (PAI-1) have all been shown to haveprognostic value in breast cancer, i.e. high tumorlevels are associated with a poor prognosis.In orderto further substantiate the prognostic value of uPAand PAI-1, we have tested the cutpoints (medianvalues and optimized cutpoints) from our first study(Cancer Res 53: 2513–2521, 1993) in an independentgroup of breast cancer patients. Breast cancer cytosolsfrom 100 premenopausal and 150 post-menopausal node positivepatients were included. The median observation time was80 months (range 49–145). Univariate analysis showed thathigh PAI-1 levels (above the median PAI-1 value)were significantly associated with short recurrence-free survival (RR:1.65; 95% CI: 1.04–2.63; P=0.03) andshort overall survival (RR: 2.46; 95% CI: 1.52–3.96;P=0.0001) in postmenopausal patients. Postmenopausal patientswith high uPA levels (above the median uPAvalue) had a significantly shorter recurrence-free survival (RR:2.04; 95% CI: 1.17–3.56; P=0.01) andoverall survival (RR: 2.07; 95% CI: 1.16–3.70; P= 0.01) than patients with low uPA values.Nearly identical results were obtained when using theoptimized PAI-1 or uPA value.In a Cox multivariateanalysis which included other established prognostic factors, highPAI-1 was found to be an independent prognosticvariable predicting short overall survival with a relativerisk of 2.27 in postmenopausal women, and highuPA was found to be an independent prognosticvariable predicting short recurrence-free survival with a relativerisk of 1.86 in postmenopausal women. The presentstudy indicates that uPA and PAI-1 are independentand significant prognostic variables in subsets of breastcancer patients.     

Prognostic value of cytosolic p53 protein in breast cancer.

The prognostic value of cytosolic p53 protein was evaluated in 458 operable breast carcinomas by immunoblotting using the monoclonal antibody PAb 1801. Two hundred and five carcinomas (45%) showed positive p53 accumulation and 55% were p53 negative. When comparing p53 positivity and other clinicopathological parameters, significant differences were found with younger age (p = 0.017), premenopausal status (p = 0.003), increasing tumor size (p = 0.026), negative estrogen receptor (p = 0.003) and negative progesterone receptor (p = 0.047), but not with histologic grade, axillary lymph node status, stage or erbB-2 expression. With a median follow-up of 34 months (range 3-70), relapse has occurred in 73 patients. Disease-free survival curves showed that patients with p53-positive tumors had a significantly shorter disease-free survival than patients with p53-negative carcinomas (log-rank test, p = 0.027). A multivariate analysis of disease-free survival showed that p53, tumor size, histologic grade and progesterone receptor had significant independent prognostic value. The immunoblotting technique was controlled with p53 immunohistochemistry in 94 paired samples. We obtained a statistically significant correlation (p = 0.0004) between the two methods. Our results show that the immunoblotting technique offers an alternative approach in evaluating the p53 status of breast biopsy material using cytosolic extracts, and confirm that p53 accumulation is a significant independent indicator of a poor prognosis in operable breast carcinoma.     

保乳术后放疗对乳腺癌局部淋巴结转移患者预后的影响

  目的  探讨术后放疗(post-mastectomy radiation therapy, PMRT)对局部淋巴结阳性行保乳手术的乳腺癌患者预后的影响, 针对不同的pN分期以及淋巴结转移率(lymph node ratio, LNR)提出更具针对性的术后放疗方案。  方法  回顾性分析天津医科大学肿瘤医院1998年2月至2007年3月152例行保乳手术并有局部淋巴结转移的原发浸润性乳腺癌患者的临床病理资料, 比较LNR和pN分期对患者预后的指导意义, 并在LNR基础上, 根据PMRT与否比较无病生存期(disease-free survival, DFS)和总生存期(overall survival, OS)。  结果  152例患者被分为pN1(114例)、pN2(23例)、pN3(15例), 其中LNR < 0.21为114例, 位于0.21~0.65为26例, >0.65为12例。单因素分析显示淋巴结切检总数、pN、LNR、雌激素受体(estrogen receptor, ER)状态、孕激素受体(progesterone receptor, PR)状态、放疗与否均与DFS、OS具有相关性(P < 0.05), 诊断年龄和化疗方案仅与OS具有相关性(P < 0.05)。多因素分析显示, LNR、PMRT依然是DFS、OS的独立预测指标(P < 0.05), 而pN差异无统计学意义(P>0.05);分组分析时仅在LNR < 0.21术后放疗对预后的影响差异有统计学意义。  结论  LNR作为一个独立预测指标, 可用于评价行保留乳房手术治疗发生淋巴结转移的乳腺癌患者的预后。针对不同的LNR分级, 需要进一步细化PMRT的适应症。      

Prognostic value of epidermal growth factor receptor in node-positive breast cancer

Summary The prognostic significance of EGFR (epidermal growth factor receptor) was studied in a cohort of 68 node-positive patients with breast cancer, who entered a controlled protocol of adjuvant therapy between February 1980 and June 1984. EGFR radioligand binding assay was carried out on frozen stored samples. Twenty five (37%) of 68 primary sites and 9 (41%) of 19 lymph node metastases assayed were EGFR-positive with a cut off value of 5 fmol/mg membrane protein; there is no statistical difference between the two distributions. EGFR was significantly correlated to ER and histological grade. EGFR-positive tumors and high levels of EGFR were mainly found in the ER-negative group of tumors (p = 0.008) and in histological grade III (p = 0.007). Fifty five patients could be followed for 40 to 92 months. EGFR was an independent prognostic factor for survival after 40 months (p = 0.05). EGFR⁺/ER^– patients had the lowest survival probability, but statistical significance was not reached (p = 0.06). The EGFR phenotype appeared as a prognostic parameter in node-positive patients, individualizing subgroups of patients with different early outcome, with potential therapeutic implication especially in the group of ER-negative patients. These results emphasize the need for a standardized assay methodology and for further clinical studies, particularly in protocols where adjuvant hormonal therapy is prescribed on the basis of steroid hormone receptor status, in order to assess the respective prognostic worth of EGFR and ER (or PR).     

Prognostic value of protein tyrosine kinase 6 (PTK6) for long-term survival of breast cancer patients

The cytoplasmic tyrosine kinase PTK6 (BRK) shows elevated expression in approximately two-thirds of primary breast tumours, and is implicated in EGF receptor-dependent signalling and epithelial tumorigenesis. Using immunohistochemistry, we performed a retrospective study on 426 archival breast cancer samples from patients with long-term follow-up and compared the protein expression levels of PTK6, the HER receptors, Sam68 (a substrate of PTK6), and signalling proteins including MAP kinase (MAPK), phosphorylated MAPK (P-MAPK), and PTEN. We show that PTK6 expression is of significant prognostic value in the outcome of breast carcinomas. In multivariate analysis, the disease-free survival of patients of >or=240 months was directly associated with the protein expression level of PTK6 (P相似文献   

Prognostic factors in node-positive operable breast cancer patients receiving adjuvant chemotherapy

Summary A retrospective analysis of prognostic factors in 214 consecutive node-positive (N+) operable breast cancer patients, receiving Melphalan+5-fluorouracil adjuvant chemotherapy between 1980 and 1984 was performed. Median follow-up was 95 months. Actuarial disease-free interval (DFI) and survival (S) were determined according to age, menopausal status, histology, size of primary tumor (T), multifocality, tumor location, hormonal receptor status, number of N+, size of N+, tumor spread in axillary fat, and interval between surgery and onset of adjuvant chemotherapy.On univariate analysis two factors were prognostic for DFI and S: number of N+and T size. A comparison between traditionally classified T1 and T2 patients revealed no signifciant difference, but when the cut-off point was shifted from 2 cm to 3 cm, T size represented a highly significant prognostic factor. In patients with T3 cm 5-year DFI was 54% and 5-year S was 76%, while in patients with T>3 cm the respective values were 23% (p<0.001) and 41% (p<0.001). These significant DFI and S differences persisted after adjustment for number of N+ by bivariate analysis.Multivariate analysis supported the importance of T>3 cm as a strong adverse predictor. Four adverse variables, T>3 cm, number of N+4, multifocality, and tumor spread in axillary fat were used to divide our patients into three subsets with significantly different DFI: Group I, with none of the above factors; Group II, with only one factor present; and Group III, with more than one factor present (5 years DFI 66%, 45%, and 21%, respectively; p<0.001).     

Prognostic impact of cyclin-dependent kinase inhibitor p27kip1 in node-positive breast cancer

BACKGROUND AND OBJECTIVES: p27kip1 (p27) plays an important role as a negative regulator of cell cycle-dependent kinase activity during progression of the cell cycle. The most important prognosticator of breast cancer is nodal status, and the aim of this study was to determine the prognostic implication of p27 in breast cancer patients with lymph node metastases. METHODS: Immunohistochemical staining for p27 was performed on tissues from 102 patients with node-positive breast cancer. RESULTS: A nuclear staining over 50% was defined as high expression. High expression of p27 was shown in 59 patients (57.8%). A significant correlation was found between high p27 and positive estrogen receptor status, but there was no correlation between p27 staining and age, menopausal status, nodal status, or tumor size. Low expression of p27 was significantly associated with shorter survival. A multivariate analysis also showed that the only independent variable was p27. CONCLUSIONS: The results indicated that low expression of p27 was an independent factor associated with poor prognosis. Therefore, p27 can be an important tool in making therapeutic decisions.     

Prognostic value of thymidine kinase in cancer of the breast

We have measured by a radioenzymatic assay the thymidine kinase in the cytosol of 182 primary infiltrating breast cancers. Maximal follow-up is 95 months. Thymidine kinase was found to be related to SBR grade, tumour size and absence of oestradiol receptors (RE). Univariate analysis has pointed out a significant linkage between overall or metastase free survival and thymidine kinase, using a cut-off level of 80 mU/mg protein which is the most discriminating value. Thymidine kinase appeared to be particularly useful in lymph-node-positive, RE-negative and grade 3 patients. Multivariate analysis of the overall survival and of the metastase free survival (Cox model) revealed that they were strongly related to thymidine kinase status.     

淋巴结转移率评价腋窝淋巴结转移的保乳治疗乳腺癌患者预后的价值

目的 探讨淋巴结转移率(LNR)评价接受保留乳房治疗(BCT)并发生腋窝淋巴结转移的乳腺癌患者的预后是否优于pN分期.方法 回顾性分析1998-2007年间152例接受BCT并发生腋窝淋巴结转移的原发浸润性乳腺癌患者的临床资料,比较LNR和pN分期评价乳腺癌患者无病生存率和总生存率的价值.结果 152例患者中,pN1期114例,pN2期23例,pN3期15例.LNR≤0.20者114例,LNR为0.21～0.65者26例,LNR＞ 0.65者12例.单因素分析显示,淋巴结切检总数、pN分期、LNR、雌激素受体状态、孕激素受体状态、放疗均与患者的无病生存率和总生存率有关(均P ＜0.05);诊断年龄和化疗方案仅与患者的总生存率有关(均P＜0.05).多因素分析显示,LNR为影响患者无病生存率和总生存率的独立因素(均P ＜0.05),而pN分期与患者的无病生存率和总生存率无关(均P ＞0.05).在不同pN分期中,LNR也与患者的预后有关.结论 在评价接受BCT、发生淋巴结转移的乳腺癌患者预后时,LNR作为一个独立的预测指标,更优于pN分期.     

Prognostic and predictive value of thymidine phosphorylase activity in early-stage breast cancer patients

The antitumor effects of 5-fluorouracil (5-FU) and its derivatives depend upon the activity of nucleoside metabolic enzymes in tumor tissues. Thymidine phosphorylase (TP) converts 5'-deoxy-5-fluorouridine (5'-DFUR), an intermediate metabolite of capecitabine, to 5-FU. The relationship between TP expression in tumor tissues and patient survival was retrospectively examined in early-stage breast cancer patients treated with either oral 5'-DFUR administered for 6 months or surgery alone in a prospective randomized controlled trial. Thymidine phosphorylase expression in tumor cells and tumor-associated stromal (TAS) cells was examined by immunohistochemistry in 650 tissue samples from patients in this trial (n = 1217). Eight-year follow-up data showed that high TP expression in tumor cells was a significant prognostic indicator of a favorable outcome only for the patients in the 5'-DFUR group. Thus, TP expression was shown to be a predictive factor of 5'-DFUR efficacy. Conversely, a low TP expression in TAS cells was also a potent favorable prognostic indicator. These results on TP status in 2 tumor cell types could provide novel information for predicting prognosis for a patient subgroup, which would receive a probable therapeutic effect from 5'-DFUR, and presumably, from adjuvant therapy of capecitabine in early-stage breast cancer. Determination of TP status might also identify a patient subgroup whose prognosis is quite favorable even without adjuvant therapy. Further investigations on prognostic and predictive implications of TP activity in a clinical setting are warranted.     

Prognostic value of breast cancer aromatase.

The estrogen receptor, progesterone receptor, and intratumoral aromatase content of 127 breast carcinomas were determined. Patients whose tumor contained either estrogen or progesterone receptors had a longer disease-free interval, but no difference in survival was observed. Measurable aromatase activity was detected in 78 of 113 (69%) tumors. There was no relationship between aromatase activity and disease-free interval or survival.     

Prognostic relevance of receptor tyrosine kinase expression in breast cancer: A meta-analysis

Background

Receptor tyrosine kinases (RTKs) may facilitate tumor progression if activated aberrantly. The prognostic impact of human epidermal growth factor receptor 2 (HER2) overexpression and effectiveness of its therapeutic targeting is well established, but the effects on prognosis of overexpression of other RTKs is unknown. Here we evaluate the association of RTK expression and survival in breast cancer.

Methods

PubMed was searched to identify studies evaluating the association between expression of RTKs other than HER2 and survival of women with breast cancer. Published data were extracted and computed into odds ratios (OR) for death at 5 years with 95% confidence intervals (CI). Data were pooled in a meta-analysis using the Mantel–Haenszel random-effect model. For studies reporting data for more than one RTK the lowest and highest OR were used for separate analyses.

Results

Sixteen studies comprising 11,056 patients were included in the analysis. There was an association between overexpression of RTKs and decreased 5-year OS and this was highly significant when using highest ORs from studies reporting more than one RTK (OR = 2.42; 95% CI = 1.92–3.06, P < 0.001). Similar results were observed for 5-year BCSS. Worse OS was seen with overexpression of fibroblast growth factor receptor 2/3 (FGFR) (OR = 3.81; 95% CI = 1.79–8.11) and epidermal growth factor receptor (EGFR)/HER1 (OR = 2.45; 95% CI = 1.90–3.15).

Conclusion

Overexpression of various RTKs is associated with poor outcomes. This data suggests the clinical evaluation of combination of agents against RTKs or relevant oncogenic nodes.     

Prognostic value of circulating soluble E-selectin concentrations in node-negative breast cancer patients.

Several studies have suggested that endothelial cells participate in tumor development. Soluble E-selectin (sE-selectin) is specifically released by activated endothelial cells, and its serum concentration can be considered a marker of endothelial activation. In this study, we assessed the prognostic value of sE-selectin concentrations in node-negative breast cancer patients. Serum sE-selectin concentrations were measured by an ELISA method prior to surgery in 456 node-negative breast cancer patients. We analyzed also tumor size (TS), histoprognostic grading, and steroid hormone receptor status. The mean sE-selectin concentration was 24.9 +/- 15.0 ng/ml. The sE-selectin concentrations were mildly correlated with the TS but not with the other factors. For prognostic analyses, the median follow-up duration was 7.5 years. The cutoff sE-selectin concentration used was 40 ng/ml. In overall survival studies, univariate analyses demonstrated a prognostic value of sE-selectin, TS, and histoprognostic grading, and multivariate analyses demonstrated a prognostic value of sE-selectin and TS. For disease-free survival, univariate and multivariate analyses demonstrated a prognostic value of sE-selectin and TS. sE-selectin concentration is an easily measurable and strong prognostic factor in node-negative breast cancer patients. These results provide further evidence for the role of adhesion molecules expression by endothelial cells in tumor progression.     

双侧腹股沟淋巴结转移对淋巴结阳性阴茎癌预后评估的价值

目的探讨双侧腹股沟淋巴结转移在淋巴结阳性阴茎癌预后评估中的价值。方法回顾性分析60例淋巴结转移阳性阴茎鳞状细胞癌患者资料。所有患者均接受区域淋巴结清扫手术。Kaplan-Meier法绘制无复发生存曲线并通过Log—rank检验加以分析,COX回归模型进行多因素生存分析。结果60例患者中18例有双侧腹股沟淋巴结转移,其3年无复发生存率（26．7％）显著低于单侧腹股沟淋巴结转移患者（65．3％）,差异有统计学意义（x^2=10．6,P=0．001）。经多因素生存分析,阳性淋巴结数目和双侧腹股沟淋巴结转移均是独立的生存预后因素（均P〈0．05）。生存曲线比较显示双侧腹股沟淋巴结转移且阳性淋巴结数〉2个的患者预后差。结论在考虑了淋巴结阳性阴茎癌阳性淋巴结数目的影响后,双侧腹股沟淋巴结转移仍是其重要预后指标。     

Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients.

Urokinase-type plasminogen activator (uPA) may be responsible for the invasive and metastasizing capacity of tumor cells. Evidence has been presented that primary breast cancer patients with tumors containing high levels of uPA experience a worse prognosis. In the present study we have assessed uPA status in routinely prepared cytosols of 671 primary human breast tumors and have evaluated its association with disease-free and overall survival. Isotonic regression analysis with length of disease-free survival as an end point revealed 1.15 ng/mg protein as the best cutoff point to discriminate between uPA positive (32% of the tumors) and uPA negative. In both Cox univariate and multivariate regression analysis (including also patient's age, menopausal status, lymph node status, and the number of positive lymph nodes, tumor size, and estrogen and progesterone receptor status), uPA positivity was significantly associated with increased rates of relapse and death. Corrected for all relevant factors in multivariate analyses for subgroups of patients, uPA positivity was significantly associated with an increased relapse rate in the subgroups of node-negative (P = 0.002; relative failure rate, 2.33), node-positive (P < 0.0001; relative failure rate, 1.95), postmenopausal (P < 0.0001; relative failure rate, 2.59), and steroid receptor-positive patients (P < 0.0001, relative failure rate, 2.76). We conclude that uPA positivity of human primary breast tumors is an important independent variable for the identification of patients at high risk for recurrence, also in clinically important subgroups of patients.     

Prognostic value of p53 for local failure in mastectomy-treated breast cancer patients.

PURPOSE: The loss of p53 function is a recognized adverse prognostic factor in invasive breast cancer. Several studies have shown a relationship between the nuclear accumulation of p53 protein (a surrogate marker of p53 inactivation) and poor disease-free and overall survival. In general, however, these studies did not report the prognostic value of p53 for local failure, which we have therefore assessed retrospectively here. MATERIALS AND METHODS: Accumulation of p53 protein was evaluated by immunohistochemistry in 1,530 mastectomy-treated breast cancer patients (259 radiation therapy [RT]- and 1,271 mastectomy only [No RT]-treated patients). Statistical comparisons were made between p53 protein accumulation, estrogen/progesterone receptors, nodal status, tumor size, and local failure rate (LFR). Local failure was defined as tumor recurrence involving the chest wall and/or the ipsilateral supraclavicular/axillary lymph nodes. The median follow-up period was 62 months. RESULTS: In the No RT group, the LFR was 9.1% and 16. 5% in p53-negative and p53-positive patients, respectively (P<.001). Multivariate analysis revealed that p53 protein accumulation was significantly associated with an increased risk of local relapse (relative risk [RR], 1.7; 95% confidence interval [CI], 1.2 to 2.4). Nodal status and tumor size were also significant factors. In the RT group, the LFR was 9.3% and 21.5% in p53-negative and p53-positive patients, respectively (P = .009). Multivariate analysis revealed that p53 protein accumulation was significantly associated with an increased risk of local relapse (RR, 2.5; 95% CI, 1.1 to 5.7), as was nodal status. CONCLUSION: Nuclear accumulation of p53 protein is independently associated with a significantly increased local failure rate in breast cancer patients treated with mastectomy, with or without radiation.