Precision medicine just got its playbook.
It’s long and complicated and chockablock with buzzwords like big data, biomarker tests, targeted therapies and rapid learning (not to mention five pages of health industry acronyms), but the crack team of medical experts who created it believe their recommendations will help guide us all to a healthier future.
“We clearly believe as a panel that precision medicine is the future of medicine and particularly the future of oncology,” said Dr. Gary Lyman, a researcher with Fred Hutchinson Cancer Research Center and part of the National Academies of Sciences, Engineering and Medicine (NASEM) committee that created the report.
Published Friday (with a public webinar slated for March 10), the report, titled Keys to Unlocking Precision Medicine, focused on the crucial nuts and bolts of precision medicine: biomarker tests and molecularly targeted therapies.
“The timely development of biomarker tests and associated therapies is critical to realizing the full potential of precision medicine,” said committee chair Dr. Harold L. Moses of the Department of Cancer Biology at Vanderbilt University. “Our report lays out a strategy to ensure that patients have access to effective tests and treatments that are based on solid evidence of their ability to improve health outcomes.”
Lyman said the committee hopes to get responses from the major government and non-government agencies mentioned in the recommendations.
“We hope this will be a reference document and a starting point for at least some if not many of these recommendations to be implemented,” he said. “Time will tell.”
The result of 18 months of extensive research and expert testimony, the report sets basic ground rules and goals for the rapidly emerging field of precision medicine, which is being used more and more in cancer treatment. Annual spending on molecularly targeted therapies for oncology alone already exceeds $10 billion, outpacing conventional chemotherapies. In 2015, the FDA approved 18 new agents for cancer and nearly all were based on the principle of precision medicine.
What is that principle?
As President Barack Obama put it when he launched the Precision Medicine Initiative on Jan. 30, 2015 – which by coincidence took place on the same day the NASEM committee had its first meeting – it’s the simple notion that every patient is unique.
Along with our individual personality quirks, we’ve got individual DNA quirks: genetic pathways that go haywire; proteins that overexpress. Molecularly targeted therapies are designed to counteract these quirks and help us outsmart diseases like cancer. Instead of surgery, chemo, and radiation – what Lyman calls “blunt instruments” used in a non-precise fashion – cancer patients would be treated by therapies that specifically target the molecular underpinnings of their disease.
But the process of testing for the quirks and designing the therapies to combat them is complex and progress has been hampered by regulatory and reimbursement uncertainties, clinical practice challenges, and limitations in data collection and analysis.
“It’s a very challenging area, based on the human genome and its 30,000 different genes and hundreds of thousands, or even millions, of mutations,” Lyman said. “To identify the ones that are really important and find or develop the right strategy or agent that targets it is extremely complicated and costly.”
The 229-page NASEM report will be used to inform policy impacting multiple stakeholders: patients, health care providers, public and private insurers, researchers, regulators, test and drug developers and manufacturers and more. It’s designed to move precision medicine forward in a way that will ensure patients have timely access to appropriate tests that accurately direct targeted therapies and at the same time protect them from potential harm due to poorly validated or inappropriately used tests. It also makes key recommendations regarding insurance coverage and reimbursement.
The report identifies 10 goals – for a complete list, see the bottom of the story – that address everything from the need for “accurate, reliable, clinically useful and appropriately implemented biomarker tests” to the establishment of a sustainable national database for the tests and their pre-existing (or forthcoming) targeted treatments that promotes rapid learning.
First and foremost, the report recommends that the U.S. Department of Health and Human Services immediately help develop a set of common evidence-based standards for the tests and treatments that can be used to inform regulatory, insurance coverage, and imbursement decisions, and strengthen clinical guidelines and standards of care.
In a nutshell, committee members want to make sure the patient gets tests and treatments that work; that these tests and treatments – which can be costly – are accessible to all; and that information about what works and what doesn’t is shared.
Targeted therapies are not new. Some have been around for years.
In breast cancer, tamoxifen and a class of drugs known as aromatase inhibitors all target estrogen, essentially cutting off the food supply of ER+ (estrogen-receptor-positive) tumors. Breast cancer agents Herceptin and Perjeta target mutations in a gene called HER2 (human epidermal growth factor receptor 2), which can lead to the overexpression of the HER2 protein, which makes breast cells grow and divide uncontrollably.
“While oncology is the poster child for this whole arena, there are now genetic mutations or biomarkers or targeted therapies in a wide range of diseases outside of oncology,” Lyman said, adding that thousands of biomarker tests currently exist.
But as the report points out, a bad biomarker test is as problematic and potentially harmful as a bad drug.
“You need good science to establish that the test is reliable, that the test is associated with the disease and an outcome of interest and, finally, that the treatment actually improves patient outcomes compared to standard treatment or usual care,” he said. “Those three things – analytic validity, clinical validity and clinical utility – are what are needed before these tests should be permanently part of our care of patients on a routine basis.”
To get there will require time, resources and well-done, well-designed studies, he said.
“Over the next generation, we believe that precision medicine can totally change medical care, patient outcomes and quality of life,” Lyman said. “But it comes with methodologic challenges and reimbursement challenges because it’s really these biological targeted therapies that are driving up health care costs. We need to make sure the right science is being done, the right treatment is getting to the right patient, that we’re getting better results, improved outcomes and less toxicity. Then with time, perhaps we’ll see lower costs.”
Patient advocates like Janet Freeman-Daily are excited about the promise of precision medicine.
“There have been more new drugs approved for lung cancer in the past four years than in the previous four decades,” she said. “I’m very hopeful that they are onto something and that they’ll find drugs that work for everyone. Right now, in non-small cell lung cancer, about 75 percent of patients have an actionable mutation. That means, either there’s an approved drug or a clinical trial they can try.”
Freeman-Daily, 59, had two lines of treatment (both involving chemo and radiation) after being diagnosed with stage 3A lung cancer in 2011, but the disease progressed after each treatment and her cancer became metastatic. According to the American Cancer Society, the five-year survival rate for stage 4 non-small cell lung cancer is about 1 percent.
Research led her to a clinical trial, though, involving a drug called crizotinib or Xalkori – “Sounds like an alien race, doesn’t it?” – and at this point she’s had no evidence of disease for 38 months and counting.
“The mutation I have is ROS1,” she said. “And the preclinical work suggested that a drug they were testing for [another mutation], c-MET, would work for my mutation, as well. And it did. In fact, it’s one of the big success stories. The response rate is like 80 to 90 percent.”
But not only is Freeman-Daily still alive, she has fewer side effects than she did with traditional treatment.
“There’s some of what I like to call antisocial gut behaviors – incredibly smelly farts and diarrhea interspersed with constipation,” she said. “And I have other issues like fatigue and edema [swelling] in my legs. But it’s so much easier than chemo. Some people still can’t tolerate it. Some people get liver problems and can’t keep taking it. But I have a pretty good quality of life.”
Lyman said most targeted therapies come with fewer side effects than traditional cancer treatments, which are notorious for short- and long-term effects like hair loss, bone pain, neuropathy, nausea, fatigue and lymphedema along with late effects like secondary cancers, and heart and lung problems.
These side effects are not only debilitating for many patients, they’re costly.
“Targeted therapies don’t have the broad array of side effects of surgery, chemo and radiation,” said Lyman. “They’re able to target critical disease pathways in selective patients with a positive biomarker test. And be avoided in those patients unlikely to benefit. This not only reduces the risk of futile treatment toxicities but has the potential to reduce costs compared to treating all patients blindly.”
Targeted treatments also don’t hinge on the anatomic origin of a patient’s cancer like lung or breast or colon or prostate.
“We have a Facebook group for ROS1-positive cancers and it’s more than just lung cancer,” said Freeman-Daily. The 87-member group, which includes melanoma and angiosarcoma patients, provides a place for patients to “share treatment experiences, trial options and other information with fellow ROS1ers.”
The new precision medicine playbook is big on sharing information, too.
“It’s virtually impossible for any individual or even any group to stay totally on top of developments in this rapidly evolving area,” Lyman said. “We need to develop strategies that include experts in informatics as well as the clinicians and laboratory scientists to find a way to identify, catalog and annotate [learn what each mutation does]. This has to be automated if we’re ever going to keep up with the rate of expansion of knowledge in this area.”
Toward that end, the report calls for a slew of federal entities (including Health and Human Services, the Food and Drug Administration, National Institutes of Health, Centers for Medicare & Medicaid Services, Patient-Centered Outcomes Research Institute, the Department of Veterans Affairs) to develop a sustainable, national repository of biomarker tests, molecularly targeted therapies and long-term clinical patient data to facilitate rapid learning approaches.
In other words, a big precision medicine “brain” that can sift and sort and recognize patterns and help health providers consistently make treatment recommendations based on the latest, greatest data.
“This isn’t something that a single institution or even a group of institutions is likely to keep on top of,” Lyman said. “This has to be a concerted national effort, just like the ‘moonshot.’ We’re calling for this to be a national priority.”
It’s a big lift. But from all indications, the payoff will be even bigger.
“If this field develops in a rigorous, evidence-based, scientific way with appropriate studies,” said Lyman, “it will totally revolutionize the care of patients with cancer.”
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from the National Academies of Sciences, Engineering and Medicine’s report
“Key to Unlocking Precision Medicine”
Diane Mapes is a staff writer at Fred Hutchinson Cancer Research Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she also writes the breast cancer blog doublewhammied.com. Reach her at firstname.lastname@example.org.