The Lucky Years: How to Thrive in the Brave New World of Health (18 page)

The idea that we can edit our genes and even change the entire human genome of future generations might make Darwin shift in his grave, for he’s the one who suggested that nature selects the best genes to live on and procreate, that nature—not human engineering—should be the ultimate judge. I sometimes wonder what he would think about the value of DNA sequencing when it can’t tell the whole story or, worse, leads to unintended consequences such as unnecessary surgery or treatment that’s costly and painful.

We should remember that precision medicine is a double-edged sword. While it can open the door to new and better ways to take care of ourselves, it’s not nearly as “precise” as most people think.

Let me start with a fictional character whose story mirrors what can happen in real life. We’ll call him Larry. He’s in his mid-thirties, which some say is the prime of life. He shouldn’t be diagnosed with a rare, inoperable tumor. But he does indeed get such a grave diagnosis, and despite the best that conventional cancer medicine can offer him, the disease progresses rapidly. He finalizes plans for his family’s future, including his two young children, and prepares to enter hospice care, thinking that he’s got days, maybe weeks, to live. And that’s when he consents to having his tumor sequenced, a strategy he hadn’t contemplated before. It reveals a mutation in a gene that appears to be driving the growth of the cancer. Better yet, it shows that his cancer could be targeted with a particular drug, but one not normally used for his type of cancer. With nothing to lose, he starts taking the pills. And the tumor shrinks. Months later, he is still alive and no longer a candidate for hospice care.

Some would say that story exemplifies personalized or precision medicine—the medicine of the future, in which we will tailor treatments to a person’s unique physiology and health condition. But this approach is far from new. From Charaka, the father of ancient Indian practices (Ayurveda) to Hippocrates, the first father of modern medicine, many doctors throughout history have practiced the personalized approach to some degree using available technology for treating a disease. Today, however, personalized medicine is much more precise from a molecular standpoint. It focuses chiefly on DNA and how single-nucleotide polymorphisms (SNPs) and environmental factors influence an individual’s biology and risk for disease. SNPs are variations in DNA sequences that are thought to provide the genetic markers for our response to disease and drugs. For example, a variation on a particular gene may indicate a predisposition for high cholesterol. Other variations may provide a marker for celiac disease or indicate a higher risk for Alzheimer’s.

It’s important to realize that these DNA differences do not
cause
the disease, but they are a marker of the relative risk of the disease. Since the completion of the Human Genome Project in 2003, hundreds of published, peer-reviewed studies have described the associations between SNPs and specific diseases, traits, and conditions. As you can imagine,
these studies have opened the door for the personal genomics industry by providing a platform by which DNA, obtained through a simple saliva sample or tube of blood, can reveal your individual genetic map. It’s also the platform behind sequencing tumors and understanding their characteristics within the context of the body’s DNA.

Personalized medicine has its limitations amid its promises. At the end of January 2015, President Obama presented his new Precision Medicine Initiative during the State of the Union address. He said the goal is “delivering the right treatment at the right time, every time, to the right person.” To fund the initiative, Obama asked Congress for $215 million, more than half of which would help the National Institutes of Health (NIH) develop “one of the largest research populations ever assembled,” a group of at least 1 million volunteers who would share genomic data, lifestyle information, and biological samples. This data would further be linked to their electronic health records. The National Cancer Institute (NCI) would receive another $70 million to support efforts to identify genes that spur malignant tumor development, an endeavor first proposed by the NIH’s director, Dr. Francis Collins, more than a decade before.

While this project is honorable, it can ignore the bigger picture and downplay basic preventive measures such as diet and exercise that aren’t as sexy as taking pills to tinker with genes. And therein lies the main challenge of precision medicine: it implies that if you know your genome, you can fit treatments to it. But that’s a reductionist view—it’s looking at just one chunk of the information, much of which could actually be useless in terms of knowing true risk factors and longevity. It also misses the value of prevention. For example, if we’re going to prevent the 86 million adults who are currently prediabetic from being diagnosed with diabetes in the next decade, it’s not going to come from sequencing DNA and prescribing molecular therapies. It’ll happen through old-fashioned diet and exercise.

Cardiologist Eric Topol, director of the Scripps Translational Science Institute, stated it perfectly in an article for the
Journal of the American Medical Association
: “If you really want to change medicine, you have to
have all the information on the individual. That includes their environment, the bacteria in their gut, and other distinguishing characteristics.”
⁶
And he’s right. Precision medicine’s greatest prospects, at least in the short term, lie in the development of cancer therapeutics and pharmacogenomics, the customization of drugs and dosages to fit a person’s genetic profile.

The power and utility of pharmacogenomics is exemplified by a 2015 study that found that children with acute lymphoblastic leukemia (a type of cancer in which the bone marrow makes too many immature white blood cells) and a particular genetic variation in their DNA were at greater risk for experiencing severe nerve damage when treated with the drug vincristine.
⁷
Such a finding can inform safer dosing of this widely used anticancer drug. Thus far, labels on more than 150 medications contain pharmacogenomic information, although genetic testing before use isn’t necessarily recommended.

The allure of drugs that target mutant DNA and more or less play with our internal switches does indeed sound appealing, as well as exciting. But along with the lack of context this approach gives you, there is a big hurdle to clear, which few people like to talk about: the pricing. During his presentation at the White House as chronicled in the
JAMA
article, Obama showcased William Elder Jr., a twenty-seven-year-old man who was born with the inherited DNA for cystic fibrosis, a disorder triggered by a rare genetic defect that causes severe damage to the lungs and digestive system and can be life threatening. William had already been living with symptoms of the condition for twenty years when Obama introduced him. He was in medical school and had every intention to live to see his grandchildren. In 2012, William started a new drug designed to target the specific defect that causes cystic fibrosis and the effects were almost immediate: his breathing improved within hours.

But these breaths do come with a hefty price. The drug he takes, ivacaftor (Kalydeco), costs $300,000 annually. And it’s not even a universal cure for the disease. Kalydeco is approved for treating patients with any of ten specific mutations in the cystic fibrosis gene. Patients like William, who have one of those ten mutations, represent fewer than 10 percent of the thirty thousand or so individuals with the disease in
the United States, according to the Cystic Fibrosis Foundation. Vertex, the company that manufactures Kalydeco, plans to market the medication alongside another experimental drug that treats the cystic fibrosis genetic defect associated with half of the cases in the United States. The company is also investigating the drug combination in people with another type of mutation that causes cystic fibrosis.

Is the $300,000 price tag fair? As I mentioned, I routinely witness new anticancer drugs on the market that come with exorbitant price tags and may buy only a few more days or weeks of life. In the future, we will have to figure out the real value of these drugs and how to pay for them. Cost should be driven by benefit, with what’s called value-based pricing. If you have a drug that buys five to ten more years of life, it should cost more than the drug that provides minimal benefits. The current model is untenable if drug companies can charge whatever they want—especially given the fact that many of these new drugs work best in combination with other drugs, multiplying the costs by two or three.

The irony of this is that technology costs have come down considerably in the past decade, but not the cost of drugs. And that will have to change if we’re going to enjoy this brave new world of medicine. The predatory practice of pricing as high as possible for a new drug is inappropriate, and I am simply calling for an orderly system with guidelines. We have to provide incentives for biotechnology and pharmaceutical companies to make progress and take risks. But just because their patents give them a temporary monopoly on the market, that doesn’t mean prices should reflect that. Change will happen faster once more doctors and hospitals stand up to the pharmaceutical industry and compel it to establish a more rational and transparent approach to drug pricing. Memorial Sloan Kettering Cancer Center in New York City, for example, has invented an interactive calculator (www.drugabacus.org) that compares the current cost of more than fifty cancer drugs with what the prices would be if those drugs were tied to factors such as how much they extend the life of patients and the side effects those patients endure. It’s a smart idea: fix prices to real values, which for patients are quality and length of life. Memorial’s project has shown that in many cases, the
calculator computes a price that is lower than the drug’s market price. And of course, this includes the cost of developing the drug.

Although people like to lament the power of Big Pharma, doctors and hospitals can also score some victories. In 2012, Memorial Sloan Kettering decided not to give its patients with colorectal cancer the drug aflibercept (Zaltrap), a new product made by Sanofi, the world’s fifth-largest pharmaceutical company. Originally, the drug cost $11,000 per month, and the doctors didn’t think the effects of the drug justified such a high price tag. So they banded together, wrote a newspaper editorial laying out their decision, and Sanofi relented, cutting the price by 50 percent for oncologists like me in the United States.

Even with lowered price tags, many in the medical community question whether focusing on the genetic underpinnings of disease is the most cost-effective approach when it comes to improving health. And even I can sympathize with this concern. Precisely because I cofounded a company that performed genetic screening, I can say that genes don’t tell the whole story. In lectures, I like to use the following analogy: you can take a car apart and examine all of its pieces, but that won’t tell you how long it will take to drive that car from point A to B. In addition to the car parts, you have to consider how those parts work together in a complex system. You have to consider the quality of the oil and gasoline, as well as the environment in which the car is moving. And you have to think about all the other variables that help determine the car’s functionality, from weather and road conditions to the driver’s competency, the traffic, and the path taken.

Obama’s Precision Medicine Initiative isn’t the first to create a database to collect and mine health information with a focus on genomics. The NIH has already launched three trials to study patients’ cancers for genetic abnormalities. Then patients can be enrolled into an appropriate clinical trial of an investigational drug that might hit the specific molecular blips, or “on” switches, driving their cancer. One of these trials is the NCI-MATCH (Molecular Analysis for Therapy Choice) trial, which is accepting adults with cancers that have stopped responding to traditional treatment. Pediatric MATCH is the one for children.
And the third trial is the Lung Cancer Master Protocol for Squamous Cell Carcinoma, or Lung-MAP—a collaborative effort between private and public sectors that implements a similar molecular approach for people with squamous cell lung cancer, which currently lacks effective treatments other than surgery. The Dana-Farber Cancer Institute also launched its Profile program in September 2011. It’s the first hospital in the United States to provide tumor genotyping to all patients with cancer. The goal is to create a large-scale study similar to the famous Framingham Heart Study, which laid the foundation for a great number of cardiovascular disease studies over the past half-century. These large-scale studies should help us learn the answers to questions like: Do cancer patients with a variation in gene
X
live longer or shorter? In the words of the NIH’s Francis Collins, eventually the plan is to “generate the knowledge base necessary to move precision medicine into virtually all areas of health and disease.”
⁸

One thing to keep in mind is that precision medicine, no matter how technical it gets and useful it becomes across all fields of medicine, will always entail a little bit of art and science. Just as you can’t buy devices and fully take care of yourself based on those alone, you can’t rely on genomics to understand fully your body and how to treat it. DNA must be looked upon in the context of other things in your life. Take, for instance, the woman I mentioned earlier who was told a few years back she has a very high likelihood of developing Alzheimer’s disease due to a gene variant, but several years later, she is told that she also has a protective gene that renders her risk as average. Or consider the woman who is informed she has an alteration in the BRCA1 gene that dramatically raises her risk of breast cancer. While she is considering having her breasts removed, a second opinion at a major cancer center tells her that the alteration she has in BRCA1 doesn’t raise her risk for breast cancer at all. Her alteration is a variant that has no increased risk. All of these are true stories of patients I have worked with, and they highlight the complexity and the evolving nature of modern medicine. Despite the progress and promise in the study of DNA, it’s just a small fraction of the total amount of information contained in your body.