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You say "to-may-to," I say "to-mah-to." You say "theranostics," I say "companion diagnostics." Could these terms be the diagnostic equivalent to two varieties of fruit growing on the same vine? Well, actually, it depends on whom you ask.
Jan Groen, PhD, president and CEO of MDxHealth headquartered in Belgium, finds the term "theranostics" a bit outdated. "Theranostics is older terminology -- the terms CDx and theranostics are used interchangeably. Some people say CDx is a little broader, but at conferences and meetings both terms refer to predictive markers linked to a specific therapy."
But Glenn Hoke, PhD, president and CEO of Theranostics Health, might take issue with that suggestion. Hoke presented his company's proteomic approach to cancer at the 2012 8th annual Mid-Atlantic BIO Conference in Bethesda, Md. He distinguishes their assays for patients with malignant tumors as "theranostics" by virtue of their focus on providing a molecular map of the signaling activity in the tumor, measuring the activity of multiple drug targets for oncologists to consider when treating their patients. Thus, the assay was not developed with, or to guide use of, a specific drug, but rather to give physicians more actionable information as they treat their patients.
Lines of Distinction
As pharmaceutical companies address the increased specificity and the molecular nature of their compounds, they are seeking accompanying tests or companion diagnostics to determine who should be treated with their product. The presence of a target like HER2 is used to guide therapy with anti-HER2 drugs. While HER2 might be detected by its CDx, if it is not driving the downstream pathways, then the therapy may be ineffective. A CDx is a focused test to guide use of one therapy and a theranostics is focused more on the patient's best therapeutic approach.
 A New Mentality
Any way you slice it, these emerging test/drug partnerships are quickly ripening in a healthcare system aimed toward a harvest of personalized medicine. The reason being that development of companion tests narrows the field of prospective patients for a given therapy, and that translates into savings in both dollars and human suffering.
"It's a different mentality to use a proper diagnostic before beginning a treatment. It's changing and happening as we speak," said Prof. Wim van Criekinge, PhD, chief scientific officer at MDxHealth. "Especially in oncology, most of the available treatments are effective in only a minor fraction of patients - 10 to 20%. So being able to identify them saves the healthcare system 80% of very expensive treatment which has no effect. Additionally, payers have an interest in trying to select the patients who really benefit, because therapies are quite expensive whereas diagnostics are relatively cheap. And the greatest value is to the patients who may get effective treatments and avoid unnecessary side effects from ineffective therapies."
Emerging Tests
MDxHealth is on the verge of debuting a test that Groen proudly noted "could be the very first epigenetic companion diagnostic to come to the market." He explained that an epigenetic test examines changes on the DNA level caused by environmental factors such as diet, pollution, radiation, sunlight, etc., that might lead to the development of cancer. Most diseases, he said, are a mix of genetic and epigenetic factors. Working in partnership with Merck Serono, which has developed a new candidate drug called cilengitide for use in treating patients with malignant brain tumors, MDxHealth's test will identify patients with either MGMT-methylated or -unmethylated brain tumors. That in turn will tell oncologists which patients could benefit from this new drug.
"We have completed Phase 3 clinical trials - done all of the testing over a couple thousand patients, and are in the end validation stage of this CDx," detailed Groen. "It will help a lot of patients with brain cancer. For all of us, that is a very good feeling."
The enthusiasm for a new test is just at high at Theranostics Health where their first theranostic application in oncology is expected to go to market within the first half of this year.
Their TheraLink HER Family Solid Tumor assay quantitatively measures the activity of the signaling pathways that are driving a cancer, providing more than just the presence of drug targets.
"All cancers are really a function of aberrant signal transduction pathways and these can be caused by mutations or other variants early in the etiology of the cancer," explained Ron Hencin, PhD, vice president of business development at Theranostics Health. "When the pathways have been perturbed leading to the growth of cancer, the cells continue to divide when they shouldn't or don't die when they should-then you get a tumor that can metastasize to other parts of the body."
The assay uses a few pathology sections taken from a small tumor biopsy to profile a suite of 14 different proteins that cover the activation status of the HER family receptor and the downstream signaling pathways they modulate, providing evidence on the nature of their role in the cancer. Many of these proteins are already targeted by therapies on the market or in development. The assay, now in the final validation stage, will be run as a laboratory diagnostic in the company's CLIA-certified laboratory.
Outlook
Hoke believes we've only seen the first examples of an increasingly prolific crop of companion tests-particularly using proteomic approaches. "In the last 15 years we've seen the genomic era take off and hit a peak. Now is the beginning of the proteomic era. Generally, what's been used to measure the presence of proteins is immunohistochemistry, but IHC doesn't have the sensitivity and ability to look at the activity level of these signaling pathways. IHC looks at a gross level-is the protein there or not? But a lot of these proteins, especially the portion that is active, are present at a very low level and may be missed via IHC. I think we're going to see a lot of new technologies coming along - including our Reverse Phase Protein Microarrays - to perform more sensitive proteomic analysis, and it will really take off."
Hoke said it's no stretch of the imagination to believe the FDA will routinely require CDx assays to guide the use of molecular targeted therapies to support regulatory requirements and eventual allowance to market. Also, you will see more theranostic approaches, looking at the patient's molecular uniqueness, to give physicians more actionable information to select the best therapeutic strategy.
"If you look at the government's healthcare plans, we'll clearly have to go to better testing to identify patients who might respond to a given therapy, as well as those who have no potential to respond," Hoke declared. "The healthcare system cannot carry the burden of costs for treating every patient with a $50,000 regimen of a targeted therapy, of which only 20 percent will respond. The economics are going to drive this. That is exactly where we are headed."
Valerie Neff Newitt is on staff at ADVANCE.
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