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Summary: This resource provides information about cancer biomarker test characteristics that may help differentiate among available tests.
By: Clinical Education at JAX | January 2024
The number of companies offering cancer biomarker tests for treatment decision making is growing rapidly, as are the types of tests available. It can sometimes be difficult to determine the important differences. The following provides some questions and information about test characteristics that may help differentiate among available tests.
Biomarkers can include DNA, RNA and proteins. Labs have different processes to determine which biomarkers to include on the tests they offer. In most cases, tests include biomarkers that are associated with targeted treatments, either FDA-approved or in active clinical trials, or those known to impact prognosis. Some tests are developed for solid tumors while others are specific for hematologic or cancer types seen most frequently in pediatric cases. There may be other biomarkers included as well, based on other, lab-specific criteria, such as loss of heterozygosity (LOH).
Not all test platforms are able to detect the same type of variants. For example, a platform validated to detect changes of a single or a few nucleotides within a gene cannot detect a fusion between two chromosomes, or changes in protein expression. Many labs provide testing options that analyze the sample on more than one platform in order to provide information about different types of biomarkers. Knowing what type of variants the test can detect is important to ensure that you will get the information you expect.
How likely is it that the test will detect a biomarker if it is present?
Many oncology providers use a large panel in place of tests that analyze only a few recommended genomic variants, such asEGFR variants in non-small cell lung cancer. The ability of the larger panel to detect certain variants will depend on its sensitivity and specificity.. When targeting specific variants, the ordering provider should confirm that the large panel test is able to detect these variants with the same sensitivity and specificity as more targeted tests.
The testing platform affects the sensitivity and specificity of detection. In general, broader tests have somewhat lower sensitivity than narrow, more focused tests. For example, whole genome sequencing will have a lower sensitivity for any one particular variant than a lung cancer panel that only tests for a few specific variants. That said, the sensitivity of larger panels is often sufficient to adequately detect the variants of interest.
There are several categories of “actionable” variants that a laboratory may report. These include treatments associated with:
Results may also include biomarkers without associated treatments, such as biomarker profiles associated with prognosis.
A consensus statement from the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists suggests how variants should be categorized based on their clinical impact.
Each lab uses its own algorithms and processes to identify clinical trials. One difference among reporting practices is the level of specificity of the identified trials. Some labs may provide any trial that is testing a treatment related to a gene in which a variant is identified. Other labs may filter trials and provide a smaller list, more targeted to the specific variants identified. There also may be differences in filtering based on the characteristics of the cancer diagnosis (e.g., breast cancer vs. triple negative breast cancer). In all cases, the oncology provider will need to further investigate the clinical trials listed to determine which, if any, the patient is eligible for based on additional clinical information.
Genomic variants are abundant in tumor cells; some are benign, while others disrupt or alter the function of the gene and affect tumor growth. Others have unknown or unclear effects on the cancer cells; these are called variants of uncertain significance, or VUS.
Laboratories vary in their reporting practices for VUS. In some cases, such as hotspot panels, the test does not detect VUS. In panels where the entire gene is assessed, the lab may or may not choose to report VUS. In this case, when labs do not provide the information on the report, they may be able to provide it when asked by the ordering clinician. Although VUS are not actionable, some clinicians want the information in case more data becomes available in the future.
Genomic variants are present in non-cancer cells as well as cancer cells. The ultimate goal of cancer biomarker testing is to identify the variants that are driving the growth and proliferation of the tumor and associated targeted treatments. Doing this requires filtering out variants that are unlikely to be contributing to cancer cell growth.
Labs differ in whether they use a tumor sample alone or a tumor sample in combination with a non-cancer sample (e.g., blood) to help interpret results. Somatic testing (tumor-only) approaches rely on databases that record population frequency of variants that occur in the germline by chance alone, not related to disease. Existing databases may not represent all ethnicities and may not have information about frequency of all variants. Paired somatic/germline testing (tumor-normal) approaches assess variants in both cancer cells (somatic) and non-cancer cells (germline) to help determine which variants are unique to the tumor. This approach requires sequencing of two full genomes (or parts thereof, depending on approach used), which significantly increases the cost of the test.
Does the lab report germline variants and secondary findings?
Paired somatic/germline testing (tumor-normal) may identify germline variants associated with hereditary syndromes. Labs vary in whether they report these germline variants or just use them for filtering. Generally, germline variants identified through cancer biomarker testing needs to be confirmed with dedicated germline testing. It is important to note that biomarker tests are not optimized to identify germline variants. While biomarker testing can detect single nucleotide variants (SNVs), small insertions and deletions, and gene-wide copy number alterations, this type of testing generally cannot detect large deletions or duplications that impact one or more exons. Therefore, dedicated germline testing may still be indicated if a germline variant is not identified on a biomarker test.
Secondary findings are germline variants that are associated with increased risk for conditions unrelated to the test indication. The American College of Medical Genetics and Genomicshas identified over 90 genes associated with hereditary syndromes that are clinically actionable. They recommend that labs report pathogenic variants found in any of these genes, regardless of the test indication.
It is important to know whether the lab reports germline variants and, specifically, secondary findings because it will impact pre-test counseling and, potentially, the care plan and post-test discussion.
Lab practices can differ significantly with regard to the logistics of test ordering and reporting as well as available support. The following questions address some of these differences.
Exploring Cancer Biomarker Testing (CME|CNE). Learn about benefits, limitations, and challenges of using large biomarker tests.
Interpreting Cancer Biomarker Testing – When is Additional Testing Indicated? (CME|CNE). Learn when additional cancer biomarker testing is indicated for further evaluation of genome-informed therapy.
Choosing the Best Genomic Tumor Test (CME|CNE). Learn about the benefits and limitations of different genomic tumor test options for patients with cancer and how to determine the best test for each patient.
Testing to Identify Genomic Variants Related to Cancer. Defines and compares benefits and limitations of types of genomic testing for identifying targeted treatments.
All information in this resource is provided for educational purposes only.