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Rare cancer recoveries could be key to wider treatments

Grace Silva survived cancer, against the odds, to meet her grandchildren.JOANNE RATHE/GLOBE STAFF

For years, they have been among modern medicine’s most arresting fables: a 54-year-old woman sees her tumors melt away in a clinical trial, but no one else with the same lethal thyroid cancer responds. An elderly man with advanced bladder cancer enrolls in a safety study of two therapies and is the one person to see his cancer vanish for over a year. A drug flops in a clinical trial, but works for a 73-year-old woman with bladder cancer who is still alive five years later.

Physicians have traditionally viewed the rare cancer patients who bounce back from near-certain death as inspiring anecdotes, not science. But a study published by a Boston team Wednesday in the New England Journal of Medicine highlights a radical shift in thinking: researchers are harnessing a powerful arsenal of biomedical tools to unlock the secrets of individual “exceptional responders.”

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“If we can figure this out in one patient, maybe we can understand how to do this in more patients,” said Dr. Nikhil Wagle, a breast oncologist at Dana-Farber Cancer Institute and a leader of the new study. “And maybe, ultimately, we can understand how to do this in all patients.”

Over the past two years, a trickle of cases -- including two from Boston -- have made it clear that such investigations can explain why a particular patient responded and also point to new research ideas and treatments for others. Last month, the National Cancer Institute launched a nationwide search for exceptional responders as part of a pilot study that will use DNA sequencing and other tools to understand why the therapies worked. Those results will be compiled in a central database, with the hope the insights could guide the design of new clinical trials and personalized treatments.

In the meantime, individual hospitals are setting up their own programs. A Boston-area team of physicians, cancer researchers, and genome specialists collaborated to unravel the case of Grace Silva, 58, of Dartmouth.

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Four years ago, Silva woke with painful swelling around her neck. At first, her doctor thought she had an infection, but a specialist felt a lump and urged a biopsy.

In a flash, her life changed. Silva learned she had a gravely serious type of thyroid cancer. She asked whether she could delay surgery until after her daughter’s wedding in Mexico in a few weeks, but her doctors said no.

After the surgery, X-rays revealed that lesions remained in her neck. A high fever that felt like a sign of pneumonia turned into something more; the cancer had spread to her lungs.

Dr. Jochen Lorch, a medical oncologist at Dana-Farber who was one of Silva’s doctors, said her cancer had an especially grim prognosis. Patients typically live for five months.

He told Silva about a study that she could try; there were no guarantees that it would help at all, but he had nothing else to offer and there was a possibility it might delay the disease’s progression.

“I decided to try it and here I am, four years later,” Silva said. Six other patients with her type of cancer in the trial had no response.

Lorch, Wagle, and colleagues launched a study and pinpointed a mutation that explained why Silva’s cancer was unexpectedly vulnerable to the trial drug, called everolimus. When the cancer returned a year and a half later, Silva agreed to a lung biopsy. The researchers found that a different gene mutation had developed, which explained why the drug stopped working.

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Then, they studied the new mutation in cells in a dish, gaining new scientific insights that they thought might be helpful in understanding how other cancers develop resistance to the same drug. But they also found that experimental drugs being developed now had a good chance of working for Silva because they targeted a spot far away from the mutation in Silva’s cancer. Researchers are currently seeking approval for a trial with a drug made by Millennium Pharmaceuticals in Cambridge for Silva and other patients with her type of cancer.

Although she no longer has the energy or time to work or garden while managing her disease, Silva treasures the time she has gotten to spend with her family -- and to become a grandmother.

“I didn’t have any grandchildren and now I have two, and just being with my family in general,” Silva said. “I feel very lucky.”

Dr. David Solit, director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at Memorial Sloan Kettering Cancer Center in New York, first used genome sequencing two years ago to study why a woman with bladder cancer had an extraordinary response to the drug everolimus.

He is now collaborating with researchers in Boston to open a new kind of clinical trial, called a “basket trial,” based on insights from how the bladder cancer patient responded. Instead of testing a drug on breast cancer patients or lung cancer patients, basket trials accept any cancer patients whose tumors harbor mutations that are likely to make them vulnerable to a drug.

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Solit pointed out that throughout history, physicians have studied extreme cases of disease in order to gain fundamental insights that help broad group of patients. What is new is the availability of cheap, sophisticated molecular tools that allow scientists to learn from individual patients whose disease takes an unexpected trajectory.

“You should never let one of these not get analyzed ... because it’s a missed opportunity to find a subpopulation of patients who might benefit from the drug,” Solit said.

An early example that this was possible in cancer unfolded a decade ago, at the dawn of therapies targeted to the specific genes that drive cancer.

In lung cancer trials, a subset of patients responded to a drug called gefitinib, but others did not. Doctors at Massachusetts General Hospital and other institutions began to examine the gene that was the target of that drug and found that some people with a particular mutation had cancers that were vulnerable to the drug -- laying the basis for a genetic test that could determine which patients should receive the therapy.

“The whole mind-set in cancer is different than five to 10 years ago,” said Dr. Lecia Sequist, a medical oncologist at Mass. General. “So now when you see this unexpected, above the curve, super-response to any kind of treatment, now the mind-set is let’s investigate and try to find why that is.”

Carolyn Y. Johnson can be reached at cjohnson@globe.com. Follow her on Twitter @carolynyjohnson.