BEFORE IT CAN REACH ITS FULL POTENTIAL, IT HAS TO BECOME MORE PRECISE
Tania Swain got bad news: her ovarian cancer had come back. This was in November 2013; almost three years before, Swain, who is herself a physician, had been surprised by the initial diagnosis. And despite the surgery that removed 30 pounds of liquid and tissue from her ovaries, spleen, and appendix, and the chemo drugs that were swished around the space they left, the cancer was back. She feared that this time the diagnosis was truly the “kiss of death.”
But this time, Swain learned about the
Clearity Foundation, a nonprofit organization that compiles its own database of mutations that cause ovarian cancer and help patients find the best individualized treatment. After another surgery in December 2013, her doctors sent a tissue sample to Clearity. “They look at the proteins and receptors, and the different ways that the tumor tissue itself has mutated to find how they can best attack it,” Swain says. Her tumor had an unusually high concentration of a protein called Ki-67, which was good news—her cancer would be
more responsive to typical chemotherapy agents.
The treatment worked well—Swain felt less ill after the chemo than she had the last time. Though her cancer has since returned, she’s hopeful because she’s so impressed by the progress of cancer treatment, and advances in precision medicine in particular. “I finished my training [to become a doctor] in 1982, when CAT scans were just coming online. I think cancer treatments now are as different as night and day compared to then,” Swain says.
Precision medicine, an emerging field in which treatments are tailored to an individual’s genes, environment and lifestyle, is on the cutting edge of cancer treatment. President Obama launched his
Precision Medicine Initiative earlier this year; several research institutions have undertaken large-scale clinical trials in which patients with different diseases can enroll, one of which was conducted by the Memorial Sloan Kettering Cancer Center with results published last week. And while some patients like Swain have benefitted from what researchers have figured out so far, precision medicine isn’t nearly as widespread—or precise—as proponents want it to be. To bring this field to its full potential, researchers will need to figure out how to best tailor treatments to suit every patient’s biological differences. And the more they learn, the more difficult that seems.
“What’s happened in science is really breathtaking—the human genome was first sequenced in 2003, and today we can do the same thing in a matter of hours,” says
Razelle Kurzrock, the director of the Center for Personalized Cancer Therapy at the Moores Cancer Center at the University of California, San Diego. Since researchers can read the genes more effectively than ever before, treatments that target the mutations have suddenly become a reality.
HOW DOES PRECISION MEDICINE ACTUALLY WORK?
On their most basic level, cancers are diseases in which normal cells grow more quickly than they die. Genes regulate this cycle of growth and death. Mutations in these genes can affect a person’s cancer risk, but they can end up in the genome in different ways. Germline mutations are those that you inherit; women who are born with the BRCA mutations have a higher risk of developing breast and ovarian cancer as adults. Acquired mutations are the ones that are added to your genome after you are conceived; women with HER2-positive breast cancer (about
one fifth of all breast cancers) weren’t born with that mutation: It developed over time due to environmental and lifestyle factors.
Cancer happens when several of these mutations converge in one or a cluster of cells. And, importantly, the same mutation can happen in lots of different places in the body. “It’s no longer that important where the disease originates, if it’s in the lung or in the breast or in the brain—what’s important is the [genetic] driver of the disease,” Kurzrock said in a
2013 presentation.
Precision medicine—also known as personalized medicine or individualized medicine—mostly targets these acquired mutations because those are what make the cancerous cells different from the other cells in your body. When a patient is diagnosed with lung cancer, for example, her doctor will take a tiny sample of the tumor and sequence the genes found in the cells. Usually they’ll only look at a handful of genes to look for mutations known to drive cancer, but sometimes they’ll sequence all of the patient’s genes to better understand the genetic factors that have brought the cancer about.
Once they’ve identified the mutations driving the cancer, doctors can prescribe drugs that target and destroy only the cells with that mutation. That’s a lot better for the patient than existing chemotherapy drugs, which kill all rapidly reproducing cells, whether they are cancerous or not. Patients receiving treatments targeted specifically at cancer cells tend to experience fewer side effects, feel better, and recover more quickly, as Swain did.
That all sounds simple and elegant in theory. But at the moment, precision medicine is a bit less precise than that. Cancer cells have lots of different mutations, and sometimes it’s hard to identify just which one is driving the cancer. Researchers have only identified about 50 genetic mutations known to drive cancer. Though they suspect that there are hundreds, they just haven’t found them yet, which means that sometimes genetic tests of tumors come back without any mutations known to cause cancer. Even if they do find a cancer-driving mutation, doctors sometimes can’t prescribe a drug to treat it because it simply does not exist, or is only approved to treat a different kind of cancer.
Most of these questions haven’t been addressed yet because the field of precision medicine is so new. Many of them will take years of dedicated research to answer fully. But right now researchers are making some impressive headway, systematically tackling what seems to be an unfathomably complex issue. Their answers have meant that precision medicine treatments are starting to become available to patients in the U.S. and beyond, but it’s also shown them just how far they have to go.
A NEW WAY OF TESTING TREATMENTS
Researchers are answering many questions about how to treat cancer through new, large-scale clinical trials. In the past, when scientists wanted to test a new cancer drug on patients, they would group them by the location of their cancer—lung, breast, colon. But with the rise of precision medicine, researchers have realized that cancers with the same driving mutation, no matter where they are in the body, have more in common. New clinical trials, conducted by cancer-focused research institutions like the
National Cancer Institute and Memorial Sloan Kettering Cancer Center (MSKCC), have tested treatments on patients with the same cancerous mutation in different parts of the body.
In MSKCC’s study the
results of which were published last week in the
New England Journal of Medicine, the researchers tested a drug on 122 patients worldwide. In a traditional clinical trial, only patients with cancer in the same part of the body would be eligible to participate; if it worked, the researchers would have found a new drug to specifically treat colon cancer, for example. But in this new kind of trial, called a basket trial, the researchers tested the drug on people who had cancers of the blood, breast, thyroid, ovaries, colon, and several rare forms. But these cancers all had something in common: they were all driven by the same mutation. The researchers found that the treatment worked better on cancers in some parts of the body than in others. That means that doctors have to take location
and mutation into account when selecting a treatment.
“I think that many people may not know is that we really have to look at our patients in the context of where the tumor came from and the entire complement of genetic and potentially non-genetic abnormalities in that cancer,” says
David Hyman, the acting director of Developmental Therapeutics, MSKCC’s drug development program that focuses on precision medicine, and one of the study authors. “We need to marry the information about the genetics of tumors with our understanding about their basic function in order to make real breakthroughs in individual patients.”
THE FLIPSIDE OF GENES
This study didn’t show Hyman and his collaborators why treatments work better for some types of cancer than others—or why a treatment’s efficacy differs between individuals with cancers in the same location with the same primary mutation. On an abstract level, though, researchers know why these variations exist: other genes, not the ones driving the cancer. “Most people don’t know that their genes can interfere with the drugs they take, even with special cancer treatments,” says
Keith Stewart, the director of Mayo Clinic for Individualized Medicine.
The way a patient metabolizes the treatment can mean that she needs a higher or lower dose. Sometimes cells without the cancer-driving mutation survive the treatment, which can mean that the cancer comes back. “[Treatments can] suppress the cells they’re supposed to, but the other cells keep growing. It’s like a whack-a-mole game,” Stewart says. “And they’re often growing because they’re drug-resistant,” which means they’re harder for doctors to treat the next time.
The next step for precision medicine will be to combine multiple targeted treatments so that they fight more cells, not only the ones primarily driving the cancer—like using several hammers to whack all the moles at once. “Let’s say we do a profile of biomarkers and genomic markers on a patient and, rather than deciding to give patients one drug, we might give them three drugs, like we do to treat AIDS and other diseases,” Kurzrock says. By stopping multiple pathways, doctors could take the tumor out completely, she adds, and put the cancer in remission.
Precision medicine is a relatively new field, but this particular facet--the cocktail approach--is even newer.
“Everyone needs their own individual cocktail,” Kurzrock says. And that’s not how the FDA approves cancer drugs at the moment--each drug has a specific dosage for a cancer depending on its location in the body. Recently doctors have started using these treatments off-label, like using a drug approved for melanoma to treat a lung tumor because they share a driver mutation, but they can’t do this with several drugs at once for fear of how they might interact in the body . But it seems likely that this multi-pronged approach will be one of the main ways we treat cancer in the near future, likely combined with immunotherapy, a way of harnessing the immune system so that it recognizes and combats cancers that are otherwise able to slip past it.
That combination, of various targeted drugs and immunotherapy, seems like the closest we’ve ever come to a cure for cancer since we knew what cancer was. That’s not to say it’s right around the corner; in addition to lots more research and new drug development, there are issues to work out on the patient-facing side of the issue.
MOVING MOUNTAINS TO READ GENES
Precision medicine is only possible because of how quickly and easily we can now sequence the human genome. But most people in the U.S. still have never gotten their genome sequenced. Genetic sequencing is still limited to university medical centers and hasn’t yet made its way to community hospitals, so most Americans’ doctors aren’t suggesting it. Even people who do want to get a genetic test have trouble because insurance often doesn’t cover the testing, which usually costs about $300 for a cancer panel. “For whole genome sequencing, cost is definitely still a barrier, it still costs about $10,000 dollars,” Stewart says. In the Mayo Clinic’s rare disease practice, most patients need this whole genome sequencing so that doctors can finally diagnose illnesses that have eluded treatment for years, and insurance only covers it about a third of the time, Stewart says.
Eventually the process of sequencing a genome will become even cheaper, and insurance will catch up and cover genetic sequencing as it becomes more common for myriad medical procedures—the model will be “sequence once, query often,” Stewart says. He means that, soon, a person’s entire genome will simply become a part of her medical record that her doctor can refer back to throughout her life.
But there is another factor that stands in the way of precision medicine becoming more widespread, Stewart says: cost of sequencing, insurance coverage, and education. Not enough people (including many physicians) know what the genome can tell us given the current state of research, and just as importantly, what it can’t. That means that patients aren’t asking their doctors for genetic tests, and doctors aren’t suggesting them. So patients are not getting the best treatments possible or, worse, they’re afraid of getting their genome sequenced because of the other information a genetic test could reveal.
It’s true that whole genome sequencing in particular can reveal some incidental findings, uncovering other mutations that could affect a patient’s health, or those of his loved ones. But the role of genetic counselors is to discuss the results and help patients understand what they really mean. At the Mayo Clinic, before they see their doctors, cancer patients watch a short educational video about what their cancer genome can tell them (and what it can’t), and why they may or may not want their genes sequenced. “We have patients enter the doctor’s office with that knowledge and discuss it with the physician. ‘Would [a genetic test] be helpful in my situation?’ They can decide,” Stewart says.
For Swain, the choice to get a genetic test was an obvious one. She knew it would help her find the best possible treatment, but even as a doctor she struggled to understand just what was going on in her body. “It was still a little overwhelming. All that information just comes at you,” she says. Without that treatment, however, she may not have survived; when she was first diagnosed with Stage 3 ovarian cancer, in 2011, she had a
39 percent chanceof living at least five more years. Now, almost five years later, Swain is hoping that this third round of treatment has finally rid her body of ovarian cancer. The genes driving her cancer have changed—“which speaks to the polymorphism of this cancer,” she says—and the drugs she’s using to kill it have changed accordingly. But she’s optimistic: “I am very happy with the status of my markers and I’m feeling good.”
Precision medicine is just starting to make a difference for patients like Swain, and in just a few years it will be an even more powerful force against cancer for thousands of people around the world. But there’s a lot that needs to happen to get us there. Patients have to understand how genes play a role in cancer and treatment; organizations like insurance companies and pharmaceutical companies need to acknowledge the importance of these genetic markers so they can support and discover treatments that really work. And of course scientists will continue to conduct larger, more sophisticated experiments new ways to more effectively target tumor cells. In the process, they’ll likely answer some questions about how our genes affect us, even before cancers develop.
“I think the human genome is the book of life. I feel we don’t fully understand its power and value at this time, and I’d like to know what we’re missing,” Stewart says.
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