Gene Test May Change Treatment, Extend Life For Lung Cancer Patients

Ruzanna Harutyunyan's picture
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Researchers at the University of Colorado Cancer Center have shown that a readily available gene screening test can help doctors know which people with advanced non-small-cell lung cancer will benefit from adding a second cancer drug to standard chemotherapy.

Patients who test positive for the EGFR gene may live twice as long as those who are EGFR- when given the a combination of chemotherapy and cetuximab—a drug that blocks a key pathway particular gene-driven tumors use to grow and spread—as their first-line treatment, the study shows.

“The results of this study could very well change the way lung cancer patients are treated in the future, similarly to how screening for estrogen-driven breast cancer changed how patients with HER2+ breast tumors are treated,” said Fred Hirsch, MD, PhD, professor of Medicine at University of Colorado Denver and the paper’s lead author.

The paper, published in the July issue of the prestigious Journal of Clinical Oncology, is from a phase II randomized study out of the Southwest Oncology Group, a consortium of cancer researchers. It comes on the heels of the large, randomized European FLEX study, which showed that some advanced non-small-cell lung cancer patients who got the combination therapy lived longer than others who got the same therapy.

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“We needed a tool to tell us which patients to put on cetuximab, because it does not make sense to give an expensive drug that has side effects for someone it will not help,” Hirsch said. “We believe that EGFR FISH is that tool.”

The EGFR FISH test, which was developed at the University of Colorado Cancer Center, is available in most laboratories, so lung cancer patients around the world could be quickly screened in the future to see if they would benefit from cetuximab plus chemotherapy. They will soon begin a 1,000-patient phase III trial to validate the findings, and they anticipate FDA approval of the tool to select patients for EGFR inhibitors in the near future.

“When we give patients the right drugs for their exact tumor type, we can help them live a longer, more comfortable life with the disease,” said Paul A. Bunn, Jr., MD, UCCC director and professor of Medicine at UC Denver, who co-authored the study. “I am already using this test to screen my patients for this gene, and if they test positive, I am giving them the combination therapy. They are doing very well on it. We are hopeful that this test will shift how we choose which therapies to give to each individual patient, which is key to getting the best results.”

In the UCCC study, EGFR+ patients lived an average of 15 months after diagnosis with the combination therapy, compared to an average of 7 months for EGFR- patients. EGFR+ patients’ tumors also shrunk twice as much on the combination therapy.

The Colorado group, which includes Hirsch, Bunn, and UC Denver professors of Medicine Wilbur Franklin, MD, and Marileila Varella-Garcia, PhD, previously found similar results using the EGFR FISH test to predict which patients would do well on Tarceva (erlotinib), another EGFR inhibitor drug. EGFR also plays a role in colorectal cancer, so the test could also be used to predict which of those patients may benefit from EGFR-blocking drugs.

Approximately 215,000 people in the United States will be diagnosed with lung cancer in 2008, according to the American Cancer Society. Only about 40 percent will be alive one year later, and only about 15 percent will be alive five years later. Because there is no effective screening test for lung cancer, most people are diagnosed when the disease has spread beyond the lung. Lung cancer kills more adults in the United States than any other cancer.

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Comments

Newer "smart" drugs hit not just one target inside cancer cells, but multi-targets. Many of the newest drugs target enzymes called kinases, which act like growth switches for cancer, relaying signals from the surface of cells through a series of complicated pathways to the nucleus. These latest cancer therapies are liken to antibiotics. Just as doctors culture bacteria to select the most effective antibiotic, physicians may choose the best cancer therapies based on patients' specific biological makeup. Targeted therapies don't always live up to expectations, though. Iressa studies showed that the drug doesn't prolong survival. Erbitux also has not been shown to extend life. Avastin and Tarceva help patients with advanced disease live only a few months longer. Some doctors say traditional chemo has a major advantage over targeted therapy, because it kills tumor cells, rather than checks their growth, chemo sometimes leads to cures. Some patients end therapy with no detectable traces of cancer in their bodies. However, further evaluations have found tiny reservoirs of cancer cells even in patients who enter remission after taking these smart drugs. Cancer cells are smart too. Patients sometimes become resistant to targeted therapies as cancers mutate in ways that make drugs ineffective. Cancer cells are smart, they will find ways around therapy if you don't get rid of them. Doctors eventually hope to develop enough options that they can prescribe multi-drug "cocktails" for cancer patients, much like the combination therapy now given to AIDS patients. By developing therapies that work even in drug-resistant tumors, doctors are trying to get one step ahead of cancer. The challenge is to identify which patients the targeted treatment will be most effective. Tumors can become resistant to a targeted treatment, or the drug no longer works, even if it has previously been effective in shrinking a tumor. Drugs are combined with existing ones to target the tumor more effectively. Most cancers cannot be effectively treated with targeted drugs alone. What is needed is to measure the net effect of all processes within the cancer, acting with and against each other in real time, and test living cells actually exposed to drugs and drug combinations of interest. The key to understanding the genome is understanding how cells work. How is the cell being killed regardless of the mechanism? The core understanding is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a targeted drug could perturb any of these pathways, it is important to examine the effects of drug combinations within the context of the cell. Both genomics and proeomics can identify potential therapeutic targets, but these targets require the determination of cellular endpoints. Gregory D. Pawelski