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CDx for Drug Eligibility

Vol. 19 • Issue 3 • Page 12
Molecular Edge

Lab tests to determine if a patient is eligible to receive a specific therapy are identified as companion diagnostics (CDx). These tests usually evaluate if a disease type (e.g., tumor or virus) manifests or expresses specific therapeutic targets or biomarkers of therapeutic efficacy. Companion tests also can be used to identify genetic traits that indicate the likelihood of adverse drug effects.

One could argue that CDx are not new; antibiotic therapy has been selected on the basis of tests for antibacterial susceptibility and resistance for decades. The difference now is that CDx tests are required or recommended before the initiation of therapy (antibiotics can be administered without a previous culture or susceptibility test, i.e., empiric therapy). In some cases, CDx tests have been developed alongside the agent (e.g., HercepTest and Herceptin, Genentech); in others, the companion has been identified after molecular analyses were performed in responsive and non-responsive populations (e.g., KRAS mutations and anti-EGFR agents). For some CDx tests, the FDA has included a requirement or recommendation in the drug's label.

CDx in Oncology

This category of clinical tests has come to prominence in the last few years due to the significant impact of CDx in the field of oncology, where certain biomarkers in tumors have been associated with successful therapeutic responses. Analysis of breast cancer tissue for the presence of estrogen receptor (ER, ESR1) is probably the first and most commonly performed CDx (although not always recognized as such). This test determines eligibility of the patient to receive estrogen receptor antagonists such as tamoxifen.

In addition to ER testing, all breast cancers are tested for the expression or gene amplification of Her2 (ERBB2), which is undoubtedly the most well-recognized companion diagnostic. Her2 positivity identifies patients who are more likely to respond to therapy with trastuzumab (Herceptin), a humanized monoclonal antibody against the Her2 protein.

More recently, molecular testing for KRAS mutations surfaced as a useful companion test to identify patients with metastatic colorectal cancer (CRC) who would not benefit from therapy with the anti-EGFR (epithelial growth factor receptor) agents cetuximab (Erbitux) and panitumumab (Vectibix). Multiple studies have shown that patients with KRAS mutations in codons 12 or 13 do not benefit from these therapeutic agents. The use of KRAS mutation testing as a companion diagnostic was rapidly endorsed by the National Comprehensive Cancer Network (NCCN) and the American Society for Clinical Oncology (ASCO).1, 2

CDx in Microbiology

One of the most well-known CDx tests is the tropism assay for HIV (Trofile® Monogram Biosciences, San Francisco, CA). This assay determines the ability of HIV to infect lymphocytes with one of two receptors in the cell surface (CCR5 or CXCR4). Viruses that exhibit tropism for CCR5 can be treated with CCR5 antagonists, a relatively new class of antiviral therapy.3Although not strictly considered a ­companion diagnostic, determination of influenza A virus resistance to oseltamivir (Tamiflu) and other antiviral agents could possibly become a companion diagnostic test, especially if resistance becomes more widespread or starts to be seen in more than one serotype (currently resistance is mostly associated with seasonal H1N1 but a few cases of novel 2009 H1N1 oseltamivir resistance have been reported).

CDx in Pharmacogenomics

Pharmacogenomics is a discipline that studies the influence of genetic variation in drug response. Thus, pharmacogenomic tests are directly linked to a specific therapeutic agent and can be considered the quintessential CDx. Most pharmacogenomic tests in clinical use are used to determine the likelihood of adverse events based on a patient's genetic variation. Perhaps the most well-known pharmacogenomic companion tests are the assays for warfarin sensitivity. These assays determine the presence of genetic variants in the VKORC1 and CYP2C9 genes, which determine the patient's ability to metabolize warfarin. Patients who are slow metabolizers are at increased risk of developing complications such as bleeding.

Another well-known CDx is the pharmacogenetic test to identify mutations in the UGT1A1 gene as a predictor of potential adverse reactions to the chemotherapeutic drug irinotecan (Camptosar) for the treatment of metastatic colon cancer.

Histocompatibility Testing

Clearly, certain alleles in the human leukocyte antigen (HLA) system are associated with autoimmune diseases and adverse drug reactions. For example, the presence of HLA-B*1502 is a genetic marker for serious cutaneous adverse reactions (SCARS) induced by carbamazepine, a drug used to treat seizure disorders, in individuals with Asian ancestry. The FDA recommends to screen all Asian patients for the presence of HLA-B*1502.

Another example of an HLA-related CDx is the association of serious and sometimes fatal hypersensitivity reaction to the AIDS drug abacavir (Ziagen) in patients with the HLA-B*5701 allele. Testing for this allele has been recommended by the Department of Health and Human Services.4

Dr. Monzon is medical director of Molecular Diagnostics, The Methodist Hospital, Houston, TX.


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