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The ability to predict how the course of cancer will likely play out in an individual patient based on genetic factors is already changing the way certain cancers are approached, but it will take unprecedented levels of cooperation between researchers, federal regulators, drug developers, patient groups and clinical oncologists to continue advances in the field.
The collective knowledge of practicing oncologists is becoming increasingly important to advances in biomarker discovery, according to Shawnmarie Mayrand-Chung, PhD, JD, Program Director, representing the National Institutes of Health to the Biomarker Consortium (www.biomarkersconsortium. org). Dr. Mayrand-Chung explained the purpose of the Biomarker Consortium, formally launched in 2006, at the recent Biomarker World Conference in Philadelphia.
“Doctors are a frontline link to patients,” Dr. Mayrand-Chung said. “Involving practicing physicians in the process of biomarker research will provide insight into their day-to-day experiences with patients and contribute to designing effective clinical trials.” If individual clinical oncologists report discoveries in their patients to the Consortium, for example, collective results can provide the basis of new discoveries. “Research is inherently slow,” Dr. Mayrand-Chung said. “If we can speed it up by aggregating the observations we make through clinical interactions, it just makes sense.”How Reliable Are Biomarkers in Cancer Treatment and Drug Development?
The discovery of how likely a cancer treatment will work in people with certain types of cancer based on the genetic makeup of either the person or the tumor has already changed how certain forms of aggressive breast cancer are treated, but many oncologists remain skeptical whether such predictors will eventually be 100% accurate in all patients and in all cancers.
Dr. Scott Patterson, executive director of medical sciences for Amgen, is a biomarker believer. He cited the Food and Drug Administration’s (FDA) “Critical Path Initiative”, which encourages researchers to utilize cutting-edge scientific tools and discoveries like biomarkers to measure the progress of a disease, or the effects of a particular treatment, quicker and more accurately than the traditional “phase 1-to-phase 4” method does.
Dr. Patterson cites the example of the KRAS biomarker to demonstrate the validity of using other biomarkers for targeted drug development and cancer therapy. Mutation of the KRAS gene can lead to overexpression of epidermal growth factor receptors (EGFR) and continued tumor growth.
“Even though biologists have known about the presence of a mutant KRAS gene in the tumors of patients with pancreatic, colon, and lung cancers, there has been a long standing-debate over whether this is indicative of a poor prognosis,” he said. Skeptics site preclinical studies in mice and studies conducted with relatively small patient samples, which seemed to indicate some patients with KRAS mutations may respond to chemotherapeutic agents that target EGFRs.
Amgen examined its archive of tumor samples from patients enrolled in their phase II studies with metastatic colorectal cancer (mCRC) in an attempt to come to a more definitive conclusion about the KRAS mutation’s role and then went on to conduct studies in more than 400 patients with metatastic colorectal cancer (mCRC) in its pivotal trial to compare their response to the best supportive care only (in this study it was FOLFIRI) and FOLFIRI combined with the Amgen drug panitumumab (Vectibix).
“The best supportive care along with panitumumab gave people with the wild type (normal) KRAS gene the best chance of objective response,” Dr. Patterson said, citing data from the study. In patients with a wild-type KRAS gene, 34% achieved a stable disease state, 17% showed a partial response to the combination therapy, and 36% went on to progressive disease. In comparison, 70% of patients with mCRC and a confirmed KRAS mutation in the study saw their disease worsen and none had a partial response to therapy, although disease stabilized in 12% of the patients.
Dr. Patterson said while these findings are promising, the treatment of individual patients is best left in the hands of their oncologists and he hopes for the day when there is a clearer understanding by patients and physicians on how and when to collect and interpret cancer-related biomarkers like KRAS. Amgen is preparing to study this subject further, Dr. Patterson said, to “ultimately generate a companion diagnostic for first- and secondline therapies.”
The reality, according to Dr. Patterson, is the example of panitumumab and the KRAS genetic marker “will not be unique.” Indeed, he said, “oncologists on both sides of the Atlantic are hoping treatment can eventually be determined at primary diagnosis. That’s what I’m hearing, and that’s what we’re pushing for.”Pharma Companies Find Biomarker Research to Be a Lonely Road