Jose M. Escudero

Comparison of Serum Human Epididymis Protein 4 with Cancer Antigen 125 as a Tumor Marker in Patients with Malignant and Nonmalignant Diseases

BACKGROUND Human epididymis protein 4 (HE4), a precursor of human epididymis protein, has been proposed as a tumor marker for ovarian cancer. We evaluated HE4 in comparison with cancer antigen 125 (CA 125) in healthy individuals and in patients with benign and malignant diseases. METHODS CA 125 and HE4 serum concentrations were determined in 101 healthy individuals, 535 patients with benign pathologies (292 with benign gynecologic diseases) and 423 patients with malignant diseases (127 with ovarian cancers). CA 125 and HE4 cutoffs were 35 kU/L and 140 pmol/L, respectively. RESULTS HE4 and CA 125 results were abnormal in 1.1% and 9.9% of healthy individuals and in 12.3% and 37% of patients with benign diseases, respectively. Renal failure was the most common cause of increased HE4 in patients with benign disease, who had significantly higher HE4 concentrations (P = 0.001) than patients with other benign diseases. HE4 showed a higher specificity than CA 125 in patients with benign gynecologic diseases, with abnormal concentrations in 1.3% and 33.2% of the patients, respectively. HE-4 concentrations were abnormal primarily in gynecologic cancer and lung cancer. By contrast, CA 125 was increased in many different nonovarian malignancies, including nonepithelial tumors. A significantly higher area under the ROC curve was obtained with HE4 than with CA 125 for differentiating benign from malignant diseases (0.755 vs 0.643) and in the differential diagnosis of gynecologic diseases (0.874 vs 0.722). CONCLUSIONS HE4 has significantly higher diagnostic specificity than CA 125, and the combination of CA 125 and HE4 improved the detection of ovarian cancer in all stages and histological types.

Mucins CA 125, CA 19.9, CA 15.3 and TAG-72.3 as Tumor Markers in Patients with Lung Cancer: Comparison with CYFRA 21-1, CEA, SCC and NSE

Tumor marker serum levels were prospectively studied in 289 patients with suspected, but unconfirmed, lung cancer and in 513 patients with lung cancer [417 non-small cell lung cancer (NSCLC) patients and 96 small cell lung cancer (SCLC) patients]. In patients with benign disease, abnormal serum levels were found for the following tumor markers: CEA (in 6.6% of patients); CA 19.9 (6.2%); CA 125 (28.7%); NSE (0.7%); CYFRA (8.7%); TAG-72.3 (4.2%); SCC (3.5%), and CA 15.3 (3.5%). Excluding patients with renal failure or liver diseases, tumor marker specificity improved with abnormal levels in 0.5% for NSE, 0.9% for SCC, 2.8% for CEA, CA 15.3 and TAG-72.3, 3.8% for CA 19.9, 4.2% for CYFRA and 21.4% for CA 125. Excluding CA 125, one of the markers was abnormal in 15% of patients without malignancy. Tumor marker sensitivity was related to cancer histology and tumor extension. NSE had the highest sensitivity in SCLC and CYFRA and CEA in NSCLC. Significantly higher concentrations of CEA, SCC, CA 125, CA 15.3 and TAG-72.3 were found in NSCLC than in SCLC. Likewise, significantly higher CEA (p < 0.0001), TAG-72.3 (p < 0.001), CA 15.3 (p < 0.0001) and CA 125 (p < 0.01) were found in adenocarcinomas than in squamous tumors. Using a combination of 3 tumor markers (CEA, CYFRA 21-1 in all histologies, SCC in squamous tumors and CA 15.3 in adenocarcinomas), a high sensitivity may be achieved in all histological types. Tumor markers may be useful in the histological differentiation of NSCLC and SCLC. Using specific criteria for the differentiation of SCLC and NSCLC, the sensitivity was 84.2 and 68.8%, the specificity was 93.8 and 99.7%, the positive predictive value was 98.3 and 98.5% and the negative predictive value was 57.7 and 93.3%, respectively.

Usefulness of Serum Tumor Markers, Including Progastrin-Releasing Peptide, in Patients with Lung Cancer: Correlation with Histology

Background: Tumor markers have been extensively studied in lung cancer, reporting some relationship to the histology, but their clinical utility is not clear. Methods: ProGRP, CEA, SCC, CA 125, CYFRA 21-1 and NSE were studied prospectively in 155 patients with unconfirmed suspicion of lung cancer and in 647 patients with lung cancer: 182 squamous, 205 adenocarcinomas, 19 large-cell lung cancer (LCLC), 175 small-cell lung cancer (SCLC) and 66 unspecific non-small-cell lung cancer (NSCLC). Results: Abnormal tumor marker serum levels were found in less than 5.3% of the patients with benign diseases, excluding CA 125 (21.3%). Tumor markers were related to histological type and tumor extension with significantly higher CEA (p <0.01) and CA 125 (p <0.007) serum levels in adenocarcinomas, SCC (p <0.0001) and CYFRA 21-1 (p <0.008) in squamous tumors and ProGRP (p <0.0001) and NSE (p <0.0001) in SCLC. Tumor markers may be useful in the histological differentiation of NSCLC and SCLC. Patients with SCC serum levels >2 ng/ml were always NSCLC, while those with SCC <2 ng/ml and ProGRP >100 pg/ml and NSE >35 ng/ml were all SCLC patients. The sensitivity was 76.7 and 79.5%, specificity was 97.2 and 99.6%, with a positive predictive value of 98.6 and 98.6% and a negative predictive value of 60.7 and 92.9% in the differentiation of NSCLC and SCLC, respectively. Conclusions: Tumor marker determination in patients with suspicious signs of lung cancer suggests, in a few hours, the histological diagnosis in the majority of lung cancer patients.

Prospective Evaluation of Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 15.3 (CA 15.3) in Patients with Primary Locoregional Breast Cancer

BACKGROUND The utility of carcinoembryonic antigen (CEA) and carbohydrate antigen 15.3 (CA 15.3) as prognostic factors in primary breast cancer is unclear. METHODS We prospectively studied CEA and CA 15.3 in the sera of 2062 patients with untreated primary breast cancer diagnosed between 1984 and 2008. RESULTS Increased CEA (>5 microg/L) and CA 15.3 (>30 kU/L) concentrations were found in 12.7% and 19.6% of the patients, respectively, and 1 or both tumor markers were increased in 28% (570 of 2062). Increases in each tumor marker correlated with larger tumor sizes and nodal involvement. Tumor size, estrogen receptor (ER), and CEA were independent prognostic factors by multivariate analysis in the total group [disease free survival (DFS) and overall survival (OS)] as well as in node-positive (NP) and node-negative (NN) patients. Nodal involvement and histological grade were independent prognostic factors in the total group as well as in NP patients. By contrast, adjuvant treatment and CA 15.3 were independent prognostic factors only in NN patients (DFS and OS). All patients with CEA >7.5 microg/L had recurrence during follow-up. Use of both tumor markers allowed discrimination of the groups of risk in T1 NN patients: 56.3% of recurrences were seen when 1 or both tumor markers were increased, whereas only 9.4% of recurrences were seen in T1 NN patients without increases of either marker. CONCLUSIONS CEA and CA 15.3 are useful prognostic factors in NP and NN breast cancer patients. CEA >7.5 microg/L is associated with a high probability of subclinical metastases.

Assessment of a Combined Panel of Six Serum Tumor Markers for Lung Cancer

RATIONALE We have previously identified six serum tumor markers (TMs) (carcinoembryonic antigen, carbohydrate antigen 15.3, squamous cell carcinoma-associated antigen, cytokeratin-19 fragment, neuron-specific enolase, and pro-gastrin-releasing peptide) related to the presence of lung cancer (LC). OBJECTIVES To validate their individual performance in an independent cohort, and to explore if their combined assessment (≥1 abnormal TM value) is a more accurate marker for LC presence. METHODS We determined these six TMs in 3,144 consecutive individuals referred to our institution by their primary care physician because of the clinical suspicion of LC. MEASUREMENTS AND MAIN RESULTS LC was excluded in 1,316 individuals and confirmed in 1,828 patients (1,563 with non-small cell LC and 265 with small cell LC). This study validated the previously reported performance of each individual TM. We also showed that their combined assessment (≥1 abnormal TM) had a better sensitivity, specificity, negative predictive value, and positive predictive value (88.5, 82, 83.7, and 87.3%, respectively) than each TM considered individually and that it increased the diagnostic performance (area under the curve) of a clinical model that included tumor size, age, and smoking status. In patients with radiographic nodules less than 3 cm, the negative predictive value of the TM panel was 71.8%, hence providing some support for a more conservative diagnostic approach. Finally we identified two TMs (neuron-specific enolase and pro-gastrin-releasing peptide) that differentiate the risk of non-small cell LC from that of small cell LC. CONCLUSIONS The combined assessment of a panel of six serum TMs is a more accurate marker for LC presence than these same TMs considered individually. The potential of these TMs in the diagnostic and screening settings deserves further research.

CA 19–9 in pancreatic cancer: retrospective evaluation of patients with suspicion of pancreatic cancer

CA 19.9 serum levels were prospectively determined in 573 patients admitted to hospital for suspicion of pancreatic cancer. The final diagnosis was 77 patients with no malignancy, 389 patients with pancreatic cancer, 37 neuroendocrine pancreatic cancer, 28 cholangiocarcinomas, 4 gallbladder cancer, 27 ampullary carcinomas, and 11 periampullary carcinomas. CA 19.9 was determined using a commercial assay from Roche Diagnostics, and 37 U/ml was considered as the upper limit of normality. Abnormal CA 19.9 serum levels were found in 27%, 81.5%, 85.7%, 59.3%, 63.6%, and 18.9% of patients with benign diseases, pancreatic cancer, cholangiocarcinomas, and ampullary, periampullary, or neuroendocrine tumors. Significantly higher concentrations of CA 19.9 were found in patients with than in those without malignancy or with neuroendocrine tumors. CA 19.9 serum levels were higher in pancreatic cancer or cholangiocarcinoma than in other malignancies (p < 0.0001). CA 19.9 serum levels were also correlated with tumor stage, treatment (significantly lower concentrations in resectable tumors), and tumor location (the highest in those located in the body, the lowest in those in the tail or uncinate) and site of metastases (highest in liver metastases). A trend to higher CA 19.9 serum concentrations was found in patients with jaundice, but only with statistical significance in the early stages. Using 50 or 100 U/ml in patients with jaundice, CA 19.9 was useful as an aid in the diagnosis of pancreatic cancer (sensitivity 77.9%, specificity 95.9%) as well as tumor resectability in pancreatic cancer with different cutoffs according to tumor location and bilirubin serum levels with specificities ranging from 90% to 100%. CA 19.9 is the tumor marker of choice in pancreatic adenocarcinomas, with a clear relationship with tumor location, stage, and resectability.

Circulating levels of HER-2/neu oncoprotein in breast cancer

Abstract HER-2/neu, also known as c-erbB-2/neu, is an oncogene located in chromosome 17 which encodes HER-2/neu, a transmembrane protein belonging to the EGFR family. The external domain of this protein is released by the cell and can be studied in serum by immunoassay. HER-2/neu in serum is a specific tumor marker and only slight elevations may be found in the absence of malignancy, mainly in association with liver diseases. Likewise, the highest concentrations of this oncoprotein are found in patients with breast cancer, but lower concentrations may be found in other malignancies, particularly ovarian, prostate and lung cancer (mainly adenocarcinomas). HER-2/neu assay sensitivity in patients with untreated primary loco-regional breast cancer is <10% and seems to be related to overexpression in tissue as well as to the most important prognostic factors: tumor size and nodal involvement. Serial HER-2/neu determinations after surgery seem to be useful in the early diagnosis of recurrence, mainly in patients with HER-2/neu overexpression in tissue, but additional studies are necessary to confirm these results. HER-2/neu sensitivity (proportion of patients with abnormal values) in patients with metastasis is around 40%–45%, with a clear relationship to tissue overexpression and to site (higher in visceral metastases) and number of metastases. The clinical utility of HER-2/neu in patients with advanced disease is mainly for therapeutic monitoring. Likewise, in most of the studies published, a relationship has been found between serum HER-2/neu levels (either pretreatment or at follow-up) with tumor response.

Multicenter evaluation of a new progastrin-releasing peptide (ProGRP) immunoassay across Europe and China

BACKGROUND We performed a multicenter evaluation of the Elecsys® progastrin-releasing peptide (ProGRP) immunoassay in Europe and China. METHODS The assay was evaluated at three European and two Chinese sites by imprecision, stability, method comparison and differentiation potential in lung cancer. RESULTS Intermediate imprecision across five analyte concentrations ranged from 2.2% to 6.0% coefficient of variation. Good stability for plasma and serum samples was shown for various storage conditions. There was excellent correlation between the Elecsys® and ARCHITECT assays in plasma (slope 1.02, intercept -2.72pg/mL). The Elecsys® assay also showed good correlation between serum and plasma samples (slope 0.93, intercept 2.35pg/mL; correlation coefficient 0.97). ProGRP differentiated small-cell and non-small-cell lung cancer (NSCLC; area under the curve 0.90, 95% CI 0.87-0.93; 78.3% sensitivity, 95% specificity; at 84pg/mL), with no relevant effects of ethnicity, age, gender or smoking. Median ProGRP concentrations were low in benign diseases (38pg/mL), other malignancies (40pg/mL) or NSCLC (39pg/mL), except chronic kidney disease above stage 3 (>100pg/mL). CONCLUSIONS Increased stability of the Elecsys® ProGRP assay in serum and plasma offers clear benefits over existing assays. This first evaluation of a ProGRP assay in China demonstrated comparable differentiation potential among different ethnicities.

Variability of assay methods for total and free PSA after WHO standardization

The variability of total PSA (tPSA) and free PSA (fPSA) results among commercial assays has been suggested to be decreased by calibration to World Health Organization (WHO) reference materials. To characterize the current situation, it is necessary to know its impact in the critical cutoffs used in clinical practice. In the present study, we tested 167 samples with tPSA concentrations of 0 to 20 μg/L using seven PSA and six fPSA commercial assays, including Access, ARCHITECT i2000, ADVIA Centaur XP, IMMULITE 2000, Elecsys, and Lumipulse G1200, in which we only measured tPSA. tPSA and fPSA were measured in Access using the Hybritech and WHO calibrators. Passing–Bablok analysis was performed for PSA, and percentage of fPSA with the Hybritech-calibrated access comparison assay. For tPSA, relative differences were more than 10 % at 0.2 μg/L for ARCHITECT i2000, and at a critical concentration of 3, 4, and 10 μg/L, the relative difference was exceeded by ADVIA Centaur XP and WHO-calibrated Access. For percent fPSA, at a critical concentration of 10 %, the 10 % relative difference limit was exceeded by IMMULITE 2000 assay. At a critical concentration of 20 and 25 %, ADVIA Centaur XP, ARCHITECT i2000, and IMMULITE 2000 assays exceeded the 10 % relative difference limit. We have shown significant discordances between assays included in this study despite advances in standardization conducted in the last years. Further harmonization efforts are required in order to obtain a complete clinical concordance.