Malgorzata K. Tuxen

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.

A systematic review of dual targeting in HER2-positive breast cancer.

BACKGROUND Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15-20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer. MATERIALS AND METHODS A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included. RESULTS This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described. CONCLUSION Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.

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.

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.

Interpretation of sequential measurements of cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) based on analytical imprecision and biological variation in the monitoring of ovarian cancer

Abstract The main objective with cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) monitoring of ovarian cancer patients is to detect an early change of disease activity with high reliability. We hypothesized that a monitoring scheme for ovarian cancer patients with serological tumor markers should take into account the stochastic variation, i.e. the probability that observed increases and decreases may solely be due to analytical imprecision and normal intra-individual biological variation. The aim of this study was to provide a detailed characteristic of the within-subject mean steady state concentrations and the associated variability in healthy individuals with an age distribution representative for ovarian cancer patients. Thirty-one healthy women with a median age of 55 years comprised the study population. Sixteen blood samples were collected from each subject in four series, with four samples per series, over a period of approximately 1 year. We found that, i) natural logarithmic-transformed concentrations were more homogeneously distributed between individuals than the original concentrations, ii) the within-subject mean steady state levels, the standard deviations, and the coefficients of variation differed among subjects, and iii) the steady state variability differed among the markers. In conclusion, our data indicate that the assessment of sequential CA 125, CEA, and TPA concentrations is more complex than hitherto recognized. We suggest that it is necessary to adjust the assessment criteria to the type of marker, and that assessment may be facilitated if based on natural logarithmic transformed concentrations.

The role of second-look laparotomy in the long-term survival in ovarian cancer

BACKGROUND To elucidate the role of second-look laparotomy in the management of ovarian cancer patients, were retrospectively reviewed our experience with this procedure in epithelial ovarian cancer patients. PATIENTS AND METHODS The hospital records of 617 patients with advanced ovarian cancer were reviewed. The 308 patients who underwent second-look laparotomy were followed from four to 18 years with a median follow-up of 12 years after start of primary chemotherapy. RESULTS Patients who achieved pathological complete response (PCR), microscopic partial response (PPR mic.), macroscopic partial response (PPR mac.), stable disease (PSD), and progressive disease (PPD) at second-look laparotomy had a median survival time of 149, 39.5, 24, 14, and eight months, respectively. Secondary surgical cytoreduction could be performed only in 101 patients with macroscopic persistent disease. The group of all patients with secondary tumor debulking had no survival advantage compared with the group of patients with PPR mac., PSD, and PPD, unable to have secondary cytoreduction. Patients left with no tumor after second-look laparotomy did not survive as long as patients who achieved PCR and PPR mic. at second-look laparotomy. Factors prolonging survival after second-look laparotomy included younger age, good pre-treatment performance status, smaller primary residual tumor size, longer interval between start of chemotherapy and second-look laparotomy, and the pathologically proven CR or PR mic. CONCLUSION Second-look laparotomy appears to have a minor role in the routine management of ovarian cancer patients, especially in the context of the limited effectiveness of second-line therapy. This procedure should be limited to clinical treatment protocols to determine effectiveness of new agents.