In modern medicine, especially in oncology, some drugs prove effective only in patients with very specific mutations in selected genes. In order to identify the right patients for different treatments, companion diagnostics (CDx) are frequently used in the diagnostic laboratory. This highly tailored approach to treatment for individual patients is the basis of personalized medicine. In today’s increasingly complex world of cancer testing and treatment options, providing the most effective and safest treatment depends critically on using the test that will best predict the target population for a specific treatment.
According to the American Cancer Society, more than 1.6 million new cases of cancer emerged in the United States in 2012. By better identifying which patients will respond to which treatments, a CDx can help pathologists and physicians improve outcomes, while saving money for patients and the healthcare system. For example, therapy for metastatic colorectal carcinoma costs approximately $70,000 for a six-month treatment, but we know from studies and experience that the same kind of cancer in different patients will have different responses to the same medication. In July 2012, the U.S. Food and Drug Administration (FDA) approved therascreen KRAS, the first CDx of its kind, for testing alongside the approval of Erbitux (cetuximab), one of the drugs used in the treatment of metastatic colorectal cancer patients. If all metastatic colorectal cancer patients were properly identified as likely or unlikely to respond based on their KRAS gene as tested by an FDA-approved KRAS CDx test, drug cost savings could total as much as $753 million per year.
Most recently, CDx have changed how patients diagnosed with non-small cell lung cancer (NSCLC) are identified and ultimately treated. More than 200,000 new lung cancer cases are diagnosed every year in the United States, with NSCLC accounting for approximately 85% of cases, leading to an estimated 160,000 deaths. In a growing trend, new, targeted therapies are being developed and approved in tandem. For example, this past July, the FDA approved a diagnostic test in conjunction with the approval of Gilotrif (afatinib), which enables physicians to identify EGFR mutation-positive patients eligible for treatment with therapies that will respond well with the genetic mutation. Other FDA-approved CDx also exist for other drugs targeting specific EGFR mutations, such as Tarceva (erlotinib).
EGFR encodes a protein found on the surface of cells that acts as an antenna to receive growth signals. In some patients, genetic mutations involving EGFR lead to constant activation, where the broken antenna behaves as if it is always receiving a growth signal—even if one isn’t present. This causes uncontrolled cell division and development of advanced NSCLC. By using a companion diagnostic to identify patients whose cancer involves these EGFR mutations, oncologists can determine who is likely to benefit from targeted therapy that inhibits the EGFR protein. Approximately 120,000 metastatic NSCLC patients each year in the United States could benefit from testing for EGFR mutations.
Recognizing the importance of CDx in personalizing the most effective treatment for NSCLC, the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology jointly released a molecular testing guideline in April 2013 emphasizing EGFR (and ALK, another gene with CDx amenable to approved targeted therapeutics) analysis in lung cancers with appropriate histology where targeted therapies are being considered. The guidelines also noted the delicate balance currently available in CDx testing. Many laboratories maintain FDA-waived laboratory developed tests (LDTs) for the targeted genes under the auspices of CLIA, with a wide array of molecular approaches employed.
Thus, it’s important to note that not all CDx tests are created equal or approved by the FDA. The type of genetic mutation detected is very important when deciding what CDx test should be used within the diagnostic laboratory, in addition to regulatory and cost considerations. For example, many laboratories running FDA-waived LDTs use DNA sequencing, which can identify a wide and varied array of mutations in EGFR—including mutations so rare that their effect on the therapy offered to the patient is unknown. Conversely, the FDA-approved assays for NSCLC use polymerase chain reactions (PCR) to interrogate the most common mutations, typically emphasizing the mutations whose effect on the companion drug is known—but the PCR assays are limited only to the mutations they have been designed to find.
Even within FDA-approved CDx, there can be significant differences. For instance, the FDA-approved diagnostic test for Gilotrif is the only FDA-approved method to include the T790M mutation, which is associated with acquired resistance to TKI therapy and has been reported in about 50% of patients with disease progression after initial response to Tarceva. It is possible that without testing for this genetic variation, a patient might be at risk for all the costs and side effects with none of the benefit of some of the TKIs used to treat NSCLC.
The approvals of CDx tests and therapies are important developments in oncology, as they bring safe, effective treatment options to patients personalized to those therapies with the best chance of success against their cancer. As of June 19, 2013, approximately one-third of the FDA’s 121 approved drugs for cancer included gene-related information on the label. As new cases of cancer grow, the therapies that require CDx tests before prescribing will increase as well, resulting in a shift of oncology treatment through companion diagnostic testing.