Precision medicine, linked to DNA, still too often misses
Back in January, when President Obama proposed a precision medicine initiative with a goal of “matching a cancer cure to our genetic code,” John Moore could have been its poster child. His main tumors were shrinking, and his cancer seemed to have stopped spreading because of a drug matched to the cancer’s DNA, just as Obama described.
This summer, however, after a year’s reprieve, Moore, 54, feels sick every day. The cancer — advanced melanoma like former president Jimmy Carter’s — has spread to his lungs, and he talks about “dying in a couple of months.”
The return and spread of Moore’s cancer in a form that seems impervious to treatment shows that precision medicine is more complicated than portrayed by politicians and even some top health officials. Contrary to its name, precision medicine is often inexact, which means that for some patients, it will offer false hope rather than a cure.
“There is a paradigm shift in the treatment of cancer as we move to precision medicine,” said Dr. Lincoln Nadauld of Intermountain Healthcare, a large system of hospitals and clinics based in Utah. “But that doesn’t mean the outcomes are going to be perfect in every case.”
The idea is straightforward: customized treatments for each patient, based largely on their genetic profile. In cancer, a main focus of Obama’s plan, patients will have the tumor’s DNA sequenced, and the readout will be used to select drugs known to work against a particular mutation found in the genome. While few patients today are treated in this way, many academic medical centers are studying precision medicine and hoping to make it standard in cancer care.
But, as a tumor grows, it accumulates so many genetic changes that it’s not always clear which one is the “driver mutation” fueling its uncontrolled growth. As a result, it might not be clear which drug to use. Oncologists can also be stymied because they are shooting at a moving target. Even if they correctly identify one driver mutation, another can emerge weeks or months later, making the previous drug regimen ineffective at fighting the tumor.
“The promise of precision medicine in cancer is that you’ll be able to find an actual driver mutation and match a drug to it,” said Nadauld, who led a study in which Moore participated. “The problem is that it’s never quite as easy as we’d like it to be.”
Moore, a former government worker who lives in Apple Valley, Utah, received surgery, radiation, and traditional therapy after he was diagnosed with melanoma in 2008. His cancer went into remission. But by 2013, it had returned and spread to his right lung.
Moore, however, got another chance through the Intermountain study. His tumor harbored a genetic mutation whose cancer-causing effects could be blocked by an existing drug. Nadauld and colleagues found that approximately 80 percent of the patients in their study had such an “actionable mutation.”
About half of those 243 patients, including Moore, received a drug targeted at their cancer’s mutation. The others, randomly assigned to a control group, received conventional therapy. Moore’s medication, trametinib, which GlaxoSmithKline sells as Mekinist, was not an obvious choice for him. The US Food and Drug Administration has not approved it for his form of cancer, but based on his tumor’s DNA, his oncologists thought it might work.
“If it weren’t for the genomic testing, it wouldn’t have been considered,” Moore said.
The drug, a once-a-day pill he began taking in August 2014, bought him almost a year of improved health before his cancer returned in several places this summer.
Overall in the study, cancer patients in the precision medicine group with Moore fared better after more than two years than those in the standard-therapy group, the Intermountain researchers reported at a cancer meeting in June. Progression-free survival, meaning how long it took for tumors to grow or spread, was 23 weeks in the first group and 12 weeks in the conventional-therapy group.
The researchers are still following the patients to determine whether the precision-medicine group lives longer, a more meaningful measure than progression-free survival. But setbacks like Moore’s show that genetic profiling of tumors is, at this point, no more a cure for every cancer than angiogenesis inhibitors, which cut off a tumor’s blood supply, or other much-hyped treatments have been.
A big reason is that cancer cells are genetically unstable as they accumulate mutations. As a result, a biopsy might turn up dozens of mutations, but it is not always clear which ones are along for the ride and which are driving the cancer. Only targeting the latter can stop a tumor’s growth or spread.
Knowing which mutation is the driver and which are passenger mutations is so complicated that the Intermountain researchers established a “molecular tumor board” to help.
Composed of six outside experts in cancer genomics, the board meets by conference call to examine the list of a patient’s tumor mutations and reach a consensus about which to target with drugs. Tumor profiling typically finds up to three driver mutations for which there are known drugs, and the board reviews data on how well these drugs have worked in other patients with similar tumors.
In the case of patient Michael Goodin’s esophageal cancer last year, the board faced a quandary. The DNA profile revealed eight potentially actionable mutations, his wife, Susan, recalled. The board recommended one to target, but the drug was no match for his cancer, which had already spread. The treatment “helped him hang in there for a few months,” Susan said. He died last November at age 68.
The next difficulty, Nadauld said, is that “the mutations may be different at different places in a tumor.” But oncologists are reluctant to perform multiple biopsies. The procedures can cause pain and complications such as infection, and there is no rigorous research indicating how many biopsies are necessary to snare every actionable mutation.
But a cancer-driving mutation that happens to lie in cells a mere millimeter away from those that were biopsied can be missed. Similarly, cancer cells’ propensity to amass mutations means that metastases, the far-flung descendants of the primary tumor, might be driven by different mutations and therefore need different drugs.
“The mutations in a metastatic tumor in the liver, for example, might be different from those in the lung” where a cancer began, Nadauld said. “It becomes a real challenge.” Metastases (not the original tumor) are responsible for 90 percent of cancer deaths.
The differences in the molecular profiles of primary tumors and their metastases, and from one spot in a tumor to another, “speak to how little we know about this disease,” pathologist Gregory Tsongalis of the Geisel School of Medicine at Dartmouth College and an expert on the molecular profiling of tumors, told a meeting of the Massachusetts Biotechnology Council last month.
To be sure, sometimes precision medicine is up to the challenge posed by cancer. One Intermountain patient’s lung cancer was driven by a mutation called mTOR. Everolimus, which Novartis sells as Afinitor, is often effective against such mutations, and seemed to drive the cancer into remission.
But after a few months, Intermountain’s Dr. Derrick Haslem said, the cancer had spread to the liver. There, a biopsy and molecular profile showed, the driver mutation was in a different gene, called EGFR. The patient lucked out again: These mutations often respond to targeted therapies including erlotinib, which Genentech sells as Tarceva. The patient remains in remission.
Precision medicine might sound prohibitively expensive; determining a tumor’s molecular profile costs thousands of dollars. But the Intermountain patients’ medical costs were no greater than for cancer patients receiving standard care, Haslem said. Some of their drugs were more expensive, but the sequencing and medication costs of precision medicine were offset by fewer hospital stays and emergency room visits because the patients suffered fewer serious side effects, such as infections, low white blood cells counts, and nausea.
Moore, too, suffered few serious side effects or complications. The researchers don’t know why his treatment stopped working — whether his cancer was driven by more mutations than a biopsy revealed, or his metastases were driven by other mutations, or his disease defeated precision medicine in some other devious way.
Moore has no regrets about volunteering for the Intermountain study.
The drug he received bought him time, he said: “It’s the one drug I tried that showed some effectiveness . . . It gives you a little hope. It’s a choice between dying in a few months or deciding to keep trying.”
Correction: Because of a reporting error, an earlier version of this story incorrectly described the results of an Intermountain Healthcare study of cancer patients. Tumors didn’t grow or spread for an average of 23 weeks in the precision-medicine group and 12 weeks in the conventional-therapy group.