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By Richard Knox
By all odds, Grace Silva should have died more than three years ago. Instead, this 58-year-old grandmother is helping scientists rethink cancer treatment and research.
Silva’s case, detailed in this week’s New England Journal of Medicine, is one of only three recently published accounts of what cancer doctors call “exceptional responses” to a drug called everolimus (brand name Afinitor).
It was approved two years ago to treat certain breast cancers and is also used against some kidney and pancreas tumors. A couple of months after Silva started taking the drug, her thyroid tumors, which had spread to her lungs, melted away to nearly nothing. That basically never happens with this aggressive tumor, known as anaplastic thyroid cancer. “It was a near-complete response,” says her oncologist at Dana-Farber Cancer Institute, Dr. Jochen Lorch. “That in itself is exceptional. When we saw it, it was one of the better days around here.”
Studying The Exceptions
More remarkable still, Silva’s tumor stopped growing for 18 months. We’ll come back to what happened after that. But first, you should understand this story isn’t about everolimus or any particular cancer drug. It’s about how cancer specialists are learning how cancer works at the most basic level — by studying exceptional responders like Grace Silva.
And to appreciate why her case is important, you need to know how researchers figured out why she was an exceptional responder. It’s partly due to a five-year-old technology called next generation sequencing. It’s a cheap and rapid way of spelling out the genetic code of, in this case, individual patients’ tumors. Researchers can then look for gene mutations that are driving the uncontrolled growth that is cancer.
Until recently, it was impossibly time-consuming and expensive to decode the genetics of individual patients’ tumors. But automated next-generation sequencing machines can now do it for $350 to $1,000 depending on how much detail scientists are looking for. The price is expected to drop further. “All the big cancer centers have these sequencing efforts going on,” Lorch says. “Basically anybody who walks through the door of the Dana-Farber gets their tumor sequenced.”
Right now, doctors don’t know what most of this information means. That is, when they see a gene mutation in a tumor, they don’t know if it’s driving the tumor’s runaway growth, if it’s responsible when the cancer shrinks in response to a drug, or if it enables the cancer to resist that drug and start growing again.
But Silva’s case shows how powerful genetic information about the tumor can be. When the Harvard-MIT team analyzed her original tumor, they discovered a mutation in a gene called TSC2. It makes a protein that regulates a different protein called mTOR, which is important in regulating normal cell growth and maturation. The TSC2 mutation takes the brakes off mTOR, stimulating uncontrolled growth.
Discovering the mutation in Silva’s tumor was a eureka moment because the researchers already knew that everolimus inhibits mTOR. So that explains why Silva’s tumor was exquisitely sensitive to the drug.
But cancer is wily. It often finds a way around any particular drug, a discouraging phenomenon called resistance. Silva’s tumor became resistant and started growing again after 18 months of suppression by everolimus. Since then, Lorch has kept her cancer somewhat in bounds by conventional chemotherapy while searching for way to get another exceptional response. And once again, genetic analysis (also called genomics) has apparently come to her rescue.
The Harvard-MIT team reanalyzed Silva’s tumor and discovered a new mutation that wasn’t present in her original tumor, a mutation discovered in yeast cells 20 years ago but never seen before in humans. It’s a tiny change in the mTOR gene that blocks the effect of everolimus.
Fortunately, the researchers found that Silva’s everolimus-resistant cancer cells remained sensitive to a drug that works at a different spot on the mTOR molecule. She’s about to enter a trial of that drug, made by Cambridge-based Millenium Pharmaceuticals.
Grace Silva, who lives in Dartmouth, Massachusetts, says she never abandoned hope and says she “plans to beat this cancer” so she can go back to work, watch her two young grandchildren grow and travel to her native Portugal.
New Model For Research
If Silva turns out to be an exceptional responder to the next mTOR blocking drug, she’ll be a complete model for what cancer scientists hope will eventually become unexceptional. First, more and more patients will be treated with drugs matched precisely to their tumor genetics. And when those drugs fail, as they almost always will, further treatment will be based on genomic analysis of what’s causing the resistance.
To hasten that day, the National Cancer Institute has just launched what it’s calling the Exceptional Responders Initiative. It’s inviting cancer researchers and community specialists around the nation to send in tumor tissue from exceptional responders so mutations can be catalogued and patterns identified. Some doctors have already responded, according to a New York Times report.
Meanwhile, stories like Silva’s are causing cancer researchers to rethink the way they study new cancer drugs. Until now researchers have always studied a new drug in patients with particular kinds of cancer – breast, lung, prostate, thyroid, and so on. If fewer than 10 percent of those had exceptional responses but the vast majority did not, the study was called a failure and the drug shelved. In the future (beginning now), scientists will be doing what they call “bucket studies.” They’ll study a drug’s effects on patients whose tumors have mutations that an experimental drug is targeted against, regardless of what part of the body the cancer initially struck.
The same trial may have patients with different kinds of cancer, but the same genomics. “The molecular underpinnings are more important than the tumor type,” says Nikhil Wagle of Dana-Farber, first author of this week’s paper on Silva. “It’s what a lot of us working on precision medicine have been thinking for a long time. The reason people in the field get so excited about this...is that we want all our patients to be exceptional responders.”
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