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Biomarkers in Cancer Staging, Prognosis and Treatment Selection

Key Points

  • The TNM staging system (based on a combination of tumour size or depth (T), lymph node spread (N), and presence or absence of metastases (M)) provides a basis for prediction of survival, choice of initial treatment, stratification of patients in clinical trials, accurate communication among healthcare providers, and uniform reporting of the end result of cancer management.

  • There is a dilemma in TNM staging: frequent revisions to include new biomarkers would undermine the value conferred by the stability and universality of TNM, but a static formulation of TNM risks falling behind the state of the art in diagnostic techniques, biological concepts and biomarkers.

  • Biomarkers initially considered for cancer screening or risk assessment might also prove useful for cancer staging or grading.

  • A biomarker for use in staging or grading need not be as specific as it must be for screening, early detection or risk assessment.

  • As molecularly targeted cancer therapeutics become more common, assessing the intended target will more often be deemed necessary for prediction of clinical response, independent of TNM stage. Targeted therapies and their associated biomarkers will often 'co-evolve'.

  • The ideal biomarker assay for staging should be sensitive, specific, cost-effective, fast, and robust against inter-operator and inter-institutional variability. It must also demonstrate clinical value beyond that of the other types of information that are already available at the time of diagnosis.

  • Biomarker candidates must undergo clinical validation before receiving US Food and Drug Administration approval. For most candidate markers, that process is just beginning.

  • Despite all of the potentially useful biomarkers — for example, those identified from microarray or mass spectrometry studies — almost none have been incorporated into formal TNM staging.

Abstract

Advances in genomics, proteomics and molecular pathology have generated many candidate biomarkers with potential clinical value. Their use for cancer staging and personalization of therapy at the time of diagnosis could improve patient care. However, translation from bench to bedside outside of the research setting has proved more difficult than might have been expected. Understanding how and when biomarkers can be integrated into clinical care is crucial if we want to translate the promise into reality.

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Figure 1: Numbers of publications on biomarkers and FDA approval of biomarkers.
Figure 2: Use of multiple molecular technologies in combination to identify candidate biomarkers.
Figure 3: Schematic representation of the uses of biomarkers at different stages in the clinical evolution of cancer, with breast cancer biomarkers as an example.
Figure 4: Chronology of biomarker development.

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Acknowledgements

We thank Maria Chan (FDA) for guidance regarding Table 1 and Anna Maria Calcagno (NCI) for her constructive scientific input. This work was supported by the Intramural Research Program of the NIH, the National Cancer Institute and the Center for Cancer Research. We are grateful to Anna Barker and the reviewers whose constructive comments and suggestions significantly improved the manuscript.

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Authors and Affiliations

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Correspondence to John N. Weinstein.

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DATABASES

Entrez Gene

ABL

AFP

BCR

CGB

EGFR

ER

HER2/NEU

p53

PR

PSA

National Cancer Institute

breast cancer

colon cancer

HNSCC

leukaemia

NSCLC

lymphomas

ovarian cancer

prostate cancer

soft-tissue sarcomas

testicular cancer

FURTHER INFORMATION

Adjuvant Online

Cancer Therapy Evaluation Program

Early Detection Research Network

National Institute of Standards & Technology

NCI Genomics and Bioinformatics group

Program for the Assessment of Clinical Cancer Tests

TNM staging system

Glossary

SINGLE-NUCLEOTIDE POLYMORPHISMS

Single-nucleotide changes in DNA that differ among individuals.

BCR–ABL TRANSLOCATION

Translocation between human chromosomes 9 and 22 t(9q34;22q11), resulting in an abnormal Philadephia chromosome that codes for a fusion protein causally linked to chronic myelogenous leukaemia.

MICROSATELLITE INSTABILITY

Genetic instability in diploid tumours owing to a high mutation rate, primarily in short nucleotide repeats. This phenotype is associated with defects in DNA mismatch-repair genes.

POSITRON-EMISSION TOMOGRAPHY

Imaging technique that detects nuclides as they decay by positron emission. The emitted positron collides with a free electron, resulting in the conversion of matter to two γ-rays, which emerge in opposite directions.

COMPUTER-AIDED DIAGNOSTIC SYSTEM

A computer algorithm for interpreting digital images or laboratory tests to provide a diagnosis.

PATTERN-BASED BIOMARKER

A biomarker constructed from a pattern of individual markers that, when evaluated together, can be used for risk assessment, screening, diagnosis, staging, selection of therapy and/or monitoring of therapy. The specific markers that make up the pattern may or may not have been identified.

SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY

Imaging technology in which a photon detector array is rotated around the body to acquire data from many angles following the injection of a γ-emitting radionuclide.

DECISION SUPPORT SYSTEM

A computerized information system that supports decision-making activities.

DIFFERENTIAL DISPLAY

A gel-based technique used to identify transcripts that are differentially expressed between cell or tissue samples.

SERIAL ANALYSIS OF GENE EXPRESSION

(SAGE). A technique for identification and quantitation of transcript expression levels. SAGE is based on a process in which short oligonucleotide 'tags' from defined locations within a transcript are spliced together and sequenced for identification of the transcript.

BEAD-BASED METHODS

Methods of measurement based on small or microscopic beads (as opposed, for example, to the flat surfaces characteristic of microarrays).

MICROFLUIDICS

Technology that allows the use of very small volumes of reagents, shortening reaction times and facilitating scale-up of molecular methods.

HAPLOTYPE

A way of denoting the collective genotype of a number of closely linked loci on a chromosome that tend to be inherited together in a population.

SUPERVISED ALGORITHM

A method of statistical or machine learning in which a model is fitted to observations. The algorithm, in effect, learns by example.

LASER-CAPTURE MICRODISSECTION

A laser-based technology used to obtain materials from selected regions of cut tissue or tumour sections on glass slides. The method is used, for example, to obtain relatively pure populations of tumour cells from the heterogeneous mixture of cells in a tumour.

CYTOKERATIN

A protein component of intermediate filaments found in epithelial cells.

REVERSE-PHASE MICROARRAY

A microarray spotted with numerous tissue or cell lysates and subsequently incubated with a detection ligand (usually an antibody) to quantitate protein in the lysates.

IMMUNO-PCR

A sensitive method for detection of proteins using a combination of PCR and conventional immuno-detection. A bi-specific linker molecule with affinity for DNA and an antibody is used to attach a DNA marker to a specific antigen, resulting in an antigen–antibody–DNA complex that can be quantified using PCR.

FIELD EFFECT TRANSISTOR-BASED PROTEIN DETECTION

Technology for detecting proteins based on their completion of a circuit between two electrodes in a transistor, thereby resulting in a measurable increase in current.

QUANTUM DOTS

Semiconductor particles with size-dependent fluorescence-emission wavelengths visualized by laser-excitation spectrometry.

OVERFITTING

In multivariate predictive analysis, a statistical model can be overfitted if it has too many free parameters for the number and type of cases in the training set. The result can be a model that fits the training data set very well but does poorly when applied to other data.

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Ludwig, J., Weinstein, J. Biomarkers in Cancer Staging, Prognosis and Treatment Selection. Nat Rev Cancer 5, 845–856 (2005). https://doi.org/10.1038/nrc1739

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