[CA 125 assay in the extension assessment of newly diagnosed breast cancers: why and how?] / Le CA 125 dans le bilan d'extension des cancers du sein nouvellement diagnostiqués : pourquoi et comment ?

CA 125 assay is sometimes combined in practice with the one of CA 15-3 and CEA in the extension assessment of breast cancers. The purpose of this work is to evaluate the contribution of the initial CA 125 as an indicator of distant metastases (DM) or of serous inflammation (SI). This retrospective study concerns a population of 620 patients with breast cancer without metastatic extension (n=325) or metastatic breast cancer (n=295) diagnosed at the Georges-François Leclerc center from 1998 to 2014. Seventy-four patients had SI. We showed that initial CA 125 level is linked to the TNM clinic status, the HER2 status, the nature and the number of metastatic locations, the inflammation of the tumor or serous. The ROC curves and logistic regression analyses show that CA 125 is an independent predictive criterion of DM presence (threshold of 55 kU/L): this is the only positive marker in 7% of patients with DM. At the threshold of 110 kU/L, the CA 125 is the only predictive biologic factor for SI. In conclusion, these data present the independent predictive value of CA 125 on the presence of DM or SI on condition of usinga specific threshold for each of these uses.

Assessment of average of normals (AON) procedure for outlier-free datasets including qualitative values below limit of detection (LoD): an application within tumor markers such as CA 15-3, CA 125, and CA 19-9.

Average of normals (AON) is a quality control procedure that is sensitive only to systematic errors that can occur in an analytical process in which patient test results are used. The aim of this study was to develop an alternative model in order to apply the AON quality control procedure to datasets that include qualitative values below limit of detection (LoD). The reported patient test results for tumor markers, such as CA 15-3, CA 125, and CA 19-9, analyzed by two instruments, were retrieved from the information system over a period of 5 months, using the calibrator and control materials with the same lot numbers. The median as a measure of central tendency and the median absolute deviation (MAD) as a measure of dispersion were used for the complementary model of AON quality control procedure. The ubias values, which were determined for the bias component of the measurement uncertainty, were partially linked to the percentages of the daily median values of the test results that fall within the control limits. The results for these tumor markers, in which lower limits of reference intervals are not medically important for clinical diagnosis and management, showed that the AON quality control procedure, using the MAD around the median, can be applied for datasets including qualitative values below LoD.

Diagnosis of Pneumocystis pneumonia: evaluation of four serologic biomarkers.

The diagnosis of Pneumocystis pneumonia (PCP) relies on microscopic visualization of Pneumocystis jirovecii organisms or DNA detection in pulmonary specimens. This study aimed to assess the usefulness of (1-3)-ß-d-glucan (BG), Krebs von den Lungen-6 antigen (KL-6), lactate dehydrogenase (LDH) and S-adenosyl methionine (SAM) as serologic biomarkers in the diagnosis of PCP. Serum levels of BG, KL-6, LDH and SAM were investigated in 145 Portuguese patients, 50 patients from the Netherlands, 25 Spanish patients and 40 Portuguese blood donors. Data on clinical presentation, chest imaging and gasometry tests were available. PCP cases were confirmed by microscopy and PCR techniques. A cost-effectiveness analysis was performed. BG was found to be the most reliable serologic biomarker for PCP diagnosis, followed by KL-6, LDH and SAM. The BG/KL-6 combination test was the most accurate serologic approach for PCP diagnosis, with 94.3% sensitivity and 89.6% specificity. Although less sensitive/specific than the reference standard classic methods based on bronchoalveolar lavage followed by microscopic or molecular detection of P. jirovecii organisms, the BG/KL-6 test may provide a less onerous procedure for PCP diagnosis, as it uses a minimally invasive and inexpensive specimen (blood), which may be also a major benefit for the patient's care. The BG/KL-6 combination test should be interpreted within the clinical context, and it may be used as a preliminary screening test in patients with primary suspicion of PCP, or as an alternative diagnostic procedure in patients with respiratory failure or in children, avoiding the associated risk of complications by the use of bronchoscopy.

Assessment of serum KL-6 as a prognostic marker in pulmonary tuberculosis patients.

Although serum Krebs von den Lungen-6 (KL-6) levels are reported to increase in pulmonary tuberculosis (PTB) patients according to disease activity, the relationship between serum KL-6 levels and prognosis remains unclear. In this study, we prospectively examined serum KL-6 levels in 188 PTB patients and assessed 60-day mortality. Univariate and multivariate logistic regression analysis demonstrated that serum KL-6 levels were not significantly associated with prognosis. For receiver operating characteristic analysis, the area under the curve had low accuracy for predicting mortality. These findings indicate that serum KL-6 levels do not perform adequately for use as a prognostic marker in patients with PTB.

Assessment of circulating tumor cells and serum markers for progression-free survival prediction in metastatic breast cancer: a prospective observational study.

INTRODUCTION: Circulating tumor cells (CTC) have been recently proposed as a new dynamic blood marker whose positivity at baseline is a prognostic factor and whose changes under treatment are correlated with progression-free survival (PFS) in metastatic breast cancer patients. However, serum marker levels are also used for the same purpose, and no clear comparison has been reported to date. METHODS: The IC 2006-04 enrolled prospectively 267 metastatic breast cancer patients treated by first line chemotherapy and confirmed that CTC levels are an independent prognostic factor for PFS and overall survival (OS). A secondary pre-planned endpoint was to compare prospectively the positivity rates and the value of CTC (CellSearch®), of serum tumor markers (carcinoembryonic antigen (CEA), cancer antigen 15.3 (CA 15-3), CYFRA 21-1), and of serum non-tumor markers (lactate deshydrogenase (LDH), alkaline phosphatase (ALP)) at baseline and under treatment for PFS prediction, independently from the other known prognostic factors, using univariate analyses and concordance indexes. RESULTS: A total of 90% of the patients had at least one elevated blood marker. Blood markers were correlated with poor performance status, high number of metastatic sites and with each other. In particular, CYFRA 21-1, a marker usually used in lung cancer, was elevated in 65% of patients. A total of 86% of patients had either CA 15-3 and/or CYFRA 21-1 elevated at baseline. Each serum marker was associated, when elevated at baseline, with a significantly shorter PFS. Serum marker changes during treatment, assessed either between baseline and week 3 or between baseline and weeks 6 to 9, were significantly associated with PFS, as reported for CTC. Concordance indexes comparison showed no clear superiority of any of the serum marker or CTC for PFS prediction. CONCLUSIONS: For the purpose of PFS prediction by measuring blood marker changes during treatment, currently available blood-derived markers (CTC and serum markers) had globally similar performances. Besides CEA and CA 15-3, CYFRA 21-1 is commonly elevated in metastatic breast cancer and has a strong prognostic value.

Assessment of response to endocrine therapy using FDG PET/CT in metastatic breast cancer: a pilot study.

PURPOSE: The purpose of this pilot study was to assess whether outcome in metastatic or recurrent breast cancer patients is related to metabolic response to endocrine therapy determined by (18)F-FDG PET/CT. METHODS: The study group comprised 22 patients with breast cancer (age 58 ± 11 years, mean ± SD) who were scheduled to receive endocrine therapy. They were systematically assessed by PET/CT at baseline and after a mean of 10 ± 4 weeks for evaluation of response after induction. All patients demonstrated FDG-avid lesions on the baseline PET/CT scan. The metabolic response was assessed according to EORTC criteria and based on the mean difference in SUV(max) between the two PET/CT scans, and the patients were classified into four groups: complete or partial metabolic response, or stable or progressive metabolic disease (CMR, PMR, SMD and PMD, respectively). All patients were followed in our institution. RESULTS: Metastatic sites were localized in bone (n = 15), lymph nodes (n = 11), chest wall (n = 3), breast (n = 5), lung (n = 3), soft tissue (n = 1) and liver (n = 1). PMR was observed in 11 patients (50%), SMD in 5 (23%) and PMD in 6 (27%). The median progression-free survival (PFS) times were 20, 27 and 6 months in the PMR, SMD and PMD groups, respectively. PFS in the SMD group differed from that in the PMR and SMD groups (p < 0.0001). CONCLUSION: Metabolic response assessed by FDG PET/CT imaging in patients with metastatic breast cancer treated with endocrine therapy is predictive of the patients' PFS.

Serial determination of CEA and CA 15.3 in breast cancer follow-up: an assessment of their diagnostic accuracy for the detection of tumour recurrences.

We studied the diagnostic accuracy of carcinoembryonic antigen (CEA) and cancer antigen 15.3 (CA 15.3) in detecting breast cancer recurrence. Biomarker follow-up determinations, made over 900 patients, were related to local-regional or distant recurrence using statistical models for longitudinal data. The diagnostic accuracy was quantified in terms of sensitivity, specificity and Youden index. The biomarkers were poorly predictive of local-regional recurrence. As for distant recurrence, the best diagnostic accuracy was obtained considering the two biomarkers jointly and combining two positivity criteria: a value above the normal limit or a difference between two consecutive measurements greater than the critical difference for at least one biomarker. A third criterion, based on within-patient comparison between follow-up determinations and a baseline, failed to improve the above result. CEA and CA 15.3 might play a role in patient monitoring during follow-up for the search of distant recurrence.

Tumour markers in internal medicine: a low-cost test or an unnecessary expense? A retrospective study based on appropriateness.

OBJECTIVE AND BACKGROUND: In the last 35 years tumour markers (TM) have gained currency in clinical practice. However, in the light of indications by international guidelines, their use is often unjustified. Our aim was to quantify the use of some of the most common TM, assessing their appropriateness and their efficacy in an Internal Medicine Unit. METHODS: In the three Internal Medicine Units of the Department of Internal Medicine of Policlinico of Modena we have carried out a retrospective analysis of the assessment of the main TM (CEA, CA19.9, CA 125, CA 15.3, NSE). The analysis was divided into two distinct phases: (I) quantitative phase, in order to assess the scale of the problem in economical terms; (II) qualitative phase, in order to assess the efficacy of the tests and the appropriateness of their use. RESULTS: (I) At last one of the considered TM was requested in 5102 out of the 8253 admitted patients (62%) (period 2001-2003). The trend was similar in all three units examined. (II) The qualitative analyses revealed: (1) the most common motivation for their use (79%) was diagnostic, mostly prior to any other test; (2) a mere 5% of the requests were appropriate according to the international literature; and (3) TM showed a low positive predictive value when used for diagnosis in an unselected population such as that of an Internal Medicine unit. CONCLUSIONS: The results of our study showed that TM determination represents an overall cost for Internal Medicine units and that there is a high inappropriateness in their use compared to what it is suggested by international guidelines. Though the TM is a low-cost test when used correctly, it seems an unnecessary expense if not adequately incorporated into the decision making process.

[The prescribing of CA 15.3 in the Roubaix health insurance district]. / La prescription du CA 15.3 dans la circonscription de la caisse primaire d'assurance maladie de Roubaix.

OBJECTIVE: Appreciate medical practice concerning CA 15.3 indications. MATERIAL AND METHOD: Starting with dosages reimbursed to people on social security, the health service near the primary Health care assurance offices (caisse primaire d'assurance maladie) at Roubaix, conducted a study over a period of 3 months, in which they asked physicians for their reasons for prescribing CA 15.3. RESULTS: Of the 205 questionnaires at their disposal, only 58 prescriptions conformed to the guidelines (28.3%). Prescriptions from specialists conformed in 48.9% of cases, as opposed to 12.8% from general practitioners. DISCUSSION AND CONCLUSION: The estimated assessment of the immediate additional expenditure will be shown to be 4 million Euros a year, over the whole of France.

[Assessment of selected neoplastic markers in women receiving hormone replacement therapy]. / Ocena wybranych markerów nowotworowych u kobiet stosujacych hormonalna terapie zastepcza.

The study was performed in order to assess the serum levels of proteins believed to be the markers of neoplastic differentiation (CEA and CA 15.3) and proliferation (TPS) in women receiving hormone replacement therapy. 190 women were included into the study. Women were classified into one of four groups: healthy women receiving hormone replacement therapy (n = 76), women with diagnosed benign breast disease (BBD) receiving HRT (n = 26), women with diagnosed BBD without HRT (n = 48), and control group--age matched, regularly menstruating women without HRT (n = 40). Measurements of serum concentrations of neoplastic markers were performed using radioimmunological method. The results indicate that hormone replacement therapy does not provoke a rise in neoplastic markers concentrations above normal levels in any of assessed groups. Women with BBD using HRT were found to have the lowest TPS and CA 15.3 values and the highest CEA values. The long-term usage of HRT was found to cause a gradual rise of average concentrations of all measured markers in BBD group and in healthy women.

A re-evaluation of carcinoembryonic antigen (CEA) as a serum marker for breast cancer: a prospective longitudinal study.

PURPOSE: Carcinoembryonic antigen (CEA) is still a widely used test for monitoring breast cancer, although recent reports discourage its routine use because of low sensitivity. This is a prospective study evaluating the efficacy of CEA and CA 15.3 in monitoring breast cancer. EXPERIMENTAL DESIGN: Serum CEA and CA 15.3 were measured in 2191 patients with either benign (n = 738) or malignant (n = 1453) breast diseases. Five hundred and forty-nine patients were monitored during postsurgical follow-up for either a minimum of 5 years or until time of recurrence. Fifty-three patients with metastases were also monitored during chemotherapy. RESULTS: Elevated CEA and CA 15.3 levels were found in 16.7% and 33.0% of patients, respectively. CEA sensitivity rose to 41.3% and CA 15.3 sensitivity rose to 80.8% in metastatic patients. The adjunct of CEA increased the CA 15.3 sensitivity by 6% in the overall population and by only 2.1% for patients with metastases. During postsurgical follow-up, CEA was elevated in 38.0% and CA 15.3 in 70.2% of patients with recurrence. The combination of CEA and CA 15.3 increased the overall sensitivity by only 1.4%. Longitudinal monitoring of 53 metastatic patients undergoing chemotherapy demonstrated that, when positive, both CEA and CA 15.3 paralleled response to treatment, although CA 15.3 was a significantly more powerful marker for determining response to treatment. The cost effectiveness ratio of CEA was clearly less favorable than that of CA 15.3. CONCLUSIONS: CEA monitoring should be considered an expensive and inefficient method of follow-up evaluation for breast cancer patients, and it provides no additional value when used in combination with CA 15.3.

Assessment of CA 15.3, CEA and TPA concentrations during monitoring of breast cancer.

The variability of the tumor markers cancer antigen (CA) 15.3, carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA) during steady state concentrations and the rate of increase during progression is described. One hundred and ninety-two patients were monitored during first-line chemotherapy for metastatic breast cancer and during follow-up. Blood specimens were sampled approximately every four weeks. Steady state concentrations were registered for 77 (CA 15.3), 96 (CEA), and 127 (TPA) patients with below cutoff level values and for 28 (CA 15.3), 25 (CEA), and 11 (TPA) patients with above cutoff level values. Clinical and marker progression was registered for 75 (CA 15.3), 62 (CEA), and 57 (TPA) patients. The coefficients of total variation of steady state concentrations (comprising the intra- and interassay analytical imprecision and the within subject biological variation) were higher below (14.9% CA 15.3, 15.4% CEA, 25.9% TPA) than above cutoffs (9.6% CA 15.3,6.0% CEA, 19.9% TPA). The variability was similar for CA 15.3 and CEA but higher for TPA. During progression the rates of increase in concentrations were similar for CA 15.3 (0.0257) and CEA (0.0214) and lower than for TPA (0.0346). Our data indicate that criteria for assessment of sequential tumor marker concentrations should consider the marker in question, the steady state variability, the cutoff value, and the rate of increase during disease progression.

Comparison of diagnostic markers with repeated measurements: a non-parametric ROC curve approach.

In this paper we study a class of non-parametric statistics for comparing diagnostic markers with repeated measurements. Using adapted definitions of specificity and sensitivity, we suggest methods to compare the average of sensitivities across all specificities or a range of specificities. The theory allows for correlations introduced by the fact that markers may be obtained from the same patient at multiple visits and that both markers being compared may be obtained from the same patient. Results of the Monte Carlo simulations and an example from a breast cancer setting are provided.

Performance of immunoassays for ca 19-9, ca 15-3 and ca 125 tumour markers evaluated from an international quality assessment survey.

Data collected in the 1993 and 1994 cycles of an international External Quality Assessment (EQA) programme were cumulatively analysed to evaluate the analytical performance of the methods currently in use for routine assay of mucinous tumour markers CA 19-9, CA 15-3 and CA 125. On average the between-laboratory variability was 14.7 and 15.8 CV% for CA 15-3 and CA 125 respectively. For CA 19-9, a markedly worse between-laboratory variability (on average 27.2 CV%) was found; the agreement of CA 19-9 results worsened in the last few years when new isotopic techniques became available. The variability component attributable to systematic differences between methods/kits was relatively small for CA 15-3 and CA 125 (17% and 21% of the total variability), while it was markedly larger for CA 19-9 (45% of the total variability). The precision of the methods/kits most often used in the survey ranged from 9.6 to 13.9 CV% for CA 125 and from 10.8 to 14.1 CV% for CA 15-3. For these two tumour markers the precision of the traditional IRMAs does not appear to be different from that of the new fully automated non-isotopic techniques. The precision of CA 19-9 methods was on average worse from (11.9 to 19.2 CV%), even though the precision of the two automated systems was better than that of IRMAs. In conclusion, the results of this study indicate that the between-laboratory agreement for CA 15-3 and CA 125 assays appears satisfactory while the CA 19-9 assay shows larger differences between methods and is affected by poorer precision of kits.

Assessment of five serum marker assays in patients with advanced breast cancer treated with medroxyprogesterone acetate.

This study concerns five different tumour marker assays examined in the context of 94 patients with advanced breast cancer treated in a prospectively randomised trial of different doses of medroxyprogesterone acetate (MPA). MPA was administered at doses of 500 or 1000 mg daily and clinical evaluation of patients was carried out according to UICC criteria. Carcinoembryonic antigen (CEA) was selected as a standard marker, with three assays for MUC1 mucins (epithelial mucin core antigens (EMCA), EMCA2 and BR-MA immunoradiometric assay) differing in antibody specificities for different mucin epitopes. An additional novel assay for soluble cytokeratin was also evaluated as an example of an independent marker with a different nature and biology. Sensitivity of individual assays ranged between 44 (EMCA2) and 69% (cytokeratin) and the use of two assays in combination led to sensitivities as high as 84% (cytokeratin+BR-MA). The proportion of patients found to be assessable by each assay ranged between 51 (EMCA2) and 76% (cytokeratin). Of those patients whose marker changes were assessable, those receiving the higher dose of MPA displayed significant falls in marker levels after 12 weeks of treatment. This effect was not observed in patients receiving 500 mg. The change in cytokeratin levels in patients undergoing high dose MPA therapy proved to be most marked. Using the cytokeratin assay, 91% (of 23 patients) of patients with progressive disease showed at least a 25% rise in serum marker levels. Of these, 66% showed increases before disease progression was detected clinically with a mean lead time of 14 weeks. There was very little difference between the responses of the five tumour marker assays in patients with stable or responding disease, the proportion of these patients with stable or falling tumour marker levels ranging between 58% (CEA) and 77% (EMCA). We conclude that the cytokeratin assay has an application in monitoring response to therapy and predicting tumour progression in advanced breast cancer patients with assessable tumour marker profiles, especially if used in combination with a MUC1 mucin assay.

Comparison of immunoassays for tumor markers CA 19-9, CA 15-3 and CA 125: data from an international quality assessment scheme.

Data collected in the 1993 and 1994 cycles of an international external quality assessment (EQA) program and in a national multicenter collaborative study were cumulatively analyzed to evaluate the standardization of the methods currently in use for the assay of mucinous tumor markers CA 19-9, CA 15-3 and CA 125. On average the between-laboratory variability was 15.2 and 16.0 CV% for CA 15-3 and CA 125 respectively; the between-laboratory variability found for CA 19-9 was markedly worse (mean 28.3 CV%). The variability component attributable to systematic differences between different methods/kits was relatively small for CA 15-3 and CA 125 (18% and 24% of the total variability) but markedly larger for CA 19-9 (48% of the total variability). The agreement of CA 19-9 results worsened in the last few years when new nonisotopic techniques became available. The precision of the methods/kits most used in the survey ranged from 9.9 to 13.3 CV% for CA 125 and from 11.6 to 13.9 CV% for CA 15-3. For these two tumor markers the precision of the traditional IRMAs does not appear different from that of the new fully automated nonisotopic techniques. The precision of CA 19-9 methods was on average worse (from 11.7 to 19.6 CV%) although two automated systems exhibited a precision better than that of IRMAs. In conclusion, the results of this study indicate that CA 15-3 and CA 125 are satisfactorily assayed whereas CA 19-9 assay appears affected by larger differences between methods and by poorer precision of laboratories and kits.

Tumor markers in breast cancer follow-up: a potentially useful parameter still awaiting definitive assessment. Forza Operativa Nazionale sul Carcinoma Mammario (FONCaM).

BACKGROUND: Although tumor markers are frequently used in the follow-up of patients with breast cancer, two points are still being debated: 1) their cost/effectiveness has been neither demonstrated nor disproved; 2) the reliability of the currently used dichotomous division into a positive/negative cut-off should be definitely validated. Dynamic criteria of interpretation based on serial serum samples would probably be more effective for early detection of relapse. PATIENTS AND METHODS: The aim of the present study was to compare the dichotomous cut-off based decision criteria to a dynamic serial sample based assessment of tumor markers. Since 1989, 794 patients have been followed in 11 institutions. CEA and CA15.3 were measured once a month for three months before every clinical examination. The present paper concerns the evaluation variability in 405 patients without evidence of disease in the first three institutions joining the study. RESULTS: In patients without evidence of disease, the coefficient of variation of all samples for every patient showed a median value of 19 for CEA and 21 for CA15.3. Variability was negatively associated with the antigen level and was most likely due to the analytical component. This was also confirmed by the significant difference in variability among the three institutions evaluated. The median value of the critical difference was 53% for CEA and 57% for CA15.3. CONCLUSIONS: 1) Individually tailored dynamic decision criteria are applicable in about 50% of the cases. 2) The problem of improving the precision of tumor marker assays in the low dose range must be urgently addressed to the manufacturers of tumor markers by the scientific community in order to apply individually tailored decision criteria for patients in whom the serum level of biological markers is low.