http://www.nytimes.com/2014/10/09/health/in-genes-of-exceptional-responders-clues-to-fighting-disease.html 2014-10-09 00:49:01 In Genes of ‘Exceptional Responders,’ Clues to Fighting Disease Some people respond to drug treatments much better than others. Now researchers are studying ‘exceptional responders’ in an attempt to help all patients. === Grace Silva has a horrible form of 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 Dr. 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 “The verdict was, ‘O.K. I guess everolimus does not work in bladder cancer,” said Dr. 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 tumors disappeared. “I was at a clinical meeting and everyone was saying this drug did not work,” Dr. 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,” Dr. 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. Dr. 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,” Dr. Conley said. “Ten percent, maybe less, had this response.” On Sept. 24, the cancer institute announced it was sending letters to cancer doctors seeking exceptional responders. They are hoping for tumor samples from 300 such patients, Dr. Conley said, and want to find 100 whose tumor 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 Mrs. Silva’s story. “It is a stunningly interesting example of molecular Mrs. Silva’s symptoms started in 2010 with a badly swollen neck and throat. She saw her doctor, who gave her “I went to my doctor and said, ‘This isn’t normal,’” she recalled. Finally, Mrs. Silva, who is 58 and lives in Dartmouth, Mass., ended up at the Dana-Farber Cancer Institute in Boston where she got terrible news. She had anaplasic thyroid cancer. Anaplastic thyroid cancer, said Dr. Jochen Lorch, her oncologist at Dana Farber, “is one of the worst cancers you can get.” Surgeons removed her thyroid gland and the tumor that was growing there and gave Mrs. Silva 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, Mrs. Silva – but none of the other patients with anaplastic cancer — responded immediately. Her tumors shrank to almost nothing and stayed that way for 18 months. That, said Dr. Nikhil Wagle, another of Mrs. Silva’s doctors at Dana-Farber, “is just unheard of.” The researchers sequenced her tumor’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 tumors started to grow again. Mrs. Silva agreed to have another 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 Mrs. 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, Dr. 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,” Dr. Lorch said.