应用ROC曲线分析评价肿瘤标志物糖类抗原15-3、癌胚抗原在乳腺癌诊断与术后监测中的价值

目的评价肿瘤标志物糖类抗原15-3(carbohydrate antigen,CA15-3)、癌胚抗原(carcino-embryonic antigen,CEA)在乳腺癌诊断与术后复发转移判断中的应用价值。方法采用化学发光免疫分析法测定110例乳腺癌患者、50例乳腺良性疾病患者及40例正常对照者的血清CA15-3、CEA水平。组间比较采用χ2检验。用ROC曲线评价CA15-3、CEA在乳腺癌诊断和术后复发转移判断中的应用价值。结果 110例患者中CA15-3和CEA阳性检出率分别为32.7%(36/110)和12.7%(14/110)。I期、II期乳腺癌患者CA15-3、CEA血清含量无明显变化,与良性组和正常对照组相比差异无统计学意义(P0.050)。以43例Ⅲ期、Ⅳ期乳腺癌患者的CA15-3、CEA测定值绘制ROC曲线,分析显示,CA15-3、CEA的ROC曲线下面积(AUC)分别为82.3%、81.1%,95%可信区间分别为0.719～0.929、0.714～0.906。术后复发转移患者CA15-3、CEA阳性检出率分别为85.7%(18/21)、52.4%(11/21),AUC分别为97.8%、89.1%,95%可信区间分别为0.944～1.011、0.790～0.991。结论通过ROC曲线评价可得出,CA15-3、CEA对Ⅲ期、Ⅳ期乳腺癌诊断有临床参考价值,在术后复发转移诊断中有较高的应用价值,可作为乳腺癌术后监测复发转移的有效指标。     

利用 ROC 曲线评价 CEA、CA153在 HER -2阳性乳腺癌术后随访中的价值

目的：用ROC曲线评价CEA及CA153监测HER-2阳性乳腺癌患者术后复发转移的价值,并确立诊断HER-2阳性乳腺癌患者术后复发转移的最佳临界值。方法收集127例HER-2阳性乳腺癌患者CEA及CA153数值,将其分为复发转移及未复发转移两组。绘制ROC曲线,找到最佳临界值,同时比较最佳临界值与常规诊断值诊断复发转移的优劣。结果复发转移组较未复发转移组CEA及CA153水平显著偏高（P＜0．0001）,CEA、CA153诊断复发转移ROC曲线下面积分别为0．752、0．820,对应的最佳临界值分别为3．5 ng/mL、17．89 U/mL。 CEA和CA153最佳临界值敏感性分别为46．15％、65．38％,CEA和CA153最佳临界值特异性分别为97．33％、89．33％。结论 CEA、CA153在HER-2阳性乳腺癌患者术后判断复发转移中具有中等价值,诊断术后复发转移的最佳临界值分别为3．5 ng/mL、17．89 U/mL。     

超声BI-RADS联合血CA15-3和CEA在乳腺肿物诊断中的价值研究

目的 探讨超声BI-RADS与血CA15-3和CEA联合检测在乳腺肿物中的诊断价值。方法 选择2019年6月—2019年12月乳腺肿物患者111例,以病理结果为金标准,分析超声BI-RADS、血CA15-3和CEA联合对乳腺肿物诊断的敏感性及准确性。结果 病理示良性病变43例,乳腺癌68例。与良性病变患者相比,乳腺癌患者血CA15-3和CEA均升高(P＜0.05)。乳腺癌患者CA15-3和CEA呈正相关。超声BI-RADS、血CA15-3和CEA联合对乳腺癌诊断的敏感性达到73.5%,准确性升高至83.8%,AUC提高到0.957,均高于三者各自单独使用时的诊断效果。结论 超声BI-RADS、血CA15-3和CEA联合检测是一种提高乳腺肿物诊断敏感性和准确率的有效方法。     

Combination of Neutrophil-to-Lymphocyte Ratio and Red Cell Distribution Width With Serum Tumor Markers for the Differential Diagnosis of Breast Cancer and its Association With Pathological Features and Molecular Types

ObjectiveTo explore the neutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW) and serum tumor markers as differential diagnostic markers of breast cancer (BC) and breast fibroadenoma (FA) and their associations with histopathological indicators and molecular typing in BC patients.MethodsWe collected pathological and routine clinical test data [NLR, RDW, serum tumor markers (CEA, CA15-3, CA125, CA19-9)] of 653 patients with BC and 100 patients with FA. After identifying indicators with significant inter-group differences, we used ROC curves to determine clinically significant cutoff values. Binary logistic regression analyses and ROC curves were used to analyze combined models for the differential diagnosis of BC and FA. Ordinal multinomial logistic regression analysis was used to explore correlations between routine clinical test indicators and pathological BC features.ResultsThe BC and FA groups had significantly different CEA, NLR, and CA19-9 levels (P < .05), with respective areas under the curve (AUC) of 0.799, 0.747, and 0.711 for differentiating BC from FA and respective optimal cutoff values of 1.35 ng/mL, 1.58, and 8.55 U/mL. Binary logistic regression and ROC curve analysis showed that CEA was superior to the other 2 factors for the differential diagnosis of BC and FA. whereas the combined use of all three indicators was diagnostically most effective (AUC = 0.886; 95% confidence interval: 0.838–0.933, P = .000; sensitivity and/or specificity: 76.5%/88.9%). Ordered multinomial logistic regression analysis showed that NLR, CEA, and CA15-3 correlated positively with BC TNM staging; RDW was negatively correlated with BC histological grade; RDW, CA15-3 and CA125 were obviously associated with BC molecular typing.ConclusionThe combination of CEA, NLR, and CA19-9 may be used to screen and diagnose BC. NLR, CEA and CA15-3 are related to the TNM staging of BC. RDW is related to BC histological grading. RDW, CA15-3 and CA125 are related to BC molecular typing.     

Comparative study of CEA and CA19-9 in esophageal,gastric and colon cancers individually and in combination (ROC curve analysis)

Objective

To determine the clinical serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), individually and in combination, for the diagnosis of 50 healthy subjects and 150 cases of esophageal, gastric, and colon cancers.

Methods

The sensitivities of the two markers were compared individually and in combination, with specificity set at 100%. Receiver operating characteristic (ROC) curves were plotted.

Results

Serum CEA levels were significantly higher in cancer patients than in the control group. The sensitivity of CEA was determined: in esophageal cancer, sensitivity=28%, negative predictive value (NPV)=61.72%, and AUC=0.742
(SE=0.05), with a significance level of P<0.0001; in gastric cancer, sensitivity=30%, NPV=58.82%, and AUC=0.734 (SE=0.05), with a significance level of P<0.0001; in colon cancer, sensitivity=74%, NPV=79.36%, and AUC=0.856
(SE=0.04), with a significance level of P<0.0001. The sensitivity of CA19-9 was also evaluated: in esophageal cancer, sensitivity=18%, NPV=54.94%, and AUC=0.573 (SE =0.05), with a significance level of P=0.2054. In gastric cancer, sensitivity=42%, NPV=63.29%, and AUC=0.679 (SE =0.05), with a significance level of P<0.0011. In colon cancer, sensitivity=26%, NPV=57.47%, and AUC=0.580 (SE =0.05), with a significance level of P=0.1670. The following were the sensitivities of CEA/CA19-9 combined: in esophageal cancer, sensitivity=42%, NPV=63.29%, SE=0.078 (95% CI: 0.0159-0.322); gastric cancer, sensitivity=58%, NPV=70.42%, SE=0.072 (95% CI: -0.0866-0.198); and colon cancer, sensitivity=72%, NPV=78.12%, SE=0.070 (95% CI: 0.137-0.415).

Conclusion

CEA exhibited the highest sensitivity for colon cancer, and CA19-9 exhibited the highest sensitivity for gastric cancer. Combined analysis indicated an increase in diagnostic sensitivity in esophageal and gastric cancer compared with that in colon cancer.KEYWORDS : Carcinoembryonic antigen, carbohydrate antigen 19-9, human, Receiver operating characteristic curve, sensitivity and specificity     

Comparison of a novel assay for breast cancer mucin to CA15-3 and carcinoembryonic antigen.

PURPOSE: To compare the sensitivity and specificity of an automated microparticle enzyme immunoassay (MEIA) for breast cancer mucin (IMx BCM; Abbott Laboratories, North Chicago, IL) to that of CA15-3 and carcinoembryonic antigen (CEA) for detecting and monitoring breast cancer. MATERIALS AND METHODS: IMxBCM was compared to assays of CA15-3 and CEA in 630 serum specimens from healthy women, and from women with breast cancer, other malignancies, benign breast conditions, or other benign diseases. RESULTS: Analysis of the log-transforms for the three markers in all specimens showed a high correlation of IMxBCM with CA15-3 (r = .78), but not with CEA (r = .25). Based on a receiver-operating-characteristics (ROC)-curve analysis for any given specificity, IMxBCM was found to be a more sensitive marker than either CA15-3 or CEA for distinguishing 105 women with advanced or metastatic breast cancer from 89 healthy women (P = .003 and P = .04, respectively), from 98 women with benign breast conditions (P = .02 and P = .002), or from 191 women with benign diseases (P = .03 and P less than .0001). At 95% specificity, the sensitivities of IMxBCM, CA15-3, and CEA for detecting advanced or metastatic breast cancer were 69%, 51%, and 30%, respectively. Serial serum samples (n = 177) were analyzed in 20 additional metastatic breast cancer patients with measurable disease. Serial IMxBCM levels corresponded with the clinical course of disease in 80%, CA15-3 in 65%, and CEA in 60% of the 20 patients. CONCLUSIONS: Increased sensitivity of IMxBCM, despite a high correlation with CA15-3, suggests that IMxBCM and CA15-3 may recognize distinct epitopes on the same molecule. Although further research is indicated, IMxBCM may provide a promising marker in the clinical management of breast cancer patients.     

TPS in breast cancer--a comparative study with carcinoembryonic antigen and CA 15-3.

The serum levels of tissue polypeptide antigen were determined using the M3 monoclonal antibody (TPS) and compared with the serum levels of carcinoembryonic antigen (CEA) and breast carcinoma antigen 15-3 (CA 15-3) in 96 patients with benign breast tumors, in 25 breast cancer patients with no evidence of disease, in 139 preoperative breast cancer patients and in 298 samples of 25 breast cancer patients during therapy monitoring (4-22 samples per patient). The 95th percentile of TPS in 89 apparently healthy females was 51 U/l. The 95th percentile of TPS in patients with benign breast tumors was 55 U/l. The maximum TPS level in breast cancer patients with no evidence of disease was 56 U/l. In preoperative breast cancer the number of patients with TPS levels above the 95th percentile of TPS in benign breast tumors was significantly higher in stage III breast cancer as compared with stage I+II. This was not established for CEA and CA 15-3. During therapy monitoring TPS followed the course of the disease faster than CEA and CA 15-3 in patients with bone metastases, liver metastases, lung metastases and pleural effusion, with one exception. TPS levels could be correlated with progression of disease in patients with normal and steady levels of CEA and/or CA 15-3.     

肿瘤标志物在乳腺癌术后复发转移监测中的应用价值

目的：探讨肿瘤标志物在乳腺癌术后复发转移监测中的应用价值。方法：用多肿瘤标志物系统对121例乳腺癌术后患者（其中包括49例术后复发转移患者及72例术后无复发转移患者）血清样本的12项肿瘤标志物（CA19—9、NSE、CEA、CA242、Ferritin、B—HCG、AFP、F—PSA、PSA、CA125、HGH、CA15—3）的表达水平进行测定,Logistic回归分析与ROC曲线法评价肿瘤标志物在复发转移中的应用价值。结果i乳腺癌术后复发转移组与无复发转移组的蛋白芯片阳性率差异显著（P〈0．05）。与无复发组测定结果比较,CA19—9、CEA、Ferritin、CA125、CA15—3的表达水平及阳性率差异具有统计学意义（P〈0．05）。Logistic回归分析筛选CEA、CA125、CA15—3为监测乳腺癌术后复发转移的有效指标,ROC曲线法三者曲线下面积为0．813、0．808、0．772。CEA、CA125、CA15—3联合监测乳腺癌术后复发转移的敏感性与芯片相同（81．6％）,特异性与准确性高于芯片（95．8％VS92．7％,90．1％VS87．6％）。结论：CEA、CA125、CA153联合检测可能作为临床监测乳腺癌术后复发转移优化方案。     

HE4和 CA153联合表达在预测早期乳腺癌淋巴结转移中的意义

目的：探讨血清人附睾分泌蛋白4（HE4,human epididymis protein 4）和糖类抗原153（CA153,carbo-hydrate antigen 153）联合表达在预测早期乳腺癌淋巴结转移中的意义。方法：用酶联免疫（enzyme - linked im-munosorbent assay,ELISA）法检测100例 I - II 期乳腺癌患者血清中 HE4和 CA153水平,对不同淋巴结转移情况的 HE4和 CA153水平变化进行比较,并行 Logistic 回归分析,应用 ROC 曲线（receiver operating characteristic curve）分析 HE4和 CA153对淋巴结转移的预测价值。结果：早期乳腺癌有淋巴结转移组 HE4和 CA153水平高于无淋巴结转移组,差异有统计学意义（P <0.000）,经 Logistic 回归分析,肿瘤大小、浸润深度和 CA153水平是影响早期乳腺癌淋巴结转移的独立危险因素。HE4的 AUC 为0.792,P =0.000,95% CI：0.622～0.862。CA153的 AUC 为0.885,P =0.000,95% CI：0.612～0.859。当 HE4的截断值为105.4pg/ L、CA153的截断值为40.4U/ L 时,其乳腺癌淋巴结转移的预测价值最佳。结论：HE4和 CA153联合表达时其水平变化在预测早期乳腺癌淋巴结转移中有重要参考价值。     

Decision making using postoperative CEA and CA 15-3 for detection of breast cancer recurrence

To determine the clinical implications of postoperative levels of serum carcinoem-bryonic antigen (CEA) and CA 15-3 as follow up parameters for breast cancer, a retrospective study was conducted on 157 patients who underwent curative surgery for breast cancer. Twenty-three patients had recurrences and 134 patients were without recurrence for more than one year after measuring the tumor markers. The receiver operating characteristic (ROC) curves indicated that CA 15-3 performed more accurately than CEA in discriminating between patients with recurrence (n = 23) and those without (n=134). Of 23 patients with recurrence, CEA was elevated above the normal range (>2.9 ng/ml) in 32% and CA 15-3 was elevated above the normal range (> 20 U/ml) in 67%. The elevation of the markers preceded the clinical appearance of metastases in 2 patients for CEA and in 5 patients for CA 15-3. False positive rates for CEA and CA 15-3 in the 134 patients without recurrence were 4% and 10%, respectively. Nevertheless, these rates became 0% when the cut-off values were doubled. When the postoperative serum level of either CEA or CA 15-3 exceeds twice the upper limit of the normal range or when, in patients with unfavourable prognostic characteristics (node positive or large tumor), either of these values is between the upper limit of the normal range and double the value, recurrent breast cancer must be assumed. For such patients, further investigations with high-sensitivity radiographic modalities are warranted because early treatment may be able to provide survival benefit.     

CA125联合 CA19－9、CEA、CA72－4检测在上皮性卵巢癌诊断中的意义

目的：阐明联合检测糖类抗原（CA125、CA19－9、CA72－4）与癌胚抗原（CEA）在上皮性卵巢癌中的诊断意义。方法：对81例上皮性卵巢癌患者,81例良性卵巢肿瘤患者以及作为对照的80例健康体检者血清中的 CA125、CA19－9、CA72－4与 CEA 进行检测。采用 ROC 曲线及 AUC、Logistic 回归分析评估上述血清标记物对上皮性卵巢癌的诊断意义。结果：卵巢癌患者血清肿瘤标记物 CA125、CA19－9、CA72－4的水平与阳性率明显高于良性卵巢肿瘤以及对照组健康体检者（P ＜0．05）。ROC 曲线显示 CA125、CA19－9、CEA 与CA72－4曲线下面积分别为0．904±0．025、0．670±0．042、0．497±0．046 and 0．821±0．033。联合检测上述肿瘤标记物显示最高的敏感性（91．4％）与较好的特异性（83．9％）。与其他单一肿瘤标记物相比,CA125显示最高的敏感性与较好的特异性。结论：联合检测 CA125、CA19－9、CEA 与 CA72－4可以提高上皮性卵巢癌早期诊断的敏感性与准确性。     

The value of the tumor marker CA 15-3 in diagnosing and monitoring breast cancer. A comparative study with carcinoembryonic antigen

To estimate the utility of the tumor-associated antigen CA 15-3 in the diagnosis of patients with breast cancer, this tumor marker was measured preoperatively in 1342 patients. This group included 509 patients with malignant disease (134 breast cancer patients and 375 patients with other malignancies not involving the breast) and 833 patients with benign surgical diseases (95 patients with fibroadenoma of the breast and 738 patients with other benign diseases). The results were compared with those obtained for carcinoembryonic antigen (CEA) in the diagnosis of breast cancer. The CA 15-3 level was above normal (25 U/ml) in 31% of the patients with breast cancer, in 22% of patients with other malignancies, and in 9% of patients with benign diseases. The CEA level was elevated in 26% of patients with breast cancer (more than 3 ng/ml). There was a good correlation of CA 15-3 levels with the tumor stage of breast cancer. Both CA 15-3 and CEA also were determined in 671 patients who had received initial curative surgery of breast cancer and who regularly attended our follow-up clinic. The CA 15-3 was found to be more sensitive than CEA in detecting recurrences of breast cancer. In the postcare period, carcinoma recurred in 205 patients. Of these, 73% had CA 15-3 concentrations above 25 U/ml; only 50% had CEA values above 3 ng/ml (P less than 0.0001). Although neither CA 15-3 nor CEA were sensitive enough for the screening and diagnosis of early breast cancer, CA 15-3 was significantly better than CEA in the detection of breast cancer metastases.     

Identification and validation of new autoantibodies for the diagnosis of DCIS and node negative early‐stage breast cancers

Evidence of circulating autoantibodies in cancer patient sera has created opportunities for exploiting them as biomarkers. We report the identification and the clinical validation of an autoantibody panel in newly diagnosed patients with early‐stage breast cancer. Proteomic approach and serological screening of a discovery set of sera (n = 80) were performed to identify tumor‐associated antigens (TAAs). Autoantibody levels were then measured in an independent validation set (n = 182) against a panel of five TAAs by enzyme‐linked immunosorbent assay. Sixty‐seven antigens that elicited a specific humoral response in breast cancer were identified and five antigens (GAL3, PAK2, PHB2, RACK1 and RUVBL1) were selected for validation. GAL3 and RACK1 showed significantly increased reactivity in early‐stage breast cancer. When combined, the five markers significantly discriminated early‐stage cancer from healthy individuals (AUC = 0.81; 95% CI [0.74–0.86]). Interestingly, this value was high in both node‐negative early‐stage primary breast cancer (AUC = 0.81; 95% CI [0.72–0.88]) and ductal carcinoma in situ (AUC = 0.85; 95% CI [0.76–0.95]) populations. This autoantibody panel could be useful as a diagnostic tool in a screening strategy of early‐stage invasive breast cancer and preinvasive breast cancer. It could be particularly appropriate in complement to mammography for women with high breast density.     

Hepcidin and ferritin blood level as noninvasive tools for predicting breast cancer

BackgroundCurrently used CA15–3 and CEA have found their clinical application particularly in the follow-up of patients with advanced disease. Novel biomarkers are urgent, especially for improving early diagnosis as well as for discriminating between benign and malignant disease.Patients and methodsIn the present study, we used a proteomic approach based on surface-enhanced laser desorption/ionization–time of flight–mass spectrometry screening with the aim of identifying differentially expressed 2–30 kDa proteins in plasma of patients with malignant (65 cases) and benign (88 cases) breast lesions with respect to 121 healthy controls.ResultsWe found that the most promising SELDI peaks were those corresponding to hepcidin-25 and ferritin light chain. We evaluated the capability of these peaks in predicting malignant and benign breast lesions using the area under the receiver operating characteristic curve (AUC). The results showed a good capacity to predict malignant breast lesions for hepcidin-25 [AUC: 0.82; 95% confidence interval (CI) 0.75–0.90] and ferritin light chain (AUC: 0.86; 95% CI 0.79–0.92). Conversely, a weak and satisfactory capability to predict benign breast lesion was observed for hepcidin-25 (AUC: 0.63; 95% CI 0.41–0.85) and ferritin light chain (AUC: 0.73; 95% CI 0.49–0.97). A significant association between HER2 status and hepcidin-25 was observed and the distribution of transferrin and ferritin were found significantly different in patients with breast cancer when compared with that of controls.ConclusionsThis study provides evidence that hepcidin and ferritin light chain level in plasma may be of clinical usefulness to predict malignant and benign disease with respect to healthy controls.     

Increased alpha-fetoprotein receptor in the serum of patients with early-stage breast cancer

The alpha-fetoprotein (afp) receptor (recaf) is an oncofetal antigen found in most types of cancer. Using a competitive radioimmunoassay, we measured the concentration of serum recaf in three sets of samples.Set 1 was blind and consisted of 119 normal subjects, 43 breast cancer patients (stages i and ii), and 20 patients with benign breast conditions. In this set, the assay discriminated normal from cancer samples with a receiver operating characteristic for the area under the curve (ROC(AUC)) of 0.983; with 95% specificity and 93% sensitivity at a cut-off of 4.6 K (arbitrary) recaf units; and with 72% sensitivity and 100% specificity at a cut-off of 7.3 K units. At 7.3 K units, the specificity for benign breast conditions was 85%, and the sensitivity was 72% (ROC(AUC) was 0.773). Carcinoembryonic antigen and cancer antigen 15-3 respectively showed 39% and 41% sensitivity, with 95% specificity in comparisons of normal with cancer samples, and 34% and 44% sensitivity, with 85% specificity in comparisons of benign with cancer samples. Set 2 consisted of 353 normal, 30 benign, and 64 cancer samples (stages ii and iii). The recaf assay sensitivity in discriminating normal from cancer samples was 97%, with 97% specificity. Benign compared with cancer samples showed 87% sensitivity, with 97% specificity. Set 3 included only 40 normal and 40 cancer samples. The assay sensitivity was 89%, with 100% specificity. Sets 2 and 3 were not tested with carcinoembryonic antigen and cancer antigen 15-3.These results strongly suggest that the recaf assay could be used for detecting breast cancer in its early stages.     

Circulating immunogenic cell death biomarkers HMGB1 and RAGE in breast cancer patients during neoadjuvant chemotherapy

Neoadjuvant chemotherapy in breast cancer patients aims at preoperative reduction of tumor volume for better resection results and prognosis. As not all patients respond to neoadjuvant therapy, predictive biomarkers are needed for more efficient individual management. In prospectively collected sera of 51 consecutive locally confined breast cancer (LBC) patients receiving preoperative, neoadjuvant chemotherapy, value level kinetics of soluble high mobility group box 1 (HMGB1), soluble receptor for advanced glycation end products (sRAGE) as well as the established breast cancer biomarkers CA 15–3 and carcinoembryonic antigen (CEA) were investigated and correlated with therapy response objectified by pathological staging at surgery. In addition, biomarkers were measured in sera of 30 healthy controls (HC), 13 patients with benign breast diseases, and 28 metastatic breast cancer (MBC) patients. Pretherapeutic levels of soluble HMGB1 were decreased in MBC, while sRAGE was already decreased in LBC. In contrast, CA 15–3 and CEA were strongly elevated in MBC, but not in LBC. Combination of sRAGE and CA 15–3 enabled best discrimination of LBC from HC (AUC 78.2 %; sens 58 % at 95 % spec), while CA15-3 and CEA discriminated best between MBC and all controls (AUC 90.9 %; sens 70 % at 95 % spec). In LBC patients undergoing neoadjuvant chemotherapy, nine patients achieved complete remission (CR), 29 achieved partial remission (PR), while 13 had no change of disease (NC). NC patients tended to have higher HMGB1 and lower sRAGE levels before therapy onset (p?=?0.056 and p?=?0.054), while CA 15–3 and CEA did not predict therapeutic outcome. Furthermore, kinetics of HMGB1 during therapy correlated with efficacy of the treatment (p?=?0.053). Markers of immunogenic cell death are valuable for the diagnosis of MBC and early estimation of response to neoadjuvant therapy in LBC patients.     

Clinical Evaluation of an Immunoradiometric Assay for CA15-3 Antigen Associated With Human Mammary Carcinomas: Comparison With Carcinoembryonic Antigen

Serum levels of CA15-3, a mammary tumor associated antigen recognizedby two different murine monoclonal antibodies (115D8 and DF3),were investigated in patients with mammary carcinoma and otherbenign or malignant diseases. The reference value of the serumCA15-3 level was obtained as 24 units/ml at the 99% confidencelimit among healthy individuals (n = 462). Elevation of serumCA15-3 levels was observed in 24.3% of overall patients withmammary carcinoma. Serum CA15-3 levels in breast cancer patientscorrelated with the clinical stage; higher percentages of positivitywere observed in those with advanced breast cancer (stage IV,64.7%, recurrent, 52.4% and metastatic, 70.3%). Furthermore,elevated serum CA15-3 levels in breast cancer patients respondedwell to the effect of therapy. Although the serum CA15-3 testgave percentages of positivity of breast cancer similar to thosefound by the serum CEA test, the serum CA15-3 test revealedlower percentages of posi-tivity than the serum CEA test amongpatients with benign breast lesions, liver cirrhosis or othercarcinomas. These results suggest that the serum CA15-3 antigenlevel provides a very useful marker for diagnosis and clinicalmonitoring of patients with breast cancer.     

Serum Human Epididymis Protein-4 (HE4) - A novel Approach to Differentiate Malignant Frombenign Breast Tumors

Background: The lack of sensitivity and specificity of existing diagnostic markers like Carbohydrate Antigen 15-3(CA15-3) and Carcinoembryonic antigen (CEA) in breast cancer stimulates the search for new biomarkers to improve diagnostic sensitivity especially in differentiating benign and malignant breast tumors. Expression of Human epididymal protein 4 (HE4) has been demonstrated in ductal carcinoma of the breast tissue. So we tried to evaluate serum HE4 levels as diagnostic marker in breast cancer patients and to comparatively assess serum HE4, CEA and CA15-3 in breast tumor patients both benign and malignant. Methods: Total 90 female subjects were included in the study. We selected 30 breast cancer cases (Malignant group) and 30 benign breast lump cases (Benign group) based on histopathology report. And other 30 were age matched apparently healthy controls (Control group). HE4, CEA and CA15-3 were analysed in serum samples of all subjects by Electrochemiluminiscence immunoassay method. Results: A significant difference in the median (IQR) of HE4 (pmol/l) was identified among malignant, benign and control groups {62.4(52.6-73.7) vs 49.3(39.8-57.4) vs 52.3(50.6-63.3) P=0.0009} respectively. The cutoff value for prediction of breast cancer was determined at >54.5 pmol/l for HE4, with a sensitivity of 73.3%, specificity of 65.3%, whereas cutoff value of CA 15-3 was >21.24 (U/ml) with a sensitivity of 56.7%, specificity of 74.5%. For CEA at cutoff value >0.99 (ng/ml) the sensitivity and specificity were 96.7 % and 62.7% respectively. AUC for HE4, CA15-3 and CEA were 0.725, 0.644 and 0.857 respectively. Conclusion: Our study demonstrated that serum levels of HE4 were significantly higher in malignant group compared to benign and control groups. There is no significant difference between HE4 levels between benign and control groups. These results indicate that HE4 appears as a useful and highly specific biomarker for breast cancer, which can differentiate between malignant and benign tumors.     

Serum Tumor Marker Levels might have Little Significance in Evaluating Neoadjuvant Treatment Response in Locally Advanced Breast Cancer

Background: To determine the potential value of serum tumor markers in predicting pCR (pathologicalcomplete response) during neoadjuvant chemotherapy. Materials and Methods: We retrospectively monitoredthe pro-, mid-, and post- neoadjuvant treatment serum tumor marker concentrations in patients with locallyadvanced breast cancer (stage II-III) who accepted pre-surgical chemotherapy or chemotherapy in combinationwith targeted therapy at Fudan University Shanghai Cancer Center between September 2011 and January 2014and investigated the association of serum tumor marker levels with therapeutic effect. Core needle biopsy sampleswere assessed using immunohistochemistry (IHC) prior to neoadjuvant treatment to determine hormone receptor,human epidermal growth factor receptor 2(HER2), and proliferation index Ki67 values. In our study, therapeuticresponse was evaluated by pCR, defined as the disappearance of all invasive cancer cells from excised tissue(including primary lesion and axillary lymph nodes) after completion of chemotherapy. Analysis of variance ofrepeated measures and receiver operating characteristic (ROC) curves were employed for statistical analysisof the data. Results: A total of 348 patients were recruited in our study after excluding patients with incompleteclinical information. Of these, 106 patients were observed to have acquired pCR status after treatment completion,accounting for approximately 30.5% of study individuals. In addition, 147patients were determined to be Her-2positive, among whom the pCR rate was 45.6% (69 patients). General linear model analysis (repeated measuresanalysis of variance) showed that the concentration of cancer antigen (CA) 15-3 increased after neoadjuvantchemotherapy in both pCR and non-pCR groups, and that there were significant differences between thetwo groups (P=0.008). The areas under the ROC curves (AUCs) of pre-, mid-, and post-treatment CA15-3concentrations demonstrated low-level predictive value (AUC=0.594, 0.644, 0.621, respectively). No significantdifferences in carcinoembryonic antigen (CEA) or CA12-5 serum levels were observed between the pCR andnon-pCR groups (P=0.196 and 0.693, respectively). No efficient AUC of CEA or CA12-5 concentrations wereobserved to predict patient response toward neoadjuvant treatment (both less than 0.7), nor were differencesbetween the two groups observed at different time points. We then analyzed the Her-2 positive subset of ourcohort. Significant differences in CEA concentrations were identified between the pCR and non-pCR groups(P=0.039), but not in CA15-3 or CA12-5 levels (p=0.092 and 0.89, respectively). None of the ROC curves showedunderlying prognostic value, as the AUCs of these three markers were less than 0.7. The ROC-AUCs for theCA12-5 concentrations of inter-and post-neoadjuvant chemotherapy in the estrogen receptor negative HER2positive subgroup were 0.735 and 0.767, respectively. However, the specificity and sensitivity values were at oddswith each other which meant that improving either the sensitivity or specificity would impair the efficiency ofthe other. Conclusions: Serum tumor markers CA15-3, CA12-5, and CEA might have little clinical significancein predicting neoadjuvant treatment response in locally advanced breast cancer.     

Vaccination with a mixed vaccine of autogenous and allogeneic breast cancer cells and tumor associated antigens CA15-3, CEA and CA125--results in immune and clinical responses in breast cancer patients

In breast cancer there is often overexpression of the breast cancer antigen CA15-3, the carcinoembryonic antigen (CEA) and the ovarian cancer antigen CA125, which makes them potential target antigens for immunotherapy. In this study, we used a multi-antigen vaccine, which included the following antigens: autologous breast cancer cells (AUTOC), allogeneic breast cancer MCF-7 cells (ALLOC), and the tumor associated antigens CA15-3, CEA and CA125, plus low doses of granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interleukin 2 (IL-2). Forty-two breast cancer patients received weekly subcutaneous vaccination at the 1st, 2nd, 3rd, 7th, 11th and 15th weeks. Their lymphocyte proliferative responses to AUTOC, ALLOC, CA15-3, CEA and CA125 were tested in lymphocyte blastogenesis assays (LBA) before and after vaccination. The disease stage and serum CA15-3, CEA and CA125 concentrations were also determined pre- and post-vaccination. We found that the vaccine was safe, and the only major side effects were swelling at the site of injection, muscle pain, and weakness or fatigue. The vaccine induced a significant increase in post-vaccination lymphocyte proliferative responses to AUTOC, CA15-3, CEA and CA125 but not ALLOC, compared to pre-vaccination (p < 0.05, p < 0.01, p < 0.05, p < 0.01 and p > 0.05, respectively, a paired t Test). Computed tomography (CT), ultrasound or bone scan showed evidence of disease improvement in 2 (12%) patients after vaccination. Hepatic metastases were reduced in size and number and some actually disappeared one patient. Metastatic disease in the L5 vertebra and the skull decreased in size and some osteolytic sites completely healed in a second patient. In addition, 7 patients (44%) had stable disease and 7 patients (44%) had disease progression. We did not find vaccination significantly reduced serum tumor markers CA15-3, CEA and CA125 of these breast cancer patients. These results suggest that the vaccine mixture of autologous and allogeneic breast cancer cells and tumor associated antigens plus GM-CSF and IL-2 can be administered safely to breast cancer patients and there is evidence for improved immunity and clinical efficacy.