Scientists study miracle patients’ genes for wider cancer therapies
BOSTON — Grace Silva and Karen Coakley are both 59, mothers living in the Boston suburbs and patients at Dana-Farber Cancer Institute, where they have spent years wrestling with daunting diagnoses.
While they have never met, the two women are connected in a way that goes beyond their similar stories and their struggles with cancer. They share an intimate and uncommon link, the sort of genetic bond possible only in an age of precision medicine.
Silva is what researchers call an “exceptional responder,” the rare patient who has a surprising, dramatic response to a drug. Coakley is the unsuspecting beneficiary of what scientists are now learning from these unique patients.
In 2010, Silva was diagnosed with anaplastic thyroid cancer, an aggressive and rapidly fatal
“What we’re trying to do with these cancers is find their Achilles’ heel.”
Barbara Conley, cancer specialist
disease with no effective treatment. Despite surgery, chemotherapy and radiation, the cancer spread to her lungs. As a last resort, she enrolled in a small clinical trial the following year with other patients with the same cancer.
“It was a shot in the dark,” said Jochen Lorch, her oncologist.
Along with the other patients, Silva got a drug called everolimus, approved for advanced kidney cancer and some types of breast and pancreatic cancer. The other patients died, but Silva’s tumors virtually vanished, to the astonishment of her doctors.
Such inexplicable reversals have always existed in medicine, but until recently, outliers such as Silva remained little more than hopeful anecdotes.
That could be changing. Silva’s story, and those of other exceptional responders, have led to an intriguing set of questions: Could researchers use technologies such as genetic sequencing to figure out what made Silva’s tumor respond to treatment? Could they mine that data for clues that might help other patients? Could they ultimately find a way to make the exceptional more routine?
The quest to answer those questions led them to Coakley, whose ovarian cancer was progressing despite years of treatments, and who found herself wondering whether she was out of options and out of time.
Sometimes answers emerge
In the past, a drug under development probably would be written off as a failure if, for example, 48 out of 50 patients in a clinical trial experienced little or no benefit. But that left unanswered why a handful of patients had “a Lazarus-like, unbelievable response,” said Barry Taylor, a molecular oncologist at New York’s Memorial Sloan Kettering Cancer Center.
Maybe the drugs themselves weren’t failures, Taylor and other researchers thought. Maybe they were being given to the wrong patients. If they could figure out which genetic wrinkles caused a Grace Silva to respond so profoundly to a certain drug, they might be able to find others — people whose tumors had the same mutations — who would have the same extraordinary reaction.
That would have been difficult, if not impossible, just a few years ago, when it took weeks and cost millions of dollars to decode an individual’s DNA. Today, far more powerful genetic sequencing costs less than $1,000 and can be done in hours.
Major cancer hospitals such as Dana-Farber now routinely sequence the tumors of all patients, allowing researchers to create vast databases to study which gene mutations drive certain cancers.
The National Cancer Institute in the fall launched a nationwide search for people with a variety of cancers who had unique responses to treatments. It has already identified scores and is hoping to identify many more.
“What we’re trying to do with these cancers is find their Achilles’ heel and attack that,” said Barbara Conley, associate director of NCI’s Cancer Diagnosis Program.
The goal, she said, is to identify genetic markers that could lead toward better treatments for other patients — involving, perhaps, drugs that were abandoned in early-phase trials because they didn’t work for most participants, or approved medications that might benefit more patients than doctors realized.
Conley and others say the strategy, although promising, is not foolproof. While everimproving technologies allow researchers to study cancer tumors in unprecedented depth, some tumors contain many mutations, and it can be hard to determine which ones cause a certain reaction to a drug.
But sometimes, answers do emerge.
Curious about Silva’s remarkable response, investigators from Harvard and the Massachusetts Institute of Technology analyzed samples of her original tumor. They discovered she had a mutation in TSC2, one of two genes that regulate a protein pathway called mTOR, which her cancer relied upon to grow. The drug she had reacted to so strongly, everolimus, inhibits mTOR, probably explaining why Silva had seen such an instant, longlasting benefit.
Even before Silva, a patient at Sloan Kettering with advanced bladder cancer had experienced a similar reaction to the drug. That patient’s bladder cancer had a genetic mutation that was simi- lar to Silva’s thyroid cancer.
Nikhil Wagle, a medical oncologist at Dana-Farber, said that suggested to researchers that patients whose cancers have similar mutations “could be extraordinary responders, regardless which kind of cancer they might have. This really spurred our interest.”
Doctors at the hospital began searching their database, trying to identify other patients with the same sort of genetic mutation — regardless of where their tumors were — for a small clinical trial of everolimus that would test their theory.
They soon turned up dozens of names.
Hope but still no cure
One of them was Karen Coakley, a soft-spoken woman who had spent much of the winter on a sofa in her home in Tewksbury, north of Boston. She didn’t know much about the genetic mutations of her cancer, but she did worry she wouldn’t see another winter.
“I have to be honest,” Coakley said while sitting in her yellow sunroom on a recent morning. “In September, I didn’t think I would be here today.”
Diagnosed in July 2008 with Stage 3 ovarian cancer, Coakley had undergone surgery and chemotherapy, which sent her cancer into remission. But by 2011, it was back, and since then, she had cycled through a dizzying series of drugs. Most would work for a while, but the cancer inevitably would resurface, and her doctor would move on to the next treatment on a list that was growing shorter.
“It’s a roller coaster,” Coakley said.
In September, she began a leave of absence from her job working in accounts payable at a manufacturing company, unsure she would ever return. She watched the New England snow fall outside her window. She watched daytime TV and worked on puzzles but had energy for little else.
In February, her oncologist at Dana-Farber told Coakley she was eligible for a new drug trial. Her tumor was very similar to Silva’s, and doctors suspected Coakley might benefit from everolimus. “I think you need to do this,” the oncologist told Coakley.
Coakley began taking the drug in early March, swallowing one pill at her kitchen table each morning.
After the first month, a blood test showed a sharp drop in the levels of CA-125, a protein produced by ovarian cancer cells. A month later, when her doctor called to say a scan showed her tumors were shrinking, she burst into tears in her driveway.
Coakley returned to work at the end of March. She’s planning a trip to New York soon to see a Broadway show with one of her daughters, and she and her husband are planning to visit their other daughter in Florida in the fall. They never used to look so far ahead on the calendar.
“It’s just allowed me more freedom to do things,” Coakley said. “I don’t have this sentence hanging over my head.” Daniel, her husband of three decades who has been her chauffeur, nurse and confidant throughout the seven-year ordeal, said the couple feel “more comfortable now.”
Doctors are discovering that even people whose cancers have genetic mutations they think might respond to a certain drug often do not, for reasons that remain largely mysteries. And those who do respond often don’t benefit indefinitely. Precision medicine, for all its promise, is not a panacea.
Knowing that, neither Coakley nor her doctors use the word “cure.” None of them know how long everolimus will continue to send her cancer into retreat. Still, Coakley said, she is grateful for Silva and other exceptional responders — none of whom she has met — as well as for the researchers smart enough to pinpoint their key genetic similarities.
“I feel like I’ve gotten a reprieve,” she said. “I’ve gotten my life back.”
‘God has a plan’
For all her good fortune, Silva faces an uncertain journey.
After 18 months, the cancer in her lungs became resistant to everolimus. Since 2013, Silva has tried several therapies aimed at heading off the spread of the disease, with mixed results.
Her most recent scans show that the cancer in her lungs has grown, albeit slowly. She is waiting to begin a new trial for a drug that targets the same genetic mutation in her cancer but through a different mechanism. Her doctors hope the new treatment will spark a reaction similar to the one she surprised them with years ago.
“Now, I’m actually expecting a response,” said Lorch, her oncologist. “I’d be really disappointed if it didn’t work.”
Silva is aware of the ongoing trial at Dana-Farber and is glad that her genetic information and that of other exceptional responders is beginning to benefit people like Coakley.
“I told my doctor . . . God has a plan here somewhere; we just don’t understand it. This is happening for a reason, and maybe that reason is to help someone else,” said Silva, who was born in Portugal but raised in Massachusetts. “It’s giving people hope.”
She’s also thankful for the time she might not have had, for the blessings each unexpected year has brought. “I’m very grateful God gave me this time,” she said.
On a recent Wednesday afternoon, Silva was on the floor of her living room in Dartmouth with the two grandchildren she might never have met — Jaelynn and Maddox — when her phone buzzed with a text.
“On my way to the hospital, pretty sure I’m in labor,” read the message from her youngest daughter. Another grandchild was on the way, and once again, Silva would be there to meet him.
Later, as Silva loaded the children into her Honda CR-V for the six-mile ride to St. Joseph’s Hospital, where her daughter was undergoing a Caesarean section, another text arrived: “Healthy beautiful boy.” Soon came a picture of the 7-pound 5-ounce newborn. “He’s got my nose,” Silva said, smiling.
In the hospital’s maternity word, Silva found her daughter in a small recovery room, cradling her newest grandson, Conner, barely an hour old. She leaned over the bed, kissed them both and stroked the boy’s cheek.
“My goodness,” she said. “Look at that face.”
Grace Silva, far left, who was diagnosed in 2010 with an aggressive and rapidly fatal type of cancer, leaves the house with grandsonMaddox Santos and granddaughter Jaelynn Martinez. Silva had a surprising, dramatic response to the cancer drug everolimus. Scientists have mined her case for clues that might help other patients, including Karen Coakley, near left, who was also prescribed everolimus because her gene mutations were similar to Silva’s. Her tumors have shrunk, and she has returned to work.