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Diagnostics Research and Development Resources

Advice and Resources for Cancer Diagnostics Researchers

What Makes a Marker Useful

The Diagnostics Evaluation Branch (DEB) in the Cancer Diagnosis Program (CDP) supports the development of new markers that can aid people with cancer and their physicians in the process of clinical decision-making. There are three general categories of these markers:

  1. Diagnostic markers are used to assess the tissue of origin of a malignancy, or the specific subtype of a tumor.
  2. Prognostic markers are used to estimate the likelihood of outcome (e.g., recovery or recurrence) regardless of the treatment received by a person with cancer. For example, with most solid tumors the spread of cancer cells to lymph nodes indicates an increased likelihood of tumor recurrence, independent of the therapy given after surgery.
  3. Predictive markers are used to predict response to a specific therapy. For example, breast cancers that express the estrogen receptor tend to respond to hormonal therapies such as tamoxifen.

Some markers can be used to monitor a person’s response to therapy or to detect the growth of metastases. Markers of precancerous conditions can be used as the basis for screening strategies, or to identify populations at high risk for cancer who might benefit from preventive measures.

There is increasing interest in defining molecular targets for new therapeutic agents. For example, treatment with the monoclonal antibody Herceptin is offered to patients whose tumors have amplified the Her2/neu gene or over-express the Her2/neu gene product.

Markers are typically expressed within the neoplastic cells. However, molecules associated with non-neoplastic cells that may be components of the stroma of a cancer, or the infiltrating host inflammatory cells, may also be useful markers. 

As a marker is characterized, it is important that the researcher determines where the marker is most easily measured. While some markers are secreted into the blood or other body fluids, other markers are restricted to expression within neoplastic tissues. The sampling location and method will influence the design and sensitivity of an assay.

Cancer biomarker research focuses on the development of new assays, procedures, and techniques that provide useful information to physicians and people with cancer to help them make treatment decisions. A new marker is significant if it will have a clear impact on these clinical decisions. The nature of a “difficult decision” depends on the type of cancer, the stage of the disease, and the range of treatment options.

Ultimately a useful marker is one that meets two criteria:

  1. It can be measured reproducibly by means of a reliable and widely available assay.
  2. It conveys information about the disease that is meaningful to the physician and the person with cancer.

It may not be immediately obvious how a new marker will be most useful. Validation of a marker for cancer screening in asymptomatic people generally requires testing a large population. Most of the population will never develop cancer, so this study requires waiting many years to accumulate outcome data. Validation of a marker and test for predicting response to a specific therapy can be incorporated into the design of phase II or phase III clinical trials of novel therapeutic agents.

The assay used to measure or evaluate expression of a marker is as important as the marker itself. Assay techniques originally developed for use with cultured cells or animal tissues usually require a degree of modification to be used with patient samples. Most clinical laboratory assays, except for some blood and urine tests, are designed to work on tissues that have been preserved. Many cancer diagnoses are made by microscopic examination of a sample that is fixed in formalin and embedded in a block of paraffin. Sections of frozen tissue are often used to make a preliminary diagnosis. Assays that require fresh tissue or tissue preserved in fixatives other than formalin are typically more complicated and expensive to perform.

Clinical laboratory assays require strict controls for intra- and inter-laboratory variability in the scoring and reporting of results. To minimize bias, investigators who are scoring laboratory assays are often blinded to the clinical outcomes, and vice versa. Statisticians must be involved in designing the quality control procedures, which should be in place from the start of a study, whether it is at a single site or at multiple institutions.

The following considerations may help investigators recognize a potentially useful marker:

Is there a clinical need for this marker? Preliminary data is required to establish the importance of a marker by demonstrating that the marker has: 

  • an association with an outcome such as survival or recurrence of disease, or
  • the ability to improve classification provided by known clinical parameters such as stage of disease or nodal status, or
  • the potential to identify another subset of patients.

Is the marker or classifier evaluated in an assay that has good intra- and inter-assay reproducibility? The assay should include a well-defined scoring system that is clearly associated with an important clinical outcome. It should be reproducible in other laboratories.

Has the marker or classifier been examined in normal as well as abnormal or diseased tissue? Has it been examined in different organ sites? The exact distribution of the marker does not need to be fully established, but the setting where the marker has greatest value should be determined. It is important to develop positive and negative controls to enable assay standardization.

Can we define the patient populations for which this marker might have utility? An expected range for the prevalence of this marker in populations of potential interest should be established. Very rare (<5%) or very prevalent (>95%) markers are likely to be useful in more circumscribed settings.

Can the marker be measured in the types of specimens that will generally be available?

Who is Needed on the Research Team?

Although the concept for a new cancer biomarker may begin with a single investigator, successful development invariably requires a team approach. The members of the team will usually include:

  • A biologist who understands the biologic rationale for the marker, or a scientist who understands the genomic or proteomic analysis.
  • A clinical or anatomic pathologist or laboratory medicine staff who performs the test in a clinical laboratory and reports results and medical interpretations to the oncologist.
  • An oncologist who uses the information to recommend a course of treatment. The oncologist may recruit people to participate in a clinical trial that validates the medical utility of the new test or technique.
  • A statistician who contributes to the study design and interpretation of the clinical research. All patient-oriented cancer research requires close collaboration between investigators and statisticians from the beginning of the study.

Methods of Marker Development: Literature Resources

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