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Cancer biomarkers: selecting the right drug for the right patient

Nature Reviews Drug Discovery volume 11, pages 201–214 (2012)Cite this article

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Abstract

This Perspective highlights biomarkers that are expressed as a consequence of cancer development and progression. We focus on those biomarkers that are most relevant for identifying patients who are likely to respond to a given therapy, as well as those biomarkers that are most effective for measuring patient response to therapy. These two measures are necessary for selecting the right drug for the right patient, regardless of whether the setting is in drug development or in the post-approval use of the drug for patients with cancer. We also discuss the innovative designs of clinical trials and methodologies that are used to validate and qualify biomarkers for use in specific contexts. Furthermore, we look ahead to the promises and challenges in the field of cancer biomarkers.

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Figure 1: Rate of cancer development and progression.
Figure 2: Qualification of imaging-based biomarkers as measures of clinical benefit.

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Author information

Authors and Affiliations

  1. Gary J. Kelloff is at the National Cancer Institute, Cancer Imaging Program, EPN Rm 6058, 6130 Executive Blvd, Bethesda, Maryland 20852, USA.,

    Gary J. Kelloff

  2. Caroline C. Sigman is at CCS Associates, 1923 Landings Drive, Mountain View, California 94043, USA.,

    Caroline C. Sigman

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  1. Gary J. Kelloff
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Correspondence to Gary J. Kelloff or Caroline C. Sigman.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information Box S1

Clinical study designs with biomarkers: adaptive randomization (PDF 196 kb)

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FURTHER INFORMATION

http://clinicaltrials.gov

FDA website — Class II Special Controls Guidance Document

FDA website — Critical Path Initiative

FDA website — Draft Guidance for Industry: Qualification Process for Drug Development Tools

FDA website — Drug–diagnostic Co-Development Concept Paper

FDA website — Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics

FDA website — Guidance on Pharmacogenetic Tests and Genetic Tests for Heritable Markers

FDA website — Interactive Review for Medical Device Submissions: 510(k)s, Original PMAs, PMA Supplements, Original BLAs, and BLA Supplements

FDA website — In Vitro Diagnostic Devices: Guidance for the Preparation of 510(k) Submissions

Glossary

Adaptive clinical trial designs

Defined by the US Food and Drug Administration as study designs that include prospectively planned opportunities for the modification of one or more specified aspects of the study design and hypotheses based on analyses of data (usually interim data).

Analytical and clinical validation

The process of assessing the biomarker assay and measuring of its performance characteristics, and determining the range of conditions (including clinical settings) under which the assay will give reproducible and accurate data.

Biomarker qualification

The evidentiary process of linking a biomarker with biological processes and clinical end points. Qualification refers to the verification that the biomarker is 'fit for purpose'.

Biomarkers

Factors that are objectively measured and evaluated as indicators of normal biological or pathological processes, or are pharmacological responses to therapeutic intervention.

BRAFV600E mutation

A mutation in the BRAF gene leading to valine being substituted by glutamate at codon 600; found in human cancers such as papillary thyroid carcinoma, colorectal cancer, melanoma, non-small-cell lung cancer and hairy cell leukaemia.

Clinical Laboratory Improvement Amendments

(CLIA). US legislation defining quality assurance practices in clinical laboratories, and requiring them to measure performance at each step of the testing process from the beginning to the test result.

Companion diagnostics

In vitro diagnostic devices (assays) that provide information that is essential for the safe and effective use of a corresponding therapeutic product. The use of a companion diagnostic with a particular therapeutic product is stipulated in the instructions for use in the labelling of both the diagnostic and the corresponding therapeutic product, as well as in the labelling of any generic equivalents of the therapeutic product.

DNA ploidy

A term used to describe the number of chromosome sets or deviation from the normal number of chromosomes in a cell.

Driver mutations

Mutations that are causally associated with cancer development. Their presence is not required for maintenance of the final cancer (although it often is) but it must have been selected at some point during cancer development.

Epigenetic modulation

Heritable changes in gene expression or cellular phenotype caused by mechanisms of interaction with the genome other than changes in the underlying DNA sequence. Examples of such changes include DNA methylation and histone deacetylation, both of which serve to suppress gene expression without altering the sequence of the silenced genes.

Epithelial to mesenchymal transition

A cellular transition associated with cancer metastases in which an epithelial cell loses polarity and intercellular adhesion, and degrades basement membrane components to become a migratory mesenchymal cell.

Fit for purpose

A term used in the context of biomarker qualification. A biomarker is qualified on the basis of data that support its use in specific contexts — that is, evidence linking the biomarker to specific biology and clinical end points. The biomarker is considered to be 'fit for purpose' or qualified for use in those settings in which the supporting evidence is sufficiently robust.

Gail risk model

An algorithm formulated by Mitchell Gail (US National Cancer Institute) that uses personal and family history to estimate a woman's absolute risk of developing breast cancer.

Investigational new drug application

An application that is submitted to a regulatory agency before a drug can be studied in humans. This application contains experimental data on: how, where and by whom the new studies will be conducted; the chemical structure of the drug; the drug's mechanism of action and metabolism; any toxic effects; and how the compound is manufactured.

Next-generation gene sequencing

New technologies for high-throughput and high-speed sequencing, and potentially cost-effective sequencing of the human genome, epigenome and transcriptome (the part of the genome transcribed into RNA).

Passenger mutations

Mutations that are not selected during cancer development and do not directly contribute to cancer development. Cells that acquire driver mutations already carry biologically inert somatic passenger mutations, which are included in the clonal expansion that follows and will be present in all cells of the resulting cancer.

Standard uptake value

(SUV). A value that quantifies positron emission tomography imaging; calculated as a ratio of tissue radioactivity concentration at a specific time and injected dose at the time of injection, divided by body weight.

Umbrella clinical trial

A clinical trial protocol into which patients are enrolled, their biomarker status is obtained and then they are assigned to treatment in one of a group of clinical trials of targeted drugs. Patients are assigned to the drug that is most likely to benefit them based on their biomarker status.

Warburg phenomenon

The observation that cancer cells, unlike normal cells, preferentially utilize the glycolytic pathway rather than the Kreb's cycle to metabolize glucose.

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Kelloff, G., Sigman, C. Cancer biomarkers: selecting the right drug for the right patient. Nat Rev Drug Discov 11, 201–214 (2012). https://doi.org/10.1038/nrd3651

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