Carbonic anhydrase XII is a marker of good prognosis in invasive breast carcinoma

Hypoxia and pH influence gene expression in tumours, and it is becoming increasingly clear that the pattern of genes expressed by a tumour determines its growth and survival characteristics. Hypoxia-inducible factor-1 (HIF-1) is a key mediator of the cellular response to hypoxia and high HIF-1 expression has been identified as a poor prognostic factor in tumours. Recently, we identified the tumour-associated carbonic anhydrases (CA), CA9 and CA12 as hypoxia-inducible in tumour cell lines. Furthermore, we identified CA IX to be a poor prognostic factor in breast cancer. The aim of this study was to assess the prognostic significance of CA XII. CA XII expression was studied by immunohistochemistry in a series of 103 cases of invasive breast cancer and any association with recognised prognostic factors or relation with the outcome was examined. CA XII expression was present in 77 out of 103 (75%) cases and was associated with lower grade (P=0.001), positive estrogen receptor status (P<0.001), and negative epidermal growth factor receptor status (P<0.001). Furthermore, although CA XII expression was associated with an absence of necrosis (P<0.001), expression of CA XII in some high-grade tumours was induced in regions directly adjacent to morphological necrosis. Additionally, using univariate analysis, CA XII positive tumours were associated with a lower relapse rate (P=0.04) and a better overall survival (P=0.01). In conclusion, CA XII expression is influenced both by factors related to differentiation and hypoxia in breast cancer in vivo and CA XII expression is associated with a better prognosis in an unselected series of invasive breast carcinoma patients.     

Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma.

PURPOSE: To assess the frequency of expression and the prognostic significance of a hypoxia-regulated marker, carbonic anhydrase IX (CA IX), in a cohort of patients with invasive breast cancer. PATIENTS AND METHODS: CA IX expression was evaluated by immunohistochemistry with a murine monoclonal antibody, M75, in a series of 103 women treated surgically for invasive breast cancer. The majority of patients were treated with adjuvant hormonal or chemotherapy. The frequency of CA IX expression, its association with recognized prognostic factors, and the relationship with outcome was evaluated by univariate and multivariate statistical analyses. RESULTS: CA IX expression was present in 49 (48%) of 103 cases. The level of CA IX expression was found to be significantly associated with tumor necrosis (P <.001), higher grade (P =.02), and negative estrogen receptor status (P <.001). Furthermore, CA IX expression was associated with a higher relapse rate (P =.004) and a worse overall survival (P =.001). By multivariate analysis, CA IX was also shown to be an independent predictive factor for overall survival (hazard ratio, 2.61; 95% confidence interval, 1.01 to 6.75, P =.05). CONCLUSION: CA IX expression was associated with worse relapse-free survival and overall survival in an unselected cohort of patients with invasive breast carcinoma. The potential role of CA IX as a marker of hypoxia within breast carcinomas was also indicated by a significant association with necrosis. Further work assessing its prognostic significance in breast cancer is warranted, particularly interactions with radiotherapy and chemotherapy resistance.     

Hypoxia inducible factor-1alpha is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response

Hypoxia is common in many solid tumours, including breast cancer. Hypoxia triggers the expression of hypoxia inducible factor-1alpha (HIF-1alpha), and HIF-1alpha has been associated with an impaired prognosis in breast cancer and down-regulation of the oestrogen receptor (ER), potentially affecting the treatment efficiency of antioestrogens. The role of HIF-1alpha regarding prognostic and treatment predictive information in breast cancer has not been established and we therefore analyzed HIF-1alpha using immunohistochemistry in a cohort of 377 premenopausal stage II breast cancers arranged in a tissue microarray. The patients were included in a randomized trial with either 2 years of tamoxifen or no adjuvant treatment. The tamoxifen treatment effect could be studied in subgroups of breast cancer and pure prognostic information could be scrutinized for untreated control patients. HIF-1alpha was scored as positive in 24% of the tumours and correlated positively to tumour size, Nottingham histological grade (NHG), Ki-67, Her2 and cyclin E expression and negatively to lymph node status, cyclin D1, ER and PR (progesterone receptor) expression. Surprisingly, there was no difference in tamoxifen response for patients with high or low HIF-1alpha expressing tumours. In lymph node-positive patients as well as NHG 1/2 tumours, high HIF-1alpha protein expression was significantly associated with an impaired recurrence-free survival (p=0.014, 0.018). When analyzing the subgroup of NHG 1/2 tumours, a high HIF-1alpha expression was the only independent significant prognostic marker in multivariate analysis, including standard prognostic markers, suggesting that HIF-1alpha might be a useful prognostic marker in this subgroup of breast cancer, with a rather good but diverse prognosis.     

p27 expression as a prognostic factor of breast cancer in Taiwan.

p27Kip1 is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors. It binds to a variety of cyclin/CDK complexes, inhibits kinase activity, and blocks the cell cycle. Absent or reduced p27 expression has been shown to be a significant predictor of poor survival in breast, colorectal, prostate, non-small cell lung and esophagus carcinomas. An immunohistochemical assay was performed on 169 patients with primary breast cancers to evaluate the biologic significance of p27 expression. Decreased p27 expression was significantly associated with high grade (P = 0.00025), negative estrogen receptor (P = 0.00004), and negative progesterone receptor (P = 0.0038) breast cancers. Univariate analysis reveals that p27 expression inversely correlated significantly with overall survival (P = 0.0001). By multivariate analysis, p27 predicted the overall survival independently (P = 0.0096). Our study indicates that p27 expression is an independent prognostic marker of breast cancer in Taiwan.     

乳腺癌中HES1的表达情况及与生存预后的相关性

目的:研究HES1在乳腺癌中的表达情况,探讨其与乳腺癌生存预后的关系。方法:采用免疫组化及Western blot检测了HES1在115例乳腺癌中的表达情况,应用Kaplan-Meier生存统计学方法分析HES1与乳腺癌生存预后的相关性。结果:在乳腺癌中,HES1阳性表达与TNM高分期（P=0.003）、淋巴结转移(P=0.043)、ER阴性(P=0.001)、PR阴性(P=0.042)及三阴性类型(P=0.001)均呈显著的相关性。此外,115例乳腺癌中HES1阳性表达组其无进展生存期（P=0.005）和总生存期（P=0.001）明显少于HES1阴性表达组。结论:HES1可能是乳腺癌的一个独立预后指标。     

Higher Ki67 Expression is Associates With Unfavorable Prognostic Factors and Shorter Survival in Breast Cancer

Background: The prognostic value of the Ki67 expression level is yet unclear in breast cancer. The aim of thisstudy was to investigate the association between Ki67 expression levels and prognostic factors such as grade, Her2and hormone receptor expression status in breast cancers. Materials and Methods: Clinical and pathologicalfeatures of the patients with breast cancer were retreived from the hospital records. Results: In this study, 163patients with breast cancer were analyzed, with a mean age of 53.4±12.2 years. Median Ki67 positivity was 20%and Ki67-high tumors were significantly associated with high grade (p<0.001), lymphovascular invasion (p=0.001),estrogen receptor (ER) negativity (p=0.035), Her2 positivity (p=0.001), advanced stage (p<0.001) and lymphnode positivity (p<0.003) . Lower Ki67 levels were significantly associated with longer median relapse-free andoverall survival compared to those of higher Ki67 levels. Conclusions: High Ki67 expression is associated withER negativity, Her2 positivity, higher grade and axillary lymph node involvement in breast cancers. The levelof Ki67 expression is a prognostic factor predicting relapse-free and overall survival in breast cancer patients.     

Prognostic relevance of basal cytokeratin expression in operable breast cancer

OBJECTIVE: We investigated whether basal cytokeratin (CK5/6 or CK17) expression had an impact on survival in patients with operable breast cancer. METHODS: Expression of CK5/6 or CK17 was analyzed by immunohistochemistry in 195 women with breast cancer. RESULTS: In total, 72 (37%) tumor samples were regarded as being positive for CK5/6 or CK17. The basal-like phenotype as defined by basal cytokeratin expression, lack of estrogen receptor (ER) and absence of HER2 overexpression was found in 48 (25%) cases. Positive staining for CK5/6 or CK17 was associated with worse prognosis when compared with patients negative for basal cytokeratins in all cases (5-year cancer-specific survival rate 59.4 vs. 77.5%, p = 0.0273) and in the node-negative group (70.5 vs. 90.8%, p = 0.0208) but not in the node-positive group (43.9 vs. 65.4%, p = 0.1182). To determine the real prognostic value of basal cytokeratins, survival in a group of ER-negative patients was analyzed depending on CK5/6 or CK 17 expression. No influence on survival was observed. The outcome of patients whose cancers were positive for cyclin E regardless of ER status was not changed by CK5/6 or CK17 expression. In multivariate analysis, independent prognostic factors affecting survival in the whole group included: nodal involvement, HER2 status and cyclin E expression. Neither ER status nor basal cytokeratin expression retained statistical significance. CONCLUSION: We demonstrated that the poor prognosis associated with the basal-like phenotype of breast cancer was determined by ER absence and cyclin E expression and not by CK5/6 or CK17 expression.     

Expression of carbonic anhydrase IX in astrocytic tumors predicts poor prognosis.

PURPOSE: Carbonic anhydrase IX (CA IX) is a hypoxia-inducible enzyme, which is associated with neoplastic growth. Ectopic CA IX expression has been observed in several tumors, whose normal counterparts do not express this enzyme. Normal human brain tissue shows only slight or no expression of CA IX.EXPERIMENTAL DESIGN: We describe CA IX expression in human diffusely infiltrating astrocytomas. The association of CA IX is evaluated with clinicopathologic and molecular factors including cell proliferation and apoptosis as well as the expression of p53 and epidermal growth factor receptor.RESULTS: CA IX immunopositivity was observed in 284 cases of 362 (78%) tumors. The positive areas were often located in close proximity to necrotic regions (P < 0.001). The CA IX immunoreactivity showed strong association with tumor malignancy grades (P < 0.0001). CA IX showed no association with p53 expression nor did it correlate with epidermal growth factor receptor-amplification, apoptosis, or cell proliferation. CA IX intensity had significant prognostic value in univariate (P=0.0011, log-rank test) and multivariate survival analysis (P = 0.038, Cox analysis).CONCLUSIONS: CA IX expression is common in diffusely infiltrating high-grade astrocytomas. Our results suggest that CA IX is a useful biomarker for predicting poor prognosis of astrocytic tumors. It may also be a promising target molecule for the improvement of therapeutic interventions in astrocytomas.     

PIK3CA基因突变与乳腺癌恶性程度和预后的关系

目的 研究PIK3CA基因突变与乳腺癌患者预后的相关性.方法 采用聚合酶链反应(PCR)和荧光-单链构像多态性分析法(F-SSCP)检测250例乳腺癌组织中PIK3CA基因7、9、20号外显子突变情况,及其与患者临床病理特征和预后进行的关系.结果 250例乳腺癌组织中,PIK3CA基因突变者88例(35.2%),其中7号外显子突变8例(3.2%),9号外显子突变者40例(16.0%),20号外显子突变者47例(18.8%).PIK3CA基因突变率与患者年龄、淋巴结转移、肿瘤分型、分化程度、染色体倍数性、人表皮生长因子受体2(HER-2)表达及TP53突变无明显相关性(P＞0.05),与肿瘤大小、雌激素受体(ER)和孕激素受体(PR)表达有相关性(P＜0.05).PIK3CA基因突变的乳腺癌患者生存时间显著降低(P=0.004),尤其是ER阳性和HER-2阴性的患者(均P=0.002).结论 PIK3CA基因突变可能在乳腺癌的发生、发展中起重要作用,而且与肿瘤大小、ER表达情况及生存率有关,可作为判断乳腺癌恶性程度及预后的一个独立的分子生物学指标.

Abstract：

Objective The phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway is considered to play an important role in tumorigenesis. Frequent somatic mutations in the PI3K subunit pl 10a (PIK3CA) occur in a variety of cancer types. The purpose of this study was to determine the relationship between PIK3CA mutation in breast cancer and pathological features and outcome of patients. Methods The PIK3CA mutations in exons 7, 9, 20 were screened in 250 primary breast cancers using PCR and fluorescent ( F)-SSCP, and the results were analyzed according to their cliniopathological data. Results The frequency of PIK3CA mutations among the 250 cases was 35.2% (88/250), point mutations in exon 7 were found in 8 (3.2%) cases,40 (16.0%) cases in exon 9 and 47 (18. 8%) cases in exon 20. No significant correlation between PIK3CA mutation and age, histological type, differentiation, and lymph node metastasis was observed. Mutations were associated with larger tumor size ( P = 0. 004) and positive estrogen receptor status (P =0.008). Patients with PIK3CA mutations showed a significantly worse survival (P = 0. 004),particularly in those with positive estrogen receptor expression or non-amplified HER-2 ( both P = 0. 002).Conclusions PIK3CA mutations may play an important role in the carcinogenesis and development of breast cancer. The association with large tumor size, ER + and poor survival indicates that PIK3CA mutation could be an independent factor for tumor malignant phenotype and prognosis.     

Hypoxia-regulated carbonic anhydrase IX expression is associated with poor survival in patients with invasive breast cancer

Tumour hypoxia is a microenvironmental factor related to poor response to radiation, chemotherapy, genetic instability, selection for resistance to apoptosis, and increased risk of invasion and metastasis. Hypoxia-regulated carbonic anhydrase IX (CA IX) has been studied in various tumour sites and its expression has been correlated with the clinical outcome. The purpose of this study was to investigate the correlation of CA IX expression with outcome in patients with invasive breast cancer. We conducted a retrospective study examining the effects of carbonic anhydrase IX (CA IX) on survival in patients with breast cancer. To facilitate the screening of multiple tissue blocks from each patient, tissue microarrays were prepared containing between two and five representative samples of tumour per patient. Immunohistochemistry was used to examine expression of CA IX in patients with breast cancer. The study includes a cohort of 144 unselected patients with early invasive breast cancer who underwent surgery, and had CA IX expression and follow-up data available for analysis. At the time of analysis, there were 28 deaths and median follow-up of 48 months with 96% of patients having at least 2 years of follow-up. CA IX was negative for 107 patients (17 deaths) and positive for 37 patients (11 deaths). Kaplan-Meier survival curves show that survival was superior in the CA IX-negative group with a 2-year survival of 97% for negatives and 83% for positives (log-rank test P=0.01). Allowing for potential prognostic variables in a Cox regression analysis, CA IX remained a significant independent predictor of survival (P=0.035). This study showed in both univariate and multivariate analysis that survival is significantly inferior in patients with tumour expressing CA IX. Prospective studies are underway to investigate this correlation in clinical trial setting.     

p27Kip1 is a predictive factor for tamoxifen treatment response but not a prognostic marker in premenopausal breast cancer patients

The cell-cycle regulating protein p27(Kip1) (p27) has dual roles by acting as both a cdk inhibitor and as an assembly factor for different cdk complexes. Loss of p27 has been linked to malignant features in tumours; however, the exact role of p27 deregulation in breast cancer regarding prognostic and treatment predictive information has not been fully clarified. We have evaluated p27 expression in 328 primary, Stage II breast cancers from premenopausal patients who had been randomised to either tamoxifen treatment or no adjuvant treatment after surgery. p27 was associated with the oestrogen receptor and cyclin D1, and p27 downregulation was associated with high proliferation. There was no association between recurrence-free survival (RFS) and p27 (HR = 0.800, 95% CI 0.523-1.222, p = 0.300), indicating that p27 is not a prognostic marker. The predictive value of p27 was analysed by comparing RFS in tamoxifen-treated and untreated patients in subgroups of low and high p27 expression (HR = 0.747, 95% CI 0.335-1.664, p = 0.474 and HR = 0.401, 95% CI 0.240-0.670, p < 0.001, respectively). Only patients with p27-high tumours benefited from tamoxifen (multivariate interaction analysis p = 0.034). Our study suggests that p27 downregulation is associated with tamoxifen resistance in premenopausal breast cancer but is not linked to impaired prognosis.     

PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer.

PURPOSE: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3'-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer. EXPERIMENTAL DESIGN: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors. RESULTS: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor(+), small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction. CONCLUSIONS: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.     

Combined evaluation of expressions of cyclin E and p53 proteins as prognostic factors for patients with gastric cancer.

BACKGROUND: There is a lack of consistency regarding the prognostic value of cyclin E overexpression in gastric cancer (gastric cancer). Our aim was to report on this overexpression and to analyze its correlations with the clinicopathologic variables. Another aim was to examine if aberrant expression of both cyclin E and p53 might increase the malignant potential of gastric cancer. METHODS: Specimens from 89 patients with gastric cancer treated with "curative" intent were evaluated for cyclin E and p53 expressions using immunohistochemical method. The correlations between cyclin E overexpression alone or in combination with p53 expression and the patient's clinicopathologic variables were analyzed. RESULTS: Cyclin E overexpression and p53 expression were shown in 35 (39.3%) and 46 (51.7%) tumors, respectively. The incidence of cyclin E overexpression was significantly higher in deeply invasive cancers (P < 0.0001), in cancers with lymph node metastasis (P = 0.003), and in cancers with advanced stages (P < 0.0001). There were no significant correlations with other clinicopathologic variables. Patients in whom their tumors showed cyclin E overexpression alone or in combination with p53 survived less than patients with negative cyclin E tumors. Multivariate analysis revealed that combined cyclin E overexpression and p53 expression was significantly associated with poor survival after adjusting for other variables (hazard ratio, 3.12; P = 0.009). CONCLUSIONS: Cyclin E overexpression is a common event in gastric cancer. Gastric cancer with cyclin E overexpression exhibit increased aggressiveness in the presence of aberrant p53. The combination of cyclin E overexpression with the p53 expression in gastric cancer further distinguished a subgroup of patients with poor prognosis.     

Carbonic anhydrase IX in early-stage non-small cell lung cancer.

PURPOSE: Tumor hypoxia is associated with poor prognosis and increased tumor aggressiveness. Carbonic anhydrase (CA) IX, an endogenous marker for tumor hypoxia, catalyzes the hydration of carbon dioxide into carbonic acid and contributes to the pH regulation of tumor cells. Therefore, CA IX might allow tumors to acclimate to a hypoxic microenvironment, promoting tumor cell proliferation. We hypothesized that CA IX expression is related to tumor cell proliferation and poor disease-free survival in patients with early-stage non-small-cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: CA IX expression was measured in 75 resected NSCLC tumors to assess prognostic implications for disease-free survival. The relationship of CA IX expression with microvessel density (MVD) and proliferation (Ki-67) index was assessed via colocalization analysis. RESULTS: All patients had operable NSCLC (stage I, 58; stage II, 17). CA IX expression was present in 54 (72%) of 75 patients and was associated with tumor necrosis (P < 0.05). CA IX-positive tumor areas showed greater cell proliferation as measured by Ki-67 index (P < 0.05) and less MVD (P < 0.05) than did CA IX-negative areas in colocalization analysis. The percentage of CA IX-positive tumor cells was significantly related to postoperative recurrence and poor disease-free survival (P < 0.05). Ki-67 index and pathologic stage were also independent prognostic factors for worse disease-free survival (P < 0.05). CONCLUSIONS: CA IX expression of tumor cells may be an indicator for poor disease-free survival in early-stage NSCLC.     

Carbonic anhydrase IX as a marker for poor prognosis in soft tissue sarcoma.

PURPOSE: Hypoxia is associated with malignant progression and poor outcome in several human tumors, including soft tissue sarcoma. Recent studies have suggested that carbonic anhydrase (CA) IX is an intrinsic marker of hypoxia, and that CA IX correlates with poor prognosis in several types of carcinoma. The aim of this study was to quantify the extent of CA IX expression and to investigate whether CA IX is a marker for poor prognosis in soft tissue sarcoma patients at high risk of developing metastasis. EXPERIMENTAL DESIGN: Archival paraffin-embedded blocks were retrieved from 47 patients with deep, large, high-grade soft tissue sarcoma. Sections from two separate and representative tumor areas were immunostained for CA IX, and the CA IX-positive area fraction was quantified by image analysis, excluding areas of normal stroma and necrosis that were identified from serial H&E-stained sections. Patients were then subject to survival analysis. RESULTS: CA IX-positive area fractions of viable tumor tissue varied significantly between tumors (range, 0-0.23; median, 0.004), with positive membranous CA IX staining in 66% (31 of 47) of the tumors. Patients with CA IX-positive tumors had a significantly lower disease-specific and overall survival than patients with CA IX-negative tumors (P = 0.033 and P = 0.044, respectively). CONCLUSIONS: These data suggest that CA IX, a potential intrinsic marker of hypoxia, predicts for poor prognosis in patients with deep, large, high-grade soft tissue sarcoma. Larger studies are required to determine whether CA IX has independent prognostic value in this group of tumors.     

Preoperative CA 15-3 and CEA serum levels as predictor for breast cancer outcomes.

BACKGROUND: To investigate the association between tumor markers [cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA)] and clinicopathological parameters and patient outcomes in breast cancer. Materials and methods: A total of 740 patients with stages I-III breast cancer had preoperative CA 15-3 and CEA concentrations measured. Univariate and multivariate analyses were used to investigate associations between marker concentration and clinicopathological parameters and patient outcomes. RESULTS: Among 740 patients, elevated preoperative levels of CA 15-3 and CEA were identified in 92 (12.4%) and 79 (10.7%) patients, respectively. Tumor size (>5 cm), node metastases (> or =4), and advanced stage (> or =III) were associated with higher preoperative levels. Elevated CA 15-3 and CEA levels were associated with poor disease-free survival (DFS, P = 0.0014, P = 0.0001, respectively) and overall survival (OS, P = 0.018, P = 0.015) even in stage-matched analysis. Patients with normal levels of both CA 15-3 and CEA showed better DFS and OS than those with elevated group. In multivariate analysis, age (<35 years), tumor size (>2 cm), node metastases, estrogen receptor expression, and elevated CA 15-3 and CEA preoperative values were independent prognostic factors for DFS. CONCLUSION: High preoperative CA 15-3 and CEA levels may reflect tumor burden and are associated with advanced disease and poor outcome. Measuring preoperative levels of CA 15-3 and CEA can be helpful for predicting outcomes.     

原发性乳腺癌患者术前血清中糖类抗原153癌胚抗原和组织多肽特异性抗原水平与临床病理特征和预后的关系

目的 探讨原发性乳腺癌患者术前血清中糖类抗原153( CA153)、癌胚抗原(CEA)和组织多肽特异性抗原(TPS)水平与患者临床病理特征和预后的关系.方法 对386例Ⅰ～Ⅳ期原发性乳腺癌患者的临床资料进行严格随访,回顾性分析患者术前血清中CA153、CEA和TPS水平与乳腺癌临床病理特征和预后的关系.结果 分别有383、382和324例患者进行了术前CA153、CEA和TPS的检测,平均表达水平分别为(21.46±34.88)U/ml、(1.53±7.95)μg/L和(224.87±436.19) AU/ml,CA153、CEA和TPS的阳性表达率分别为10.7％ (41/383)、7.6％ (29/382)和63.9％ (207/324).原发性乳腺癌患者术前血清CA153的表达水平与患者的年龄和肿瘤大小显著相关(均P＜0.05),CEA的表达水平与肿瘤大小显著相关(P＜0.05),TPS的表达水平与肿瘤大小和淋巴结转移状况显著相关(均P＜0.05).术前血清CA153、CEA和TPS阳性表达患者的总生存率显著低于阴性患者(均P＜0.05).Cox多因素分析表明,ER的表达水平以及术前CA153的表达水平是影响乳腺癌患者预后的独立因素(均P＜0.05),其中术前CA153水平增高是危险因素,而ER阳性表达则是保护因素.结论 术前血清CA153、CEA和TPS的表达水平与乳腺癌患者的临床病理特征和预后有关,CA153是影响乳腺癌患者预后的独立因素,CA153表达水平增高者的预后较差.     

Preoperative CA 15.3 and prognosis in primary breast cancer

CA15.3 is a breast cancer-associated antigen encoded by the MUC-1 gene. The clinical applications of CA 15.3 are the monitoring of response in advanced breast carcinoma and the early detection of recurrences. We have investigated the prognostic value of CA 15.3 in primary breast cancer. Preoperative serum CA 15.3 was measured in 478 patients with early breast cancer. Positive CA 15.3 was defined as > 30 U/ml. CA 15.3 positivity was correlated with patient outcome in terms of disease-free survival (DFS). Seven per cent of patients had elevated serum CA 15.3. A positive association was found between CA 15.3 positivity and tumour size. Twenty-one per cent of the patients with T3 and T4 tumours had high serum concentrations of CA 15.3; while only six per cent of patients with T1 and T2 tumours had elevated concentrations of CA 15.3 (p < 0.0001). There was no correlation between CA 15.3 serum levels and menopausal status, axilary lymph node status, estrogen receptor status, p53 and erbB-2 status, and CEA serum levels. With a median follow-up of 24 months, we found that elevated CA 15.3 levels predicted a poor clinical outcome. The probability of disease-free survival at two years was 73% in patients with high preoperative CA 15.3 compared with 90% in patients with normal CA 15.3 levels (logrank p = 0.003). The association of CA 15.3 with DFS was also analysed with a Cox analysis, and was found to be independent of tumour size. The multivariate analysis showed that poor disease-free survival was significantly associated with high CA 15.3 (p = 0.04), large tumour size (p = 0.001), estrogen receptor negative status (p = 0.008), overexpression of erbB-2 (p = 0.04), and overexpression of p53 protein (p = 0.03). Preoperative serum CA 15.3 is significantly related to clinical outcome in patients with early breast cancer. High CA 15.3 indicates a poor prognosis and this is independent from tumour size. Whether the poor prognosis associated with CA 15.3 is related with the role of mucins in the adhesion of cancer cells needs to be investigated.