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Matching Cancer Drugs to Gene Mutations Raises Survival Odds

Personalized Medicine
A lab technician tests DNA samples at Pathway Genomics Corp. in San Diego, California. Photographer: Sandy Huffaker/Bloomberg

Doctors are treating cancer according to the genetic aberrations found in patients’ tumors, not just where they’re found in the body, an approach that may boost the odds of survival, according to a study.

Researchers from M.D. Anderson Cancer Center in Houston found that more than one in four patients who had no treatment options left improved after getting a drug tied to the genetic flaw fueling their cancer -- whether the tumor originated in the lung, breast or other organ -- compared with just one in 20 who got standard care. The report, the first to validate the method’s success, was presented yesterday at the American Society of Clinical Oncology meeting in Chicago.

Advances in tumor biology are leaving behind the one-size-fits-all approach to treating a disease that kills 8 million people worldwide each year, said Harold Varmus, director of the National Cancer Institute. He has started a center for cancer genomics to improve molecular understanding of the disease.

“This is going to be a radical change in the way we approach cancer care,” Varmus said in an interview. “There is no doubt that increasingly genetic information is going to be important in making decisions about how to treat patients, whether we are using old drugs or new drugs.”

Linda Barth, a 60-year-old former magazine editor in Houston, was ready for a new approach, having exhausted all the approved drugs for her endometrial cancer diagnosed in 2006. Barth tried an aggressive combination of three medicines that shrank the tumors in her lungs and neck and made her so weak she couldn’t walk. A second experimental drug provided no benefit.

Cancer Genetics

By homing in on the genetics of Barth’s cancer, researchers found she was one of 460 clinical trial patients among 1,140 screened who had a known molecular twist that helped the malignant cells grow.

Apostolia-Maria Tsimberidou, her doctor at M.D. Anderson, started Barth on a trial of two experimental drugs from GlaxoSmithKline Plc in January that targeted a gene called KRAS, which when mutated has the potential to cause normal cells to become cancerous. Her tumors have since shrunk 68 percent, according to CT scan results in May, she said.

“They know my DNA -- all of these treatments they have designed for me,” Barth said in a telephone interview. “Who knows if it will cure me? If it just stabilizes my cancer and prevents it from growing, I can live with that.”

The M.D. Anderson clinical trial program uses molecular tests to identify the biological pathways that trigger cancer, spur its growth or strengthen its resistance to treatment. Researchers look for mutations in a dozen genes including KRAS, PIK3CA, NRAS, BRAF, CKIT and EGFR.

120 Studies

After patients are assigned to one of the center’s 120 studies using experimental medicines that target their individual cancer’s traits, they are compared with similar people who don’t get matched therapy. Reasons for not getting a matched therapy might include travel difficulties or lack of insurance.

The trials tend to be a last-ditch effort to find a therapy that works for each patient. Participants in the trials failed an average of four previous drugs.

Other cancer centers are doing similar work, often looking at one tumor type or for a specific mutation. At Memorial Sloan-Kettering Cancer Center in New York, everyone with metastatic lung or colon cancer undergoes tests for dozens of variations that may influence how they respond to treatment, said oncologist Leonard Saltz.

Speeding Development

While the approach may benefit more patients who enter cancer studies and speed drug development, it narrows the number of people who qualify for experimental treatment -- and the potential size of the market, said Saltz, who is head of the colorectal oncology section at Memorial Sloan-Kettering.

“Historically it has been difficult to get drug companies to be interested in this type of approach because it potentially limits their market,” he said in a telephone interview. “If you have a drug that works in 10 percent of the population but you can sell it to everybody, that has been a widely successful business model.”

The targeted approach may also save an experimental drug from failure.

Initial studies of Pfizer Inc.’s crizotinib included patients with any kind of cancer. Researchers quickly realized that the three patients who responded to treatment, out of 37, had a defect in a gene known as ALK that is key to the growth and survival of tumor cells, said Mace Rothenberg, senior vice president of clinical development and medical affairs for New York-based Pfizer’s oncology unit.

Gene Defect

The company decided in 2009 to focus solely on lung cancer patients with the ALK mutation, a group that makes up just 5 percent of the lung cancer population. The bet paid off. The company filed for regulatory approval in the U.S. based on its early trials, with data showing dramatic response to treatment in the properly targeted patients. Pfizer has two larger studies under way.

Rothenberg said he was concerned that a drug that may only benefit 5 percent of patients might not be commercially viable.

“Fortunately, my colleagues in commercial development immediately recognized that, given the high incidence of non-small-cell lung cancer, it still accounted for a considerable number of patients,” Rothenberg said.

Matching tumors to treatment isn’t a magic bullet. The treatment stopped working in the M.D. Anderson trials after 5.2 months for those getting targeted care, compared with 2.2 months for patients treated with unmatched drug therapy.

‘More Effort’

“It is going to take a lot more effort and investigation to get beyond this,” Otis Brawley, the chief medical officer at the American Cancer Society, said in a telephone interview. “If the time to treatment failure is truly 5.2 months versus 2.2 months, I see it as progress, but it is still not satisfying.”

Eventually researchers will need to combine targeted treatments to cut off all the avenues cancer uses to grow, not just those researchers can find now using genetic and molecular tests, Brawley said. Advanced technology is identifying a dizzying array of nuances in cancer growth and development that suggest tumors within a specific type of cancer have many ways to evade treatment and flourish, he said.

Less than 5 percent of adult cancer patients are in clinical trials. Often the reason is the design, with researchers giving 1,000 patients an experimental drug that benefits only 10 percent of them, said John Marshall, chief of hematology and oncology and director of clinical research at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington.

‘Freaked-Out World’

“When you are in the trenches in a clinic and you are afraid you are going to die, and the doctor wants to flip a coin to see what treatment you should get, that’s another level of uncertainty in a freaked-out world,” Marshall said in an interview. “We’re hoping to make it much easier. If we offer them a gene test that might inform a treatment decision, they are totally engaged.”

Most patients don’t have the option now. It’s easier to give chemotherapy that is unlikely to work than to do a genetic analysis, Marshall said.

“We are getting smarter, but not fast enough.”

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