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Study: Matching Tumors to Targeted Therapies


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http://www.technologyreview.com/Biotech/20822/

Matching Tumors to Drugs

A clinical trial offers a first step toward personalizing cancer treatments.

By Courtney Humphries

For years, personalized medicine--the concept that treatments could be tailored to a person's unique genetic makeup--has been more buzzword than reality. One of the first diseases expected to benefit from a personalized approach is cancer, which appears in many genetically distinct forms. A new study led by Lecia Sequist, an instructor at Harvard Medical School and an oncologist at Massachusetts General Hospital Cancer Center , offers an initial demonstration that cancer treatment can be tailored to the genetic profile of a patient's tumor. In a small clinical trial published recently in the Journal of Clinical Oncology, patients with lung tumors were genetically screened to identify those likely to respond to a targeted therapy. Those receiving a drug matched to their tumor fared better than is typically seen with standard chemotherapy.

"It's really a giant step forward," says William Pao, a cancer researcher at Memorial Sloane-Kettering Cancer Center, who was not involved in the clinical trial. "The ultimate goal is to take a molecular fingerprint of someone's tumor and assign treatment based on molecular defects."

Standard cancer drugs are designed to preferentially kill cancer cells, but they can still be toxic to normal tissue. But cancer researchers have been working toward the goal of developing an array of drugs that could hit precise molecular targets in tumors, while being less toxic to normal cells. For example, non-small-cell lung cancer is an aggressive form of cancer that is typically treated with chemotherapy; however, in recent years, new drugs for the disease have been developed that target a specific molecule in cancer cells, called the epidermal growth factor receptor (EGFR). The drug examined in this study, Iressa, was the first EGFR inhibitor to come on the market in 2003, but its initial hype fizzled after larger trials showed that it did not lengthen survival for patients in the United States. Currently, EGFR inhibitors are used only after chemotherapy.

Increasingly, scientists have realized that cancers arise from different genetic mutations and have different points of weakness that might vary from person to person. Further research identified specific EGFR mutations in the tumors of a subset of patients that made them more susceptible to EGFR inhibitors. Many scientists have argued that the drugs could provide a greater benefit to these specific patients. In Sequist's trial, which was funded by AstraZeneca, researchers first screened patients with metastatic lung cancer for EGFR mutations and gave those with the mutations the option of receiving Iressa as a first treatment over chemotherapy. "This is a proof of concept," says Sequist. "We were trying to see if personalized medicine or genetically driven cancer therapy was feasible."

Among 31 patients who took Iressa during the trial, 55 percent had their tumors shrink noticeably in a CAT scan, and all but two had tumors that either shrank or did not grow for at least a month. The median rate of time that patients survived without their cancer progressing was about nine months. Sequist says that chemotherapy typically has response rates of 20 to 30 percent, with a survival advantage of about four months. "We had quite an improvement over what we typically see when we give a general one-size-fits-all treatment," she says. Because Iressa is an oral pill taken daily, the patients avoided the toxic side effects of daily intravenous chemotherapy treatments. The two patients who experienced a worsening of their disease were later found to have a type of EGFR mutation that confers resistance to the drug; the distinction between EGFR mutations had not been discovered when the trial began.

Iressa's maker, AstraZeneca, stopped marketing the drug in the United States after this study began, because of its poor showing in clinical trials. However, a similar drug, Tarceva, is available and is thought to have similar effects in patients.

In an accompanying editorial, Frances Shepherd, a lung-cancer researcher at Princess Margaret Hospital, in Toronto, said that while the study showed that screening tumors for their molecular makeup before treatment is feasible, it does not yet provide solid evidence that EGFR inhibitors should be used before chemotherapy. Shepherd points to previous studies showing that people with EGFR mutations survive longer under standard chemotherapy than patients without these mutations, suggesting that they might fare better regardless of their therapy. To know whether the drug is truly better than chemotherapy would require a randomized trial of the two therapies in this patient population. An ongoing study in Spain is currently addressing this question.

Pao says that while the study doesn't provide definitive answers about how to use EGFR inhibitors, it represents an important step toward personalized cancer treatment. The study, he says, is one of the first attempts to genetically screen cancer patients before treatment as a way to guide clinical decision making, rather than identifying susceptible patient populations after the fact.

. . . . . . . . .

(Technology, Published by MIT Review, By Courtney Humphries, May 27, 2008)

Disclaimer:

The information contained in these articles may or may not be in agreement with my own opinions. They are not posted as medical advice of any kind.

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It is so critical that those receiving a drug matched to their tumor fare better than is typically seen with standard chemotherapy. So many cancer patients are chasing mets because the first-line standard therapy did not work. But what happens when there are too many receptors (pathways/mechanisms) and the cancer still continues to grow and divide?

When considering a 'targeted' cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect. Although presence of a 'targeted' defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug.

Cancer cells have many mutations in many different pathways, so even if one route or two is shut down by a targeted treatment, the cancer cell may be able to use other routes. Targeted drugs have not been accompanied by reliable, specific predictive tests allowing for rational and economical use of these drugs. Molecular diagnostics (genetic profiles) approved often have been mostly or totally ineffective at identifying clinical responders to the various therapies.

Gene profile testing examines a single process within the cell or a relatively small number of processes. The aim is to tell if there is a theoretical predispostion to drug response.

Gene profile testing involves the use of dead, formaldehyde preserved cells that are never exposed to 'targeted' drugs. Gene profile tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Gene profile tests cannot discriminate among the activities of different drugs within the same class. Instead, it assumes that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Gene profile tests tell us anything about drug combinations.

If you find one or more implicated genes in a patient’s tumor cells, how do you know if they are functional (is the encoded protein actually produced?). If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?

Are you sure that you’ve identified every single protein that might influence sensitivity or resistance to these drugs? The "cell" is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one or a few targets or pathways.

There are many mechanisms/pathways to altered cellular function. Functional profiling measures what happens at the end, rather than the status of the individual mechanisms/pathways. Cancer is a complex disease and needs to be attacked on many fronts.

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