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1
Klinikum der Universität München Grosshadern, Institut für Klinische Chemie, Marchioninistrasse 15, D-81377 Munich, Germany;
2
Hospital Clinic I Provincial, Unitat de Recerca del Cancer, E-08034 Barcelona, Spain;
3
Johns Hopkins Medical Institutions, Department of Pathology, Clinical Chemistry Division, Baltimore, MD 21287-7065;
4
The University of Texas, MD Anderson Cancer Center, Section of Clinical Chemistry, Division of Pathology and Laboratory Medicine, Houston, TX 77030;
5
Institut für Klinische Chemie und Laboratoriumsdiagnostik, D-40225 Düsseldorf, Germany;
6
Antoni van Leeuwenhoek Hospital, NL-1066 CX Amsterdam, The Netherlands;
7
Zentralkrankenhaus Links der Weser, D-28277 Bremen, Germany;
8
Tumormarkerlabor, Universitätsfrauenklinik, D-91054 Erlangen, Germany;
9
Academisch Ziekenhuis, Vrije Universiteit, Centraal Chemisch Laboratorium, NL-1007 MB Amsterdam, The Netherlands;
10
St. Elisabeth Krankenhaus, D-06110 Halle, Germany;
11
Institut Gustave-Roussy, Departement de Biologie Clinique, F-94805 Villequif, France;
12
Roche Diagnostics GmbH, D-68305 Mannheim, Germany
aauthor for correspondence: fax 0-89-7095-6298, e-mail stieber{at}klch med.uni-muenchen.de
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Introduction |
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 Top Introduction References |
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Elecsys CA 15-3 is a sandwich immunoassay that uses biotinylated 115D8 and ruthenylated DF3 as capture and detection antibodies, respectively, and electrochemiluminescence as the detection technology. Details of the test principle have been described previously (2). The test is standardized against the Enzymun-Test CA 15-3 (Roche Diagnostics GmbH) in the laboratories of the manufacturer.
The analytical evaluation was carried out according to a standardized protocol of the European Committee for Clinical Laboratory Standards (3). The results of within-run imprecision (21 replicates per analysis) and between-day imprecision (1 replicate analyzed on 21 different days) studies are available as a data supplement at Clinical Chemistry Online (http://www.clinchem.org/content/vol47/issue12). The medians of the within-run and between-day CVs were 2.5–3.8% and 5.0–5.9%, respectively, at all concentrations tested (8.4–251.7 kilounits/L) for human sera and control sera.
Confirmation of target values assigned to control sera was tested in an interlaboratory survey and was 97% for PreciControl Tumor Marker Level 1 (18.4 kilounits/L) and 96% for Level 2 (58.6 kilounits/L). The medians of all participants of an interlaboratory survey of the German Society for Clinical Chemistry were confirmed for each of the two control samples used (11.8 and 16.8 kilounits/L) by 99% (on the basis of the medians of all participants in the Elecsys study); thereby demonstrating the excellent agreement of Elecsys CA 15-3 with other CA 15-3 immunoassays. Interlaboratory imprecision with controls and two human sera pools (20.3 and 76.5 kilounits/L) was calculated on the basis of all results obtained on different analyzers (five assays; nine laboratories). CVs of 7.1–7.4% were obtained, except for the control sample with low concentration (11.8 kilounits/L; CV, 9.3%).
Elecsys CA 15-3 was compared with Enzymun-Test CA 15-3 on ES 700 in seven laboratories and with AxSYM CA 15-3 (Abbott Laboratories) in three laboratories. Regression equations were calculated according to Passing and Bablok (4). The graphic presentation of the method comparison studies is shown in the data supplement at Clinical Chemistry Online (http://www.clinchem.org/content/vol47/issue12). Acceptable agreement [y = 0.94x + 0.91 (Sy|x=4.78; r = 0.970; n = 1734; 95% confidence intervals for slope and intercept, 0.93–0.96 and 0.63–1.20)] was found between Elecsys CA 15-3 (y) and Enzymun-Test CA 15-3 (x). The comparison between Elecsys CA 15-3 (y) and AxSYM CA 15-3 (x) for 1170 samples revealed a slope of 1.10 (95% confidence interval, 1.08–1.12), a negligible intercept (-0.48 kilounits/L; 95% confidence interval, -0.84 to -0.09), a correlation of 0.920, and a Sy|x of 11.55. The scatter is especially found at high concentrations, which occur only in patients with active breast cancer.
The limit of detection of the Elecsys CA 15-3 (mean +2 SD from 21 replicates of the zero calibrator) was <1.0 kilounits/L, as determined in the laboratories of the manufacturer. Linearity was evaluated by dilution of human sera with high CA 15-3 values close to the upper limit of the measuring range with either low concentration human sera or Elecsys Diluent Universal as described previously (5). The Elecsys CA 15-3 was confirmed as linear at 30–300 kilounits/L on the basis of a recovery acceptance range of 100% ± 15% from the expected concentration in the majority of the dilution series (35 of 42). No high-dose hook effect was detected in one very high concentrated sample of 46 000 kilounits/L CA 15-3. Higher concentrations are extremely unlikely to occur.
Endogenous interferences were tested in one laboratory with the model for hemoglobin and bilirubin described by Glick et al. (6) and by dilution with a lipemic serum for studying triglyceride interference. No interferences occurred up to 739 µmol/L bilirubin, 1.0 mmol/L hemoglobin, and 20.6 mmol/L triglycerides (highest concentrations tested) on the basis an acceptance range of 100% ± 10% of the expected value (37 kilounits/L without endogenous compounds). Comparison studies between serum (x) and ammonium heparinate plasma (y1; n = 31), as well as EDTA plasma (y2; n = 28) gave the following regression equations: y1 = 1.01x + 0.4, r = 0.989; y2 = 0.96x + 0.5, r = 0.984. The results indicate that both types of plasma are suitable as sample materials.
Retrospective samples were used throughout the investigation.
Sera from 272 apparently healthy individuals (177 females, 95 males; age range, 18–61 years) were measured in three laboratories. Ninety-five percent of Elecsys CA 15-3 values were <25 kilounits/L. No differences between sexes were observed.
Samples from 345 patients with various "benign" diseases (including 58 breast confirmed by biopsy, 109 gastrointestinal, 42 gynecologic, 37 renal failure, 34 urologic, 28 bacterial infections) were analyzed with Elecsys CA 15-3. The medians in the benign disease groups (11–18 kilounits/L) were close to the median in apparently healthy volunteers (13 kilounits/L). CA 15-3 was above the 95th percentile of healthy individuals (25 kilounits/L) in 4–19% of the patients studied.
We measured CA 15-3 in sera from 284 patients with active malignant diseases (other than breast cancer) at all stages and without therapy (including 34 ovarian carcinomas, 38 carcinomas of the lung, 40 pancreatic carcinomas, 37 primary liver cell carcinomas, 36 stomach carcinomas, 40 colorectal carcinomas, 48 prostate carcinomas). Median values in the different malignant groups were 15–27 kilounits/L, and 7–40% of values were above the 95th percentile of healthy individuals. Especially high concentrations up to 748 kilounits/L were found in patients with active hepatocellular, ovarian, and stomach carcinomas.
The distribution of CA 15-3 values is available as a data supplement at Clinical Chemistry Online (http://www.clinchem.org/content/vol47/issue12).
Samples from 283 patients with breast cancer at the time of primary diagnosis [including 56 Union Internationale Contre le Cancer (UICC) stage I, 126 stage II, 77 stage III, and 24 stage IV] were analyzed with Elecsys CA 15-3. A subgroup of 203 samples was measured in parallel with AxSYM CA 15-3.
For evaluating the diagnostic accuracy, we followed the recommendations of the European Group on Tumor Markers (7) and used benign breast diseases as the control group. The diagnostic sensitivity at 95% specificity increased in parallel to the tumor stage studied, as expected from the distribution shown in Fig. 1
. Analysis of ROC curves showed an area under the curve (8) of 0.53 for Elecsys CA 15-3 and 0.53 for AxSYM CA 15-3 in UICC I patients, and the values increased to >0.92 in UICC stage IV patients.
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Measurements with Elecsys and AxSYM CA 15-3 were also carried out in 538 individual samples collected serially from 98 clinically well-characterized patients during treatment and follow-up. Changes of 
25% between two consecutive samples were rated as "increase" or "decrease", respectively, except for changes within the low range of 0–10 kilounits/L, which were rated as "no change" because of the imprecision of the methods for low values. The methods had similar tendencies for a 25% increase, no change, or a 25% decrease [
coefficient of agreement, 0.72; 95% confidence interval, 0.65–0.79 (9)].
On the basis of clinical information, samples were classified according to progression/recurrence, no change, or regression/response.
The sensitivity and specificity of Elecsys CA 15-3 for detection of recurrence were evaluated in the subgroup of patients treated for UICC stage II or III breast cancer with no evidence of disease at the beginning of follow-up (Table 1
). Only the first recurrence was rated per patient. Increases occurring only before or at the time of recurrence were evaluated as true positive. Patients with an increase of values at the end of follow-up were excluded when later clinical information was not available. Analogously, progression was evaluated in patients with metastatic disease at the beginning of follow-up, and response to treatment was tested in patients with metastatic breast cancer from the beginning of or during follow-up (Table 1
). The findings confirm the previously described suitability of CA 15-3 for detection of recurrences (10)(11) and for analyzing the course of disease and treatment response in patients with metastases (12).
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The Elecsys CA 15-3 test has an imprecision (CV) <7.5%, is linear at 30–300 kilounits/L, and has resistance to various types of interferents. Diagnostic sensitivity is comparable to that of the AxSYM method as is detection of recurrence/response to therapy. Despite the clinical comparability of the Elecsys CA 15-3 and AxSYM CA 15-3 methods in the evaluation of marker changes in individuals during follow-up, to switch from one method to another requires parallel determination by both methods because results for individual patients may show method-dependent differences.
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Acknowledgments |
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References |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) in benign breast diseases and breast cancer according to UICC stage and the corresponding sensitivity.