Literature Review: Tumour Markers

Small intestinal neuroendocrine tumours (SI-NETs) are amine- and peptide producing neoplasms. Most patients display metastases at the time of diagnosis, they have an unpredictable individual disease course and the tumours are often therapy resistant. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are the clinically most used biomarkers today, but there is a great need for novel diagnostic and prognostic biomarkers and new therapeutic targets. Sixty-nine biomarkers were screened in serum from 23 SI-NET patients and 23 healthy controls using multiplex PLA (proximity ligation assay). A refined method, PEA (proximity extension assay), was used to analyse 76 additional biomarkers. Statistical testing and multivariate classification were performed. Immunohistochemistry and ELISA assays were performed in an extended cohort. Using PLA, 19 biomarkers showed a significant difference in serum concentrations between patients and controls, and PEA revealed difference in concentrations in 13 proteins. Multivariate classification analysis revealed decoy receptor 3 (DcR3), trefoil factor 3 (TFF3) and Midkine to be good biomarkers for disease, which was confirmed by ELISA analysis. All three biomarkers were expressed in tumour tissue. DcR3 concentrations were elevated in patients with stage IV disease. High concentrations of DcR3 and TFF3 were correlated to poor survival. DcR3, TFF3 and Midkine exhibited elevated serum concentrations in SI-NET patients compared to healthy controls, and DcR3 and TFF3 were associated with poor survival. DcR3 seems to be a marker for liver metastases while TFF3 and Midkine may be new diagnostic biomarkers for SI-NETs.

More than half of all new lung cancer diagnoses are made in patients with locally advanced or metastatic disease, at which point therapeutic options are scarce. It is anticipated, however, that the widespread use of Low-Dose Computed Tomography (LDCT) screening, will lead to a greater proportion of lung cancers being diagnosed at an early, operable, stage. Still, the overall rate of recurrence for surgically treated Stage I lung cancer patients is up to 30% within 5 years of diagnosis. Thus, the identification and clinical application of biomarkers of early stage lung cancer are a pressing medical need. The integrative analysis of “omic,” clinical and epidemiological data for single patients is a core principle of precision medicine. Through rigorous bioinformatics and statistical analyses we have identified biomarkers of early-stage lung cancer based on DNA methylation, expression of mRNA and miRNA, inflammatory cytokines, and urinary metabolites. Beyond a more comprehensive understanding of the molecular taxonomy of lung cancer, these biomarkers can have very practical implications in the context of unmet clinical needs of early stage lung cancer patients: First, current guidelines for LDCT screening broadly include individuals based on age and history of heavy smoking. Tumour-derived circulating biomarkers in the blood and urine associated with lung cancer risk could narrow and prioritize individuals for LDCT screening. Second, a high number of nodules are identified by LDCT, of which fewer than 5% are finally diagnosed as lung cancer. Biomarkers may help discriminate malignant nodules from benign or indolent lesions. Third, the expected rise in the numbers of lung cancer patients diagnosed at an early stage will necessitate new treatment options. Circulating, urinary and tissue-based biomarkers that molecularly categorize Stage I patients after tumour resection can help identify high-risk patients who may benefit from adjuvant chemotherapy or innovative immunotherapy regimens.

Pancreatic ductal adenocarcinoma (PDAC) prognosis remains very poor and has only marginally improved during the last decades. Epigenetic alterations have been the focus of many recent studies and offer valuable options for PDAC detection, prognosis and treatment. DNA methylation, histone modifications and microRNA (miR) level changes can be used as biomarkers. These alterations occur early in carcinogenesis and may be specific for PDAC. Additionally, epigenetic alterations can be analysed from cell-free DNA, free-circulating nucleosomes or shed tumour cells in blood. High-throughput methods are available for miR and DNA methylation level detection. In particular, multiple promising miR level changes have been discovered. No single epigenetic biomarker that offers a sufficient specificity has been discovered yet, but patterns containing multiple independent biomarkers exist.

BACKGROUND: The diagnosis of prostate cancer (PCa) is currently based on serum PSA testing and/or abnormal digital rectal examination and histopathologic evaluation of prostate biopsies. The main drawback of PSA testing is the lack of specificity for PCa. To improve early detection of PCa more specific biomarkers are needed. In the past few years, many new promising biomarkers have been identified; however, to date, only a few have reached clinical practice.

METHODS: In this review, we discuss new blood-based and urinary biomarker models that are promising for usage in PCa detection, follow-up and treatment decision-making. These include Prostate Health Index (PHI), prostate cancer antigen 3 (PCA3), four-kallikrein panel (4K), transmembrane protease serine 2-ERG (TMPRSS2-ERG), ExoDx Prostate Intelliscore, SelectMDx and the Mi-Prostate score. Only few head-to-head studies are available for these new fluid-based biomarkers and/or models. The blood-based PHI and urinary PCA3 are two US Food and Drug Administration-approved biomarkers for diagnosis of PCa. In the second part of this review, we give an overview of published studies comparing these two available biomarkers for prediction of (1) PCa upon prostate biopsy, (2) pathological features in radical prostatectomy specimen and (3) significant PCa in patients eligible for active surveillance.

RESULTS: Studies show opposing results in comparison of PHI with PCA3 for prediction of PCa upon initial and repeat prostate biopsy. PHI and PCA3 are able to predict pathological findings on radical prostatectomy specimen, such as tumour volume and Gleason score. Only PHI could predict seminal vesicle invasion and only PCA3 could predict multifocality. There is some evidence that PHI outperforms PCA3 in predicting significant PCa in an active surveillance population.
CONCLUSIONS: Future research should focus on independent validation of promising fluid-based biomarkers/models, and prospective comparison of biomarkers with each other.

OBJECTIVE: To evaluate the short-term consequences and cost-effectiveness associated with the use of novel biomarkers to triage young adult women with minor cervical cytological lesions.

DESIGN: Model-based economic evaluation using primary epidemiological data from Norway, supplemented with data from European and American clinical trials.

SETTING: Organised cervical cancer screening in Norway.

POPULATION: Women aged 25–33 years with minor cervical cytological lesions detected at their primary screening test.

METHODS: We expanded an existing simulation model to compare 12 triage strategies involving alternative biomarkers (i.e. reflex human papillomavirus (HPV) DNA/mRNA testing, genotyping, and dual staining) with the current Norwegian triage guidelines.

MAIN OUTCOME MEASURES: The number of high-grade precancers detected and resource use (e.g. monetary costs and colposcopy referrals) for a single screening round (3 years) for each triage strategy. Cost-efficiency, defined as the additional cost per additional precancer detected of each strategy compared with the next most costly strategy.

RESULTS: Five strategies were identified as cost-efficient, and are projected to increase the precancer detection rate between 18 and 57%, compared with current guidelines; however, the strategies did not uniformly require additional resources. Strategies involving HPV mRNA testing required fewer resources, whereas HPV DNA-based strategies detected >50% more precancers, but were more costly and required twice as many colposcopy referrals compared with the current guidelines.

CONCLUSION: Strategies involving biomarkers to triage younger women with minor cervical cytological lesions have the potential to detect additional precancers, yet the optimal strategy depends on the resources available as well as decision-makers’ and women’s acceptance of additional screening procedures.