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REVIEW ARTICLE
Ahead of print publication  

The issues and challenges with cancer biomarkers


1 Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
2 Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
3 Department of Radiotherapy, All India Institute of Medical Sciences, New Delhi, India
4 Formerly Chief, IRCH, All India Institute of Medical Sciences, New Delhi; Ex-Director, NCI, Jhajjar, Haryana, India

Date of Submission15-Feb-2022
Date of Decision28-May-2022
Date of Acceptance03-Jun-2022

Correspondence Address:
Subhradip Karmakar,
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_384_22

 > Abstract 


A biomarker is a measurable indicator used to distinguish precisely/objectively either normal biological state/pathological condition/response to a specific therapeutic intervention. The use of novel molecular biomarkers within evidence-based medicine may improve the diagnosis/treatment of disease, improve health outcomes, and reduce the disease's socio-economic impact. Presently cancer biomarkers are the backbone of therapy, with greater efficacy and better survival rates. Cancer biomarkers are extensively used to treat cancer and monitor the disease's progress, drug response, relapses, and drug resistance. The highest percent of all biomarkers explored are in the domain of cancer. Extensive research using various methods/tissues is carried out for identifying biomarkers for early detection, which has been mostly unsuccessful. The quantitative/qualitative detection of various biomarkers in different tissues should ideally be done in accordance with qualification rules laid down by the Early Detection Research Network (EDRN), Program for the Assessment of Clinical Cancer Tests (PACCT), and National Academy of Clinical Biochemistry. Many biomarkers are presently under investigation, but lacunae lie in the biomarker's sensitivity and specificity. An ideal biomarker should be quantifiable, reliable, of considerable high/low expression, correlate with the outcome progression, cost-effective, and consistent across gender and ethnic groups. Further, we also highlight that these biomarkers' application remains questionable in childhood malignancies due to the lack of reference values in the pediatric population. The development of a cancer biomarker stands very challenging due to its complexity and sensitivity/resistance to the therapy. In past decades, the cross-talks between molecular pathways have been targeted to study the nature of cancer. To generate sensitive and specific biomarkers representing the pathogenesis of specific cancer, predicting the treatment responses and outcomes would necessitate inclusion of multiple biomarkers.

Keywords: Biomarker, cancer, childhood malignancies, early detection, pediatrics population, qualitative, quantitative, reference values, therapeutic intervention



How to cite this URL:
Purkayastha K, Dhar R, Pethusamy K, Srivastava T, Shankar A, Rath GK, Karmakar S. The issues and challenges with cancer biomarkers. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 9]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=358008




 > Introduction Top


The United States Food and Drug Administration (US FDA) defines the biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic response to a therapeutic intervention.[1] A biomarker can be a molecule secreted by the diseased cells or a specific response of the body to the disease. Genetic, epigenetic, proteomic, glycomic, and imaging biomarkers are readily used for disease diagnosis, prognosis, and epidemiology. Such biomarkers can be assayed in non-invasively collected bio-fluids like blood or serum.[2]

Biomarkers are essential entities, and existence has been there since the understanding of human biology. The biomarker concept was laid down in 600 Bc by Susruta in India, that urine of diabetic patients attracted ants followed by milestones laid by Jozef Straus, Wilhelm Rontgen, and Henry Becquerel for blood pressure, X-ray, and radio-diagnostics, respectively. The first known malignancy marker was done 2000 years ago when breast cancer was distinguished from mastitis.[3] The first tumor marker in modern medicine was identified by Bence Jones. They, in 1846, detected a heat precipitate in samples of acidified urine from patients suffering from “Mollities osseum”[3] followed by Gold et al.[4] in 1965, who isolated a glycoprotein molecule from specimens of human colonic cancer and thus discovered the first “tumor antigen,” later identified as carcinoembryonic antigen (CEA), which was facilitated by radioimmunological assay. In 1980, the hybridoma technology enabled the discovery of ovarian epithelial cancer marker, carbohydrate antigen (CA) 125.[5]

To date, we do have many biomarkers under investigation, but major lacunae lie in the sensitivity and specificity of the biomarker in clinical practice. Various biomarkers have been used for generations by epidemiologists, physicians, and scientists to study human disease. Of all the 4000 biomarkers, which are listed in the biomarker base, 26% are developed in the area of oncology, [Figure 1]. The primary application of biomarkers has been in diagnosing and managing cardiovascular disease, infections, immunological and genetic disorders, and cancer.[6],[7] There have been many challenges in discovering biomarkers and further translating them from bench to bedside, which is evident from the decline in the number of biomarkers cleared by the US FDA over the last 10 years. A greater understanding of disease biology and drug pharmacology would potentiate the use of new biomarkers in clinical practice.
Figure 1: Distribution of biomarkers being used in various therapeutic areas

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As discussed in Biomarker Base™, in 2014, a novel cancer diagnostic biomarker is published once every 4–5 days, which is less compared to the novel prognostic biomarkers being published.

This review article gives a comprehensive insight into the various challenges in the discovery of a new biomarker. Research towards the discovery of a biomarker is very challenging, due to the complexity of the disease itself. An improved understanding of the disease is required for a structured approach towards a promising biomarker, which needs to be sensitive and specific due to the underlying etiology of the disease and further resistance to therapy. In spite of the use of a panel of markers for documenting the progression/remission of diagnostic, prognostic, and therapeutic endpoints of the disease, the mortality rate is still high in many types of cancers. Maximum research of biomarkers is done in the area of cancer; still, in a few types of cancer, a cure is not available. There is a spectrum of issues and challenges in the process of discovering an ideal biomarker. An ideal biomarker should be quantifiable, reliable, have considerable high/low expression in the disease condition, correlate with the outcome progression, be consistent across gender and ethnic groups, and be cost-effective. Further, we also highlight that these biomarkers' application remains questionable in childhood malignancies due to a lack of reference values in the pediatric population.


 > Classification of Biomarkers Top


The biomarkers can be classified broadly or categorized by characteristics, applications, genetic knowledge, and their molecular biology.

Broad classification

The broad classification of disease-specific biomarkers is based on the principle to detect disease, stage of the disease, progression, and recurrence, predict response to treatment, determine efficacy, and monitor treatment compliance. Disease-related biomarkers are categorized as predictive, diagnostic, and prognostic. Drug-related biomarkers can evaluate the effectiveness and fate of the drug in the patient.

Based on characteristics

The biomarkers can be classified as imaging biomarkers, molecular biomarkers, and nucleic acid biomarkers.

Based on applications

The biomarkers can be classified as diagnostic, prognostic, staging, and pharmacodynamic biomarkers.

Based on genetic and molecular biology validation

The biomarkers can be classified as natural history, drug activity, and surrogate markers.

Based on molecular understanding

Cancer biomarkers can broadly give us an idea of the development of cancer, type of cancer, optimal drug/regime to be used, and the relapse rates [Table 1].[8],[9]
Table 1: Classification of biomarkers based on molecular understanding

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 > Importance of Biomarkers in Cancer Top


Analysis of biomarkers is very important for individualized cancer treatment. It definitely gives an idea about the patient's tumor, risk stratification, relapse and therapeutic efficacy, and appropriate treatment that would be best for the individual.[10],[11] Integration of biomarkers and the recent technologies into the health care system has many potential benefits [Table 2].
Table 2: Various measures and their potential effects on health care

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 > Various Tissues and Body fluids for Investigation of Biomarkers Top


A biomarker's presence is not restricted to one tissue and is found in all parts of the body. Most clinicians and scientists prefer non-invasive or minimally invasive techniques for obtaining the specimen for investigation. The type of sample under investigation varies according to the cancer type [Table 3].[12],[13]
Table 3: The various specimens obtained for screening of biomarkers

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The biggest problem in biomarker evaluation is the various procedures employed for sample collection, storing the sample, further processing, and varied assay platforms for conducting the biomarker of interest. The best-recommended method for the collection of samples is to snap freeze in liquid nitrogen and take the required amount of tissue for processing at a single time point. Freeze-thaw cycles should be strictly avoided to reduce the variations in the results.


 > Detection Top


The detection of a biomarker can be quantitative or qualitative. The quantitative biomarker identifies the quantity of the marker with the disease or stage of the disease. The qualitative biomarker only bridges the marker with the disease state. The evaluation of any biomarker's validity is complex and must fulfill three primary aspects of the qualification.[14]

  • Content validity shows the degree to which a biomarker reflects the biological phenomenon studied.
  • Construct validity, which pertains to other relevant characteristics of the disease or trait.
  • Criterion validity shows the extent to which the biomarker correlates with the specific disease and is usually measured by sensitivity, specificity, and predictive power.[15]


As the complete and complex understanding of many diseases is still ongoing, the heterogeneity of the disease should always be considered during the identification and evaluation of biomarkers. In 2002, the National Cancer Institute's (NCI) “EarlyDetection Research Network” documented the systematic discovery and evaluation of biomarkers in five phases,[16],[17] which are as follows:

  • Phase I - Pre-clinical exploratory phase, the promising directions are identified
  • Phase II - Validation phase for the establishment of the clinical assay for validation of biomarker
  • Phase III - Retrospective longitudinal phase for assessment of specimens from study subjects before the onset of the disease
  • Phase IV - Prospective screening study phase evaluates the sensitivity and specificity of the biomarker in a prospective study.
  • Phase V - Cancer control phase for evaluating the overall benefits and risks of the new diagnostic test on the screened population


NCI has initiated the “Program for the Assessment of Clinical Cancer Tests (PACCT)” to ensure that the next generation of laboratory tests' development is efficient and effective. A new program started by NCI “Clinical Assay Development Program,” will help in the development of promising assays that may predict which treatment may be better or will help indicate particular cancer's aggressiveness.

An engineered systematic approach to biomarker discovery has been laid by the Jet Propulsion Laboratory-National Aeronautics and Space Administration (JPL/NASA) in seven steps [Table 4].
Table 4: The steps laid for biomarkers by JPL/NASA

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The early work on biomarkers was not very promising as the focus was mainly on discovering similar masses, identifying proteins similar to serum proteins, and colossal failure for biomarker validation in multi-centric clinical trials. The early failures in biomarker detection led to the understanding that the body fluids are complex, variable, fragile, and not abundant. Many of the confounding factors also add to the difficulty in detecting the biomarker of interest; the potential confounders can be age, gender, ethnicity, diet, metabolic factors, laboratory evaluation parameters, and many more unidentifiable factors.

There are many advantages and disadvantages associated with the use/interpretations of biomarkers [Table 5].
Table 5: Advantages and disadvantages associated with biomarkers

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An ideal biomarker should be quantifiable, reliable, have considerable high/low expression in the disease condition, correlate with the outcome progression, be consistent across gender and ethnic groups, and be cost-effective. The various assay techniques employed for discovering molecular markers are the genomics approach, proteomics approach, lipidomics approach, secretomes approach, and metabolomics approach [Table 6] and [Table 7].
Table 6: Various high-throughput technologies used in biomarker discovery in Omics science

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Table 7: List of biomarkers along with their method of investigation and their clinical applications

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 > Techniques Used in Biomarker Discovery Top


Cancer biomarkers are present in tumor tissues or serum and encompass a wide variety of molecules, including DNA, mRNA, transcription factors, cell surface receptors, and secreted proteins. The biomarker studies should be based on sound biology, and a panel of multiple biomarkers should be analyzed to increase the specificity, sensitivity, and robustness.

Few of the quality requirements are laid down by the National Academy of Clinical Biochemistry in three broad categories.[49]

  • Pre-analytical requirements: choice of tumor marker, specimen type, specimen timing, sample handling.
  • Analytical requirements: assay standardization, internal and external quality control, interferences.
  • Post-analytical requirements: reference intervals, interpretation, and reporting of tumor marker results.


The techniques used for early detection like pap smears and colonoscopy have helped us reduce the disease burden to a large extent. Few of the early detection markers like Prostate-Specific Antigen (PSA), cancer antigen 125 (CA125), Carcinoembryonic Antigen (CEA), and Alpha-fetoprotein (AFP) were very non-specific and unreliable. The lacunae in identifying robust biomarkers led the entire scientific community to adopt high-throughput screening platforms to identify biomarkers.[51]

Major challenges faced in predictive biomarker discovery are biological and clinical. Biological challenges mainly account for the biological complexity of the complex network of molecular pathways; the clinical challenges indicate favorable clinical outcomes in a specific group of patients. In the cancer prognosis, the genes mainly contribute to proliferation, angiogenesis, extracellular matrix adhesion, invasion, survival, and unknown function [Table 8].
Table 8: List of various screening levels and their usefulness

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The major targets of cancer therapy are growth factors, growth factor receptors, adaptor proteins, binding proteins, guanine nucleotide exchange factors, phosphatases, phospholipases, signaling kinases, ribosomes, transcription factors, histones, DNA, microtubules, and miRNA.[52] The various strategies employed for discovering biomarkers are gene expression profiling, gene fusions, translocations, serum/plasma proteomics, secreted protein, protein arrays, peptidomics, and mass spectrometry (MS) imaging of tissue, auto-antibodies, MS-based profiling, and next-generation sequencing (NGS). The emergence of proteomics and its application started in the post-genome era, which involved advanced techniques like electrospray ionization (ESI), matrix associated laser description ionization (MALDI), surface-enhanced laser description ionization (SELDI), and time of flight (TOF).[53] The markers can be easily found by comparing the protein maps. SELDI is faster and more reproducible than a two-dimensional (2D) page and has been beneficial in discovering biomarkers for ovarian, breast, lung, liver, prostate, and bladder cancer.[54]

The emergence of new analytical technologies such as DNA arrays, protein arrays, and MS has led to the understanding of the human genome in 2001, “The International HapMap project.” Various high-throughput technologies extensively used in molecular biomarker discovery in diverse areas are genomics, proteomics, lipidomics, transcriptomics, metabolomics, and interactomics.[55]

NGS technology targets the DNA sequence and gives elaborate data for any individual. The cancer genomes give a new dimension to biomarker research. NGS is preferred above Sanger sequencing as the NGS method is more accurate for the non-repeated elements and can detect low-frequency alleles.

The other multiplex approaches used widely for the detection of biomarkers are principal component analysis, clustering, and MS-based. The quantitative approaches used are isotope labeling like isotope-coded affinity tag (ICAT), iTRAQ, stable isotope labeling in animal culture, spectral counting, Stable Isotope Labeling by/with Amino acids in Cell culture (SILAC), extracted ion chromatogram (EIC), reverse transcription–polymerase chain reaction (RT-PCR), MASStermindTM, exponentially modified protein abundance index (emPAI), multiple reaction monitoring (MRM), nuclear magnetic resonance (NMR), x-ray, computer tomography, quantum dot molecular labels, magnetic nanotags, positron emission tomography, single-particle electron microscopy, imaging MS, and bioinformatics tools.


 > Biomarkers and Limitations Top


Most of the cancer biomarkers are proteins and have the limitations of being not cancer-specific. Genetic biomarkers are more reliable than many protein biomarkers, but genetic changes have not yet been identified for every cancer type.[56]

The limitations in biomarker discovery start as early as collecting the sample, transportation, representative tissue being processed, reference standards, sensitivity and specificity of assay method, and further the post-analytical analysis.


 > Biomarkers Discovered Top


Biomarkers in oncology play a critical role in risk assessment, screening, differential diagnosis, determination of prognosis, response to treatment, and disease progression. The biomarker discovery must undergo evaluation and validation before clinical applications. It is also very necessary to draw a distinct line between biomarkers and targets. They may be very different in various types of cancers and further planning is required in the related clinical studies.[57] Commonly used cancer biomarker in clinical practice is listed in [Table 9][57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76].
Table 9: The cancer biomarkers in clinical use

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 > FDA Approved Biomarkers Top


The qualification of biomarkers is very critical. However, the FDA document states that the clearance of a testing device for marketing does not imply that the biomarker it measures has been demonstrated to have a qualified use in drug development and evaluation. Additionally, the qualification of a biomarker does not guarantee that a specific test device used in the qualification process for a biomarker is also tested or reviewed by FDA and cleared or approved for use in patient care [Table 10].[77]
Table 10: FDA-cleared protein cancer biomarkers

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 > Biomarker Studied in Various Cancers Top


The validation of biomarkers also requires a robust statistical analysis of data from multiple studies. Based on all the pre-qualifications and the statistical power, a biomarker is associated with a definite type of cancer.

Till now, many biomarkers are explored at various levels of development and in diverse types of cancers [Table 11][78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102],[103],[104],[105],[106],[107],[108],[109],[110],[111],[112],[113],[114],[115],[116],[117],[118],[119],[120],[121],[122],[123],[124],[125],[126],[127],[128],[129],[130],[131],[132],[133],[134],[135],[136],[137],[138],[139],[140],[141],[142],[143],[144],[145],[146],[147],[148],[149],[150],[151],[152],[153],[154],[155],[156],[157],[158],[159],[160],[161],[162],[163],[164],[165],[166],[167],[168],[169],[170],[171],[172],[173],[174],[175],[176],[177],[178],[179],[180],[181],[182],[183].
Table 11: The different cancer biomarkers used at various stages of research

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 > Various microRNAs (miRNAs) Investigated as Biomarker Top


MiRNAs are also in focus and are utilized as potential biomarkers in various diseases like cancer, neurological disorders, cardiovascular disease, type-II diabetes, etc. MiRNAs are small non-coding RNAs, about 21–25 nucleotides in length, and are a new class of biomarkers. MiRNAs are reported to be used for prognosis, diagnosis, treatment response, and patient stratifications. In cancer, miRNA expression variations are evident across various cancer progression stages—overexpression or down-modulation of miRNAs in cancer results in alterations of respective oncogenes. Recent advances in the miRNA field have led to the understanding of entirely new cellular transformation mechanisms and drug resistance caused by the loss of miRNA function by a miRNA variant.


 > Biomarkers in Pediatric Cancer Top


Of all the biomarkers, very few have been evaluated for childhood cancers. The Canadian laboratory initiative in pediatric reference intervals (CALIPER) project is an initiative for determining pediatric reference intervals by establishing a comprehensive database of reference values in Canadian children stratified by age, gender, and ethnicity. Despite this study, many gaps still exist in pediatric reference intervals for cancer biomarkers. The reference intervals play a very crucial role in cancer biomarkers for dividing the risk groups. Few of the other age-stratified studies are also known in neonates. There lies a significant lacuna regarding the application of various cancer biomarkers in pediatric cancers. The CALIPER project has established the reference intervals and stratified the covariates like age and sex [Table 12].
Table 12: The pediatric cancer biomarker and their clinical relevance

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 > Biomarkers in Oncology Drug Labeling Top


Adverse events are widely associated with chemotherapies. Evaluating the drug response of the pharmacogenomics biomarkers is very important in identifying responders and non-responders, calculating drug doses, and deciding on the regimen to avoid adverse events [Table 13].
Table 13: List of FDA-approved drugs with pharmacogenomic information in their labeling

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 > Summary and Conclusion Top


Cancer is a very complex disease and is a result of many factors altogether. In cancer, alterations in genetic and epigenetic factors are well documented, which further results in protein modifications in affected cells. Based on the post-translational modifications, up-regulation, and down-regulation, these proteins affect cellular signaling.

A cancer biomarker can be genes, proteins, metabolites, lipids, or miRNA. The biggest challenge is the translation of biomarkers from laboratory identification/isolation to clinical use and interpretation. This requires a greater understanding and adherence to the guidelines of qualification laid by NCI. The Early Detection Research Network (EDRN) has defined the milestone for the qualification of biomarkers required in the biomarker development process. An ideal cancer biomarker should be cheap, robust, and translatable and guide risk assessment, detection, diagnosis, prognosis, and response to therapy. Though the lacuna is big, some progress in discovering and translating biomarkers in cancer for an adult is noticeable in research papers. Major lacunae lie in applying these biomarkers to pediatric cancer. Research on this is still lacking; the only impactful study on pediatric biomarkers is the Canadian CALIPER study, which has its limitations.

The burden of cancer is increasing day by day, and in 2012, there were 14.1 million new cancer cases, 8.2 million deaths, and 32.6 million people living with cancer (within a 5-year diagnosis) worldwide. Each year 200,000 children are diagnosed with cancer worldwide. Of these, 20% of childhood cases are in high-income groups, with an 80% survival rate, and 80% of the cases are in low-income countries with a survival rate of 20%. Fundamental challenges in resource-limited settings are late presentation and under-diagnosis, abandonment of therapy, malnutrition, lack of supportive care, lack of skilled professionals, cost, and medication availability. The new drug discovery in cancer or any other disease is entirely dependent on understanding the biomarkers and the signaling pathway leading to pathogenesis.

The development of biomarkers is very challenging in cancer due to its complexity, sensitivity, or resistance to the therapy. The cross-talks between the molecular pathways are too composite for a single biomarker to represent a type of cancer. Thus, multiple markers will be required to generate sensitive and specific biomarkers representing a kind of cancer's pathogenesis and predicting the treatment responses and outcomes [Figure 2].
Figure 2: Summary – The main highlights

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Authors contribution

K.P1. drafted the manuscript. R.D. and TS assisted in writing. KP2 assisted in the clinical discussion. AS supported with information related to cancer prevention. GKR and SK conceptualized the work and oversaw the entire project.

Acknowledgements

The authors would like to thank Dr. Eleftherios P. Diamandis, MD, PhD, FRCPI, FRSC, Hold'em for Life Chair in Prostate Cancer Biomarkers, Head of Clinical Biochemistry, Mount Sinai Hospital and University Health Network, Professor and Head, Division of Clinical Biochemistry, Department of Laboratory Medicine and Pathobiology, University of Toronto and Dr. Sudhir Srivastava, PhD, MPH, Chief of the Cancer Biomarkers Research Group, division of cancer prevention, NCI, NIH for giving us consent to use some of the valuable insights from their research articles.

Ethics approval and consent to participate

Not Applicable

Consent for publication

Authors and the institute has no objection to publishing the Review article

Availability of data and material

The reference has been quoted for each of the details

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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