The history of oncology is rife with reports of patients with advanced cancer who staged miraculous recoveries. Now scientists are starting to use sophisticated DNA sequencing technology to determine if these “exceptional responders” carry gene variations that can lead to new treatment approaches, better targeted therapies or even the re- emergence of experimental drugs once deemed failures.

“What was yesterday’s miracle event is today becoming a subject of scientific inquiry,” said Leonard Lichtenfeld, an oncologist for 42 years who is deputy chief medical officer for the American Cancer Society.

As many as 10 percent of patients respond well in clinical trials to experimental medicines that end up being rejected for approval by U.S. regulators, according to the National Cancer Institute. A handful of initial studies have already produced promising data showing why some patients have exceptional responses to drugs that do not work for others.

Collecting data

Now the National Cancer Institute and academic medical centers, including Memorial Sloan Kettering Cancer Center in New York, the Dana-Farber Cancer Institute and Massachusetts General Hospital in Boston and the Broad Institute in Cambridge, Massachusetts, are collecting data to conduct a more complete survey of exceptional responders. The plan is to create a national database for researchers.

So far, about 100 exceptional responders have been identified by researchers poring through about 10 years of clinical trials, said Barbara Conley, associate director of the NCI’s Cancer Diagnosis Program.

Starting in June, the agency will urge researchers and doctors nationwide to send in clinical data on these patients.

“We want to cast a broad net,” Conley said. “The key is, can you find another patient with the same kind of abnormality and will they respond?”

‘Melted away’

In a study presented recently at the American Association for Cancer Research meeting in San Diego, researchers analyzed the case of a 57-year-old woman with advanced thyroid cancer who was the only patient in a drug trial who experienced almost a complete disappearance of her tumor.

Her tumor “melted away” and didn’t start growing again for 18 months, something unheard of in this rare, aggressive disease, which usually kills in five months, said Nikhil Wagle, an instructor at Dana-Farber and the study’s lead investigator.

Genetic analysis revealed the patient carried a mutation in the TSC2 gene that helped make her tumor susceptible to Novartis AG’s Afinitor, used for kidney and breast cancer. The treatment works on a biological pathway called mTor that is linked to the mutation.

Researchers plan to screen other patients for mutations to the mTor pathway and enroll them in clinical trials using the drug. These patients wouldn’t be selected based on the type or placement of their tumors, but rather based on molecular profiling, Wagle said.

Exceptional responder

David Solit, director of the Center for Molecular Oncology at Memorial Sloan Kettering, was one of the first scientists to chase the case of an exceptional responder using whole-genome sequencing, studying the same biological pathway as Wagle.

Two years ago, Solit investigated the case of a woman with advanced bladder cancer who was part of a 45-patient trial testing Afinitor. While the trial was considered a failure, the woman had a complete remission and is still alive four years later, he said.

An analysis found mutations that caused a loss of function in TSC1 and NF2 genes, suggesting a new direction for researcher interest in the mTor pathway and opening the possibility that other patients who carry those mutations would find similar success using Afinitor.

Refining advances

The research also can help refine the advances already made in targeted cancer treatments and immunotherapies.

Unlike traditional chemotherapy, which kills healthy cells along with malignant ones, targeted therapies are designed to home in on specific biological aspects of cancer cells that promote a tumor’s spread and growth. Still, most patients develop resistance and the disease returns.

One patient’s dramatic results from a targeted therapy that does not help others suggests another genetic feature may be involved. By identifying a mutation in an exceptional responder, researchers can then screen other patients to see if they have the same alteration, and give them the same drug.

Drug resistance

Lecia Sequist, an oncologist at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, specializes in lung cancer patients with EGFR mutation, which is a target of drugs such as Roche Holding AG’s Tarceva. Only 15 percent of patients have the mutation, and rarer still is the patient who does not develop resistance, she said.

“I think it will give people hope to know there are patients like this and people are trying to figure out whether there are more patients like this and what can we do as oncologists to improve treatment,” Sequist said in an interview.

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