Precision Medicine: Promise, Being Fulfilled

Patients Benefit from Unique Diagnoses, New Treatments

November 28, 2018

Conner James Walker was 10 months old when he started having fevers. Over the next two months, the fevers were more frequent. When his mother, Denise, took him to the hospital for what she imagined must be dehydration due to the latest fever, doctors diagnosed the 1-year-old with cancer—acute myelogenous leukemia, or AML.

Conner went into remission after treatment for AML. But six months later, he was diagnosed with recurrent AML, which prompted a referral to Columbia for a bone marrow transplant. Conner underwent the standard tests that precede any transplant, but Denise and her husband, Chris, were invited to enroll Conner in Columbia’s Precision in Pediatric Sequencing Initiative (PIPSeq), a program funded by the Sohn Foundation to offer genomic testing of all pediatric tumors within the tristate region. PIPSeq was a game-changer for the Walker family. The sequencing of Conner’s genome revealed that—in addition to AML—he has a mutation in the RET gene, which predisposes carriers to medullary thyroid carcinoma, a stealthy malignancy that forms within the thyroid gland during middle age, remains asymptomatic until it has advanced, and is associated with a poorer prognosis than more common forms of thyroid cancer.

Because RET is a dominant mutation that can be genetically inherited from a single parent or spontaneously develop during development, Conner’s pediatric oncologists at Columbia urged Mr. and Mrs. Walker to have the entire family tested. They learned that Conner’s father and three of Conner’s siblings have the RET mutation. Although none of the children had symptoms, Mr. Walker had a palpable nodule in his throat and underwent a biopsy, performed by Jennifer Kuo, MD, director of the thyroid biopsy program and the endocrine surgery research program.

A week later, Dr. Kuo removed Mr. Walker’s thyroid gland and lymph nodes involved in the disease. “With our early intervention,” she says, “there is a very good chance that he has been completely cured and will remain cancer-free.” Using algorithms developed to predict the trajectory of the particular RET variant manifested by the Walker family, doctors will monitor Conner and his affected siblings, by monitoring their hormone blood levels over the coming decades for signs that a tumor is forming before it turns into cancer so that their thyroid glands can be removed prophylactically before the tumor poses a risk.

Such is the promise of precision medicine—plumb terabytes of data on hundreds of thousands of patients and their families to integrate insights from electronic health records with genomic and other biological data, plus behavioral and environmental parameters, to optimize the health and treatment protocols for individual patients.

“Recent studies of large patient cohorts have revealed the incredible potential of combining genetic data and electronic clinical records,” says Tom Maniatis, PhD, director of Columbia’s Precision Medicine Initiative, a collaboration of all of Columbia University and NewYork -Presbyterian Hospital. “These data not only identify potential causes of disease, they reveal targets for drug development and treatment.”

Meanwhile, the cost of genomic sequencing has fallen dramatically, giving patients and their doctors increasingly affordable access to rich troves of data that reveal both genetic quirks we inherit from our parents and genetic mutations that emerge sporadically in response to environmental factors or a failure in the quality control process of DNA replication and translation. Any given mutation could mean nothing, something, or—as in the case of the Walker children—something in the future. “If you look for that many mutations, you’re going to find something,” says Dr. Kuo. “What that something means, we don’t necessarily know at this time.”

For clinicians, then, the trick is figuring out how to make the most of such data. “In the case of the Walker family, genetic testing revealed a mutation for which the clinical significance is known. It is tied to a specific disease and there is a treatment plan,” says Dr. Kuo. “But we could have easily found a mutation of which the clinical significance is not known.”

The list of such mutations is getting shorter all the time. “Major advances are being made in the development of tools that make it possible to connect differences in a single individual’s DNA sequence with the diagnosis and treatment of specific diseases,” says Dr. Maniatis, whose own research delves into the molecular mechanisms of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). “Genetic studies are having an enormous impact on our understanding of neurodegenerative diseases such as ALS and Alzheimer’s disease by identifying disease mechanisms, cellular pathways, and possible drug targets.”

Consider how Dr. Kuo’s own clinical practices have shifted in the past five years, as investigators mine the data that have accumulated due to a basic fact of aging: The older you get, the higher your chances of developing a thyroid nodule. In the vast majority of these cases, the growth is benign, but the standard of care is to rule out malignancy by taking a needle biopsy. Historically, pathologists examined cells extracted from the nodule under a microscope, reporting their findings in accordance with the Bethesda classification system, a standardized system of six categories with associated risks of malignancy. In response to cytology findings in the murky middle of the scale—neither emphatically benign nor obviously malignant—patients and physicians alike have tended to opt for surgery. “Although thyroid surgery is a low-risk procedure,” says Dr. Kuo, “we were subjecting a lot of patients to unnecessary surgery for benign nodules.”

The silver lining of all those surgeries was a wealth of data—including the actual patient outcomes and complete pathological workups of the nodules. By analyzing DNA and RNA sequences from malignant nodules, as well as those that were benign, scientists developed molecular profiling tests to narrow the field of uncertainty and focus on the 5 percent of nodules that pose a danger. At Columbia, says Dr. Kuo, the new profiling tests have led to a dramatic reduction in the number of patients who choose surgery merely out of an abundance of caution, giving them greater confidence in the watchful waiting approach. “The ultimate goal of all of this is to gain a better understanding of the diseases that afflict our patients,” she says. “That allows us to offer patients more options in the care that they receive, which ultimately allows them to choose the path that is best suited for them.”

To hasten the kinds of insights that PIPSeq conferred on the Walker family—and that genetic profiling of biopsy materials offers—the National Institutes of Health has launched All of Us, a historic campaign to collect data from 1 million or more people living in the United States. Columbia heads the All of Us New York City consortium, one of several regional networks through which participants can enroll. “The billions of data points from All of Us will add up to one of the most powerful health research resources that we’ve ever had,” said NIH Director Francis Collins at the May 6 launch of the All of Us Research Program at Harlem’s Abyssinian Baptist Church.

The ambition of the effort vastly exceeds that of the ongoing Framingham Heart Study, named for the town in which 5,209 residents were recruited in 1948 and whose health and lifestyle—as well as those of their partners, children, and grandchildren—have yielded thousands of papers on an array of factors in human health and disease, including vital insights into cardiovascular disease. “From that study, [researchers] discovered that smoking, high cholesterol, and high blood pressure are major risk factors for heart attack and stroke,” says Dr. Collins. “Believe it or not, before this, we didn’t know those things, and many people thought that heart disease was just an inevitable part of aging.”

Perhaps even more important than the scope of All of Us is its emphasis on recruiting a nationally representative sample of participants. “This program marks an amazing opportunity to bring together the communities we serve and our research community to advance health,” says David Goldstein, PhD, the John E. Borne Professor of Medical and Surgical Research in Genetics & Development, director of the Institute for Genomic Medicine at VP&S, and principal investigator of the NYC All of Us consortium. “This bold program will work with our communities to make sure not only that the promise of precision medicine is realized but that it is done so in partnership with the community.”

In the New York City area, more than 4,000 people have already enrolled; 81 percent are from communities typically underrepresented in medical research because of race, ethnicity, sex, or gender.

“Mining data from a more diverse population will provide vital insights. Doctors will have a better idea of what variations mean and how they may influence disease occurrence and response to therapy.”

“As recently as 2016, more than 80 percent of studies based on genomic profiling were on people of European descent,” says Kevin Gardner, MD, PhD, professor and senior vice chair of pathology & cell biology, who is helping to lead the Department of Pathology & Cell Biology’s precision medicine initiatives, particularly in underrepresented minority communities. “Getting sequences from European populations doesn’t account for the diversity we would see in African patients.”

Researchers do not want the genomic revolution to exacerbate disparities in access to evidence-based treatment, says Dr. Gardner, who spent nearly three decades at the NIH, most recently as acting scientific director for the National Institute on Minority Health and Health Disparities. With the right approach, he says, precision medicine has the potential to combat disparities in disease outcomes and treatments. “The goal of All of Us is to catch up, to increase diversity and participation in clinical trials.”

The effort promises profound gains for people who have historically been underserved, says Dr. Gardner, whose own research delves into disparities in breast cancer prognoses among ethnic groups. “In profiling genomics of patients, we see differences, variations,” he says. When such variations occur infrequently, or only in select subpopulations, scientists often lack the data and clinical information to understand their implications, dismissing them as “variants of unknown significance.”

“We want to minimize these variants of unknown significance. Mining data from a more diverse population will provide vital insights. Doctors will have a better idea of what these variations mean and how they may influence disease occurrence and response to therapy.” For people coming to terms with a sarcoma diagnosis, such treatment insights are critical, says orthopedic oncologist Wakenda Tyler, MD, associate professor of orthopedic surgery at “Mining data from a more diverse population will provide vital insights. Doctors will have a better idea of what variations mean and how they may influence disease occurrence and response to therapy.”

For people coming to terms with a sarcoma diagnosis, such treatment insights are critical, says orthopedic oncologist Wakenda Tyler, MD, associate professor of orthopedic surgery at VP&S and chief of musculoskeletal oncology at NYP. “Every patient who walks in with a sarcoma has a unique disease,” says Dr. Tyler. “Their sarcoma will not genetically be the same as any other sarcoma we see that year.”

Nationwide, sarcoma survival rates five years after diagnosis hover at just 50 percent. Through a project spearheaded by Gary Schwartz, MD, chief of hematology/oncology and associate director of the Herbert Irving Comprehensive Cancer Center, every sarcoma biopsy is genetically sequenced, a service not yet available in most hospitals. The results inform the personalized treatment protocol Dr. Tyler recommends. “A patient may still need surgery and radiation,” she says, “but we can also offer targeted therapies to home in on particular genetic features of the tumor.” Already, she says, survival rates are inching upward. “Half of the patients who walk through the average oncologist’s office aren’t going to be alive in 10 years. The targeted therapies aim to increase that number to 60 or 70 percent.”

Meanwhile, because nearly every sarcoma patient undergoes surgery—which can radically alter mobility and function—Dr. Tyler has embarked on a project to connect high-risk patients with rehabilitation medicine even before their operations. For many people, the pain and impeded movement caused by a tumor forces them to compensate—favoring one leg over the other, for example. As a result, many have functional deficits or mobility impairments even before the tumor is removed, making physical and occupational therapy vital contributions to ongoing quality of life. “We get so obsessed with shrinking the tumor, the radiation, the surgery, we forget about functionality,” she says. “This way, when patients are at their weakest point, postoperatively, they’ll already have a network of physicians and staff who are aware of the functional issues and ready to support them.”

In the world of psychiatry, where diagnoses typically result from a patient’s observable behaviors, precision medicine promises similarly profound shifts in clinical care. In an effort to more fully characterize the forms of schizophrenia most resistant to treatment, Sander Markx, MD, director of the Department of Psychiatry’s Center for Precision Neuropsychiatry, and postdoc research fellow Anthony Zoghbi, MD, have embarked on a project to provide whole genome sequencing and assessment for neuronal autoimmunity for up to 3,000 patients in New York state’s psychiatric facilities. “Folks in inpatient facilities are the sickest of the sickest,” says Dr. Markx. “They’re so much sicker and so impaired cognitively that they usually can’t take care of themselves and they live their entire lives in state facilities.”

“In psychiatry you hope to control symptoms, but you don’t strive for a cure. It’s incredibly humbling to be providing precision medicine for the people who have the least resources.”

In addition to gaining clarity about the genomic corollaries to schizophrenia, Dr. Markx hopes to identify biomarkers that suggest a diagnosis of neuronal autoimmunity, in which a tumor or virus triggers an immune reaction to proteins within the brain that are typically protected by the blood-brain barrier. “The literature is overflowing with people who have a virus, followed by schizophrenia-like presentation,” he says. “They’re very sick, with seizures and autonomic instability, blood pressure and heart rate fluctuation.” Due to the atypical and severe symptoms these patients exhibit, their doctors frequently conduct a comprehensive physiological assessment in addition to psychiatric screening. When cerebrospinal fluid analyses reveal the antibodies behind their symptoms—and sometimes even an undiagnosed cancer—treatment with immune-suppressants interrupts the autoimmune attack, reversing both the neurological and psychiatric symptoms.

Dr. Markx hypothesizes that the population of such patients may be far larger than previously recognized, because only a subset of people with neuronal autoimmunity exhibits severe autonomic and neurological instability at the onset of the condition, making their initial presentation difficult for clinicians to distinguish from schizophrenia. Already, the team has transferred one patient to Columbia for treatment; after 20 years of severe and refractory psychosis, she has begun showing early signs of recovery in response to intensive treatment with high-dose intravenous steroids. “If we can refine her treatment,” says Dr. Markx, “we might be able to get her back to a normal life.” Three other patients who have similar biomarkers also are scheduled for transfer and comprehensive treatment at Columbia. “Typically in psychiatry you hope to control symptoms, but you don’t strive for a cure,” says Dr. Markx. “It’s incredibly humbling to be providing precision medicine in this way, for the people who have the least resources.”

As featured in Columbia Medicine