György Sölétormos

National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers

BACKGROUND Updated National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. METHODS Published reports relevant to use of tumor markers for 5 cancer sites--testicular, prostate, colorectal, breast, and ovarian--were critically reviewed. RESULTS For testicular cancer, alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are recommended for diagnosis/case finding, staging, prognosis determination, recurrence detection, and therapy monitoring. alpha-Fetoprotein is also recommended for differential diagnosis of nonseminomatous and seminomatous germ cell tumors. Prostate-specific antigen (PSA) is not recommended for prostate cancer screening, but may be used for detecting disease recurrence and monitoring therapy. Free PSA measurement data are useful for distinguishing malignant from benign prostatic disease when total PSA is <10 microg/L. In colorectal cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, postoperative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing may be used for screening asymptomatic adults 50 years or older. For breast cancer, estrogen and progesterone receptors are mandatory for predicting response to hormone therapy, human epidermal growth factor receptor-2 measurement is mandatory for predicting response to trastuzumab, and urokinase plasminogen activator/plasminogen activator inhibitor 1 may be used for determining prognosis in lymph node-negative patients. CA15-3/BR27-29 or carcinoembryonic antigen may be used for therapy monitoring in advanced disease. CA125 is recommended (with transvaginal ultrasound) for early detection of ovarian cancer in women at high risk for this disease. CA125 is also recommended for differential diagnosis of suspicious pelvic masses in postmenopausal women, as well as for detection of recurrence, monitoring of therapy, and determination of prognosis in women with ovarian cancer. CONCLUSIONS Implementation of these recommendations should encourage optimal use of tumor markers.

Tumor Markers in Breast Cancer – European Group on Tumor Markers Recommendations

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins (CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin (trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy.

Tumor markers in the management of patients with ovarian cancer

Epithelial ovarian cancer constitutes one-quarter of the gynecologic malignancies, but is the leading cause of death among women with gynecologic cancer. In 6070% of the women, the disease is detected at a late stage when 5-year survival is poor. The recommended primary therapeutic approach for ovarian cancer is aggressive primarydebulking surgery followed by combination chemotherapy. The efficacy is routinely evaluated by repeated vaginal examination and transabdominal ultrasonography. However, these methods are unreliable for monitoring as progressive and recurrent disease often remains hidden until the patient presents with a large tumor mass. Over the last few decades a variety of serological tumor markers has been proposed as a supplement to other non-invasive diagnostic methods. The main issue with tumor marker measurements is to obtain reliable information about changes in tumor mass before the changes are detectable by other methods. However, despite several attempts to identify useful serological markers for epithelial ovarian cancer, the results have not been as encouraging as for germ-cell tumors. The purpose of this paper is to review the applicability of CA 125, CEA, TPA, TATI, CASA, and tetranectin in screening, diagnosis, prognosis, and monitoring of ovarian carcinoma. Several compounds other than those mentioned above are being investigated as markers in the early detection and management of ovarian cancer. Some ofthese potential tumor markers listed in Table 1 will not be discussed further in this review.

Validation of New Cancer Biomarkers: A Position Statement from the European Group on Tumor Markers

BACKGROUND Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use. CONTENT In this review, we discuss the key steps in advancing a newly discovered cancer candidate biomarker from pilot studies to clinical application. Four main steps are necessary for a biomarker to reach the clinic: analytical validation of the biomarker assay, clinical validation of the biomarker test, demonstration of clinical value from performance of the biomarker test, and regulatory approval. In addition to these 4 steps, all biomarker studies should be reported in a detailed and transparent manner, using previously published checklists and guidelines. Finally, all biomarker studies relating to demonstration of clinical value should be registered before initiation of the study. SUMMARY Application of the methodology outlined above should result in a more efficient and effective approach to the development of cancer biomarkers as well as the reporting of cancer biomarker studies. With rigorous application, all stakeholders, and especially patients, would be expected to benefit.

Clinical Use of Cancer Biomarkers in Epithelial Ovarian Cancer: Updated Guidelines From the European Group on Tumor Markers.

Objective To present an update of the European Group on Tumor Markers guidelines for serum markers in epithelial ovarian cancer. Methods Systematic literature survey from 2008 to 2013. The articles were evaluated by level of evidence and strength of recommendation. Results Because of its low sensitivity (50–62% for early stage epithelial ovarian cancer) and limited specificity (94–98.5%), cancer antigen (CA) 125 (CA125) is not recommended as a screening test in asymptomatic women. The Risk of Malignancy Index, which includes CA125, transvaginal ultrasound, and menopausal status, is recommended for the differential diagnosis of a pelvic mass. Because human epididymis protein 4 has been reported to have superior specificity to CA125, especially in premenopausal women, it may be considered either alone or as part of the risk of ovarian malignancy algorithm, in the differential diagnosis of pelvic masses, especially in such women. CA125 should be used to monitor response to first-line chemotherapy using the previously published criteria of the Gynecological Cancer Intergroup, that is, at least a 50% reduction of a pretreatment sample of 70 kU/L or greater. The value of CA125 in posttherapy surveillance is less clear. Although a prospective randomized trial concluded that early administration of chemotherapy based on increasing CA125 levels had no effect on survival, European Group on Tumor Markers state that monitoring with CA125 in this situation should occur, especially if the patient is a candidate for secondary cytoreductive surgery. Conclusions At present, CA125 remains the most important biomarker for epithelial ovarian cancer, excluding tumors of mucinous origin.

Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up

CA 125 is currently widely applied in the management of patients with ovarian cancer. However, a change in results of CA 125, which should be considered significant, has not been defined. The aim of this study was to investigate the ability of CA 125 to signal progressive ovarian cancer during follow-up after firstline chemotherapy. The study patients were selected retrospectively among 255 patients with stage IC-IV ovarian cancer. The evaluation of the CA 125 information was based on the analytical imprecision, the normal intra-individual biological variation, the sampling interval, and the cut-off value. Additionally, the utility of a new assessment criterion based upon an increment of 2.5 times the baseline CA 125 concentration confirmed by a third measurement was investigated. The efficiency of CA 125 to identify progression and non-progression during follow-up varied between 76.5 and 79.9%, depending on the applied time limit for an acceptable positive lead time. The median lead time for true positive results was 95-99.5 days. Using the new elaborated criterion, the efficiency of CA 125 for identifying progression and non-progression varied between 75.7 and 78.5%, depending on the applied time limit for an acceptable positive lead time. The median lead time for true positive results was 91-95.5 days. CA 125 provided early and reliable information about progressive disease during follow-up. The applied criteria can therefore be recommended in further studies assessing the clinical utility of serological tumor markers in patients with ovarian cancer.

Design of Tumor Biomarker–Monitoring Trials: A Proposal by the European Group on Tumor Markers

A major application of tumor biomarkers is in serial monitoring of cancer patients, but there are no published guidelines on how to evaluate biomarkers for this purpose. The European Group on Tumor Markers has convened a multidisciplinary panel of scientists to develop guidance on the design of such monitoring trials. The panel proposes a 4-phase model for biomarker-monitoring trials analogous to that in use for the investigation of new drugs. In phase I, biomarker kinetics and correlation with tumor burden are assessed. Phase II evaluates the ability of the biomarker to identify, exclude, and/or predict a change in disease status. In phase III, the effectiveness of tumor biomarker-guided intervention is assessed by measuring patient outcome in randomized trials. Phase IV consists of an audit of the long-term effects after biomarker monitoring has been included into standard patient care. Systematic well-designed evaluations of biomarkers for monitoring may provide a stronger evidence base that might enable their earlier use in evaluating responses to cancer therapy.

Biological variation and analytical imprecision of CA 125 in patients with ovarian cancer.

Despite the availability of serial data on CA 125 in ovarian cancer, the problem of interpreting a change over time is still unsolved. Changes in marker concentrations are due not only to patients improving or deteriorating but also to analytical imprecision and normal intra-individual biological variation. The aim of this study was to assess the analytical imprecision (CVA) and the intraand inter-individual biological variation (CVI and CVG

PROGNOSTIC VALUE OF SERUM TETRANECTIN IN PATIENTS WITH METASTATIC BREAST CANCER

To evaluate serum tetranectin as a prognostic marker before first-line chemotherapy, serum levels were studied in 67 patients with metastatic breast cancer. In the Cox analyses, the relative risk (RR) for death of cancer varied with the cut-off level of serum tetranectin. A maximal RR of 5.0 was found for patients with serum tetranectin < or = 5.4 mg/l. The maximal RR of death for the other prognostic variables were multiple metastases 2.8, and for a poor performance status 2.0. Testing for the outcome, progressive disease, a maximal RR of 3.8 was found for patients with serum tetranectin < or = 5.3 mg/l, a maximal RR of 3.7 for multiple metastases and a maximal RR of 1.8 for a poor performance status. Significantly lower serum tetranectin values were found in patients with a poor treatment response compared to well responding patients. Serum tetranectrin seems to be useful as an additional prognostic factor in metastatic breast cancer.

Calculation of limits for significant bidirectional changes in two or more serial results of a biomarker based on a computer simulation model

BACKGROUND Reference change values provide objective tools to assess the significance of a change in two consecutive results of a biomarker from an individual. However, in practice, more results are usually available and using the reference change value concept on more than two results will increase the number of false positive results. METHODS A computer simulation model was developed using Excel. Based on 10,000 simulated measurements among healthy individuals, a series of up to 20 results of a biomarker from each individual was generated using different values for the within-subject biological variation plus the analytical variation. Each new result in this series was compared to the initial result. These successive serial differences were computed to give limits for significant bidirectional changes with constant cumulated maximum probabilities of 95% (p < 0.05) and 99% (p < 0.01). RESULTS From an individual factors used to multiply the first result were calculated to create limits for constant cumulated significant changes. The factors were shown to become a function of the number of results included and the total coefficient of variation. CONCLUSIONS The first result should be multiplied by the appropriate factors for increase and decrease to give the limits for a significant bidirectional change in several consecutive measurements.