Finding clues in genes of ‘exceptional responders’

Some people respond to drug treatments much better than others. Now researchers are studying ‘exceptional responders’ in a bid to help all patients


Grace Silva has a form of thyroid cancer that is considered untreatable, but she responded well to a drug. Photo: Kayana Szymczak/NYT
Grace Silva has a form of thyroid cancer that is considered untreatable, but she responded well to a drug. Photo: Kayana Szymczak/NYT

Grace Silva has a horrible form of thyroid cancer that is considered untreatable—usually patients are sent to a hospice and die within months of learning they have the disease. But she is still alive four years after her diagnosis. She is what cancer doctors call an exceptional responder: someone who defies all expectations by dramatically responding to a cancer drug tried not with a real rationale but more out of a doctor’s desperate urge to do something.

The annals of medicine are full of stories of exceptional responders but until recently they were just that: stories. Case histories that could not be generalized because there was no way to know why these patients somehow got better when others did not.

But now, with the advent of rapid and inexpensive gene sequencing, the National Cancer Institute has started a nationwide search for people like Silva to try to figure out the genetic changes that allowed them to respond. And The New England Journal of Medicine on Wednesday published her story as a case history in the new genetic era, which concludes with a lesson that may help doctors treat thousands of other patients with more common cancers, like breast and bladder cancer, and even help them find an alternative when a common drug stops working.

Barbara Conley, a lead investigator for the new cancer institute study, said she and her colleagues had been inspired by a couple of published papers on exceptional responders and genetic analyses that revealed why they reacted the way they did.

One study at Memorial Sloan-Kettering Cancer Center was testing a drug called everolimus that is approved for kidney and breast cancer. Researchers asked if it could treat bladder cancer. Forty-five patients got the drug. Two responded.

“The verdict was, ‘OK, I guess everolimus does not work in bladder cancer’,” said David Solit, the principal investigator. But then there were those two patients—one, in particular. Her cancer had spread to her abdomen. She was expected to live less than a year and there was no treatment for her. But with everolimus, her tumours disappeared.

“I was at a clinical meeting and everyone was saying this drug did not work,” Solit said. “I said, ‘It worked for her’.”

The investigators found out why. Her cancer had a mutation in a gene that made it dependent on a protein, mTOR, for growth. Everolimus squelches the activity of mTOR. The woman is still taking everolimus and her cancer has not recurred.

Then the group found another exceptional responder, a patient taking an experimental drug for a cancer of the ureter, the tube that carries urine from the kidney to the bladder. “She not only responded but she was cured,” Solit said. The company discontinued the drug because it was not working—except for her—forcing her to stop taking it. But her cancer has not returned.

Conley at the cancer institute and her colleagues decided to look back at a variety of early phase clinical trials of drugs that had been abandoned because, on average, they did not help patients. Were there some participants who were helped, some exceptional responders?

“Yes, they were actually there,” Conley said. “Ten per cent, maybe less, had this response.”

On 24 September, the cancer institute announced it was sending letters to cancer doctors seeking exceptional responders. They are hoping for tumour samples from 300 such patients, Conley said, and want to find 100 whose tumour samples contain enough tissue for analysis. So far, they have examined the clinical data for three cases that were sent in. Two of them really are exceptional responders, she said. Now the challenge will be to figure out why.

That may not be easy, said Charles Perou, a professor of molecular oncology at the University of North Carolina in Chapel Hill. Sometimes, he said, researchers will see hundreds of mutations in a cancer and none will explain a patient’s response to a drug. “You are left scratching your head,” he said.

In that light, he said, he certainly can see why The New England Journal of Medicine decided to publish Silva’s story.

“It is a stunningly interesting example of molecular genetics and drug response and resistance,” Perou said.

Silva’s symptoms started in 2010 with a badly swollen neck and throat. She saw her doctor, who gave her antibiotics, but the condition recurred again and again.

“I went to my doctor and said, ‘This isn’t normal’,” she recalled. Finally, Silva, who is 58 and lives in Dartmouth, Massachusetts, ended up at the Dana-Farber Cancer Institute in Boston where she got terrible news. She had anaplastic thyroid cancer. It is, said Dr Jochen Lorch, her oncologist at Dana Farber, “one of the worst cancers you can get”.

Surgeons removed her thyroid gland and the tumour that was growing there and gave Silva chemotherapy and radiation, but the cancer almost immediately reappeared in her lungs and grew rapidly—a typical scenario. “There is just a maximum amount of tumour the body can support,” Lorch said. “Tumours eat up all the nutrients around—patients lose weight very, very quickly—and poke holes in the surface of the lungs. Patients die very quickly.”

But Dana-Farber was starting a study of everolimus in thyroid cancer patients because mouse studies indicated it might work. The researchers decided to include seven patients with anaplastic thyroid cancer reasoning there were no other treatments for them.

To everyone’s surprise, Silva responded immediately. Her tumours shrank to almost nothing and stayed that way for 18 months. That, said Dr. Nikhil Wagle, another of Silva’s doctors at Dana-Farber, “is unheard of”.

The researchers sequenced her tumour’s genes and figured out why. Just as had happened with the bladder cancer patient at Memorial Sloan-Kettering, a mutation made the cancer dependent on mTOR, and the drug happens to squelch the production of that protein.

Then her tumours started to grow again. Silva agreed to have another biopsy and genetic analysis to find out why the drug had stopped working.

It turned out that a second mutation in the mTOR gene was letting her cancer evade the drug and grow. That mutation had never been seen in a human being, even though by now researchers have determined the genetic sequences of tens of thousands of cancers. But, 20 years ago, it had been seen in yeast. An experimental drug, which Silva will soon get as part of a clinical trial, overcomes the mutation’s effect, stopping the cancer’s growth, at least in laboratory studies.

Everolimus, though, is used by thousands of bladder and breast cancer patients. Why, then, did no one see the mutation that can stop it from working?

The answer, Lorch said, is that the actual genetic analysis that revealed why the everolimus stopped working was “actually quite complex”. But, he said, now that the genetic change that leads to resistance is known, investigators can look just for that mutation.

“The resistance mechanism almost certainly does not just apply to our case,” Lorch said.

 ©2014/The New York Times

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