The iconic Norman Rockwell painting of a family doctor checking the heart of a young patient’s doll may seem quaint, but it’s far from old-fashioned. On the contrary, personalized medicine is bringing the family doctor back … and the family nurse, and the family pharmacist, and a whole team of family health care providers. Only this time, they will be empowered by 21st-century tools like genomics, informatics and high-tech imaging.
Ailments will be diagnosed more quickly and accurately—or prevented before they can occur. By selecting drugs that match each patient’s unique genetic readout or by “tweaking” molecular pathways instead of blasting away like a shotgun, treatments will be more effective and will have fewer side effects.
“After having gone through a period where blockbuster drugs and massive screening were the norm, we are actually moving back to a place where we’re trying to tailor care to the individual,” says Dr. Jeff Balser, Vanderbilt University’s vice chancellor for health affairs and dean of the School of Medicine.
“I try to think of this as not getting more high-tech and therefore more distant from the patient,” Balser says. “But through technology we’re becoming more familiar with our patients as individuals and, along with that, always remembering to be personable—Norman Rockwell with a DNA sequencer.”
In 2010 Vanderbilt University Medical Center launched two major personalized medicine initiatives to advance cancer treatment and to individualize and improve drug therapy. Already this approach is showing promise.
Patients scheduled for cardiac or orthopedic procedures are being tested in advance for genetic variations that can affect their response to common blood thinners. Based on the test results, their doctors may adjust the dose or order a different drug entirely.
Similarly, by reading the genetic “fingerprints” of tumors removed from patients with certain forms of cancer, doctors can choose targeted drugs that are most likely to work.
Using genetic information to guide drug therapy is just the beginning. In the near future, genomics—the science of reading and interpreting the DNA sequence—will help Vanderbilt physicians select the best tests and procedures for their patients. Eventually, genetics will help guide efforts to prevent disease and maintain good health.
Personalized medicine is more than genetics, of course. Social, family and behavioral factors, as well as environmental and economic circumstances, also have a profound impact on health.
“Those things are just as important in tailoring care to the individual as their genetic background,” says Balser. “It’s almost like genomic medicine is what we’re using to learn how to individualize medicine, but then we can apply it to a broader set of data and circumstances.”
Vanderbilt’s expertise in health-information technology and genetic medicine puts it in a unique position to lead in personalized medicine. “Our role is to envision what new models of health care can look like and show the rest of the world what’s possible,” he says.
This, after all, is what patients expect. “When I talk about this,” Balser marvels, “people say, ‘Why isn’t that the way health care works everywhere?’”
The search for molecularly targeted therapy for advanced non-small cell lung cancer brought Michael McDill to Vanderbilt-Ingram Cancer Center (VICC) from his home in Louisville, Ky., where doctors first diagnosed his disease.
In 2009, McDill had been struggling with a persistent dry cough. An initial X-ray revealed what doctors thought was pneumonia, and the then-36-year-old was treated with antibiotics.
But McDill’s wife, Tammy, who works for a Louisville hospital, pushed for a CT scan, which led to a bronchoscopy. This time the diagnosis was clear: Michael had lung cancer, and the disease had already advanced to Stage IV—too late for a possible cure.
“I was really shocked because I am a nonsmoker, there is no history of cancer in the family, I was not in a house with radon, and I don’t work with asbestos,” explains McDill.
But Michael McDill had something unusual—a genetic mutation found in a tissue sample from his tumor. The mutation involved a gene called anaplastic lymphoma kinase, or ALK. Gene rearrangements involving ALK recently were identified in non-small cell lung cancer. The ALK rearrangements are rare, found in only 3 percent to 7 percent of cases.
Doctors in Louisville attacked Michael’s cancer with 10 cycles of chemotherapy followed by radiation. Eventually, however, his cancer started spreading again. At this point McDill’s Louisville oncologist had heard of breakthrough research on the ALK mutation in lung-cancer patients. It was a long shot, but Tammy went online searching for any cancer centers offering new treatments for patients with the specific mutation.
She found VICC’s Personalized Cancer Medicine Initiative, a new program designed to identify and target genes that are aberrant in many forms of cancer. Those genetic alterations often stimulate tumor growth and influence the sensitivity of the tumor to various forms of treatment.
VICC was one of the first cancer centers in the United States to start routine testing of the genetic mutations found in certain types of cancer.
“This is the fruit of a great deal of basic science research in the last several decades, including the Human Genome Project, in which the United States decided to sequence the entire dictionary of life in human beings,” says Dr. William Pao, Ingram Associate Professor of Cancer Research and director of personalized cancer medicine at Vanderbilt.
“Understanding the human genome at the normal level has allowed us to identify mutations in tumors that have clinical relevance for therapy. We can now begin to prioritize which drugs are more likely or less likely to work in individual patients. Based on this information we are hoping to treat our patients more rationally by matching the right patient to the right drug at the right time.”
As part of the Personalized Cancer Medicine Initiative, VICC routinely tests tumors from every patient with lung cancer or melanoma for mutations known to be important in those forms of cancer. They then use the information to help prioritize the use of targeted therapies available for those mutations.
VICC scientists recently added a panel of breast-cancer mutations to the program.
“In addition to testing for already identified mutations that may affect cancer outcomes, our cancer investigators are actively engaged in the search for other important biologic disease markers,” says Dr. Jennifer Pietenpol, PhD’90, the B.F. Byrd Jr. Professor of Oncology and director of VICC.
“Our seamless integration of research discovery and clinical testing allows the team at VICC to rapidly deliver the most promising new targeted treatments to our patients.”
This promise of access to the latest in cancer research is what brought the McDills to Vanderbilt.
“You can tell this is a Comprehensive Cancer Center that is nationally recognized. It’s very patient-centered, in my opinion,” says Tammy McDill.
Based on Michael McDill’s genetic tests, Dr. Leora Horn, assistant professor of medicine and a lung-cancer specialist, enrolled him in a clinical trial of a new drug, crizotinib, designed to treat lung-cancer patients with the ALK mutation.
“I was at least open to listening to the clinical trial option,” says McDill. “After going through chemotherapy and knowing that’s not a long-term fix and it’s so rough on you, you would be crazy not to at least explore a trial.”
Crizotinib is given in pill form, so McDill takes three pills in the morning and three pills in the evening. Like some other patients on the crizotinib trial, McDill had vision problems (a known side effect of the medication) early in his treatment regimen, but those seem to have resolved and he is showing a complete response to the targeted treatment.
Michael’s response to the new drug makes it easier for him to maintain his work schedule as a sales representative for restaurant point-of-sale equipment. He and Tammy can even look forward to going on a trip with their two young children.
“I’m excited, and I feel so much better. You live your life and watch your kids grow up and do what you want to do when you’re 38 years old,” explains Michael.
While the drug does not seem to provide a long-term cure for McDill’s lung cancer, he is prepared to keep taking the pills as long as they are working, and he plans to stick with Vanderbilt investigators for future treatment options.
“Vanderbilt doctors are always on the cutting edge with new technology,” he says.
Clopidogrel (Plavix) is an antiplatelet drug prescribed to patients with severe heart disease to prevent formation of life-threatening blood clots following cardiac catheterization and other procedures. In 2010, Plavix was second only to Lipitor as the world’s best-selling drug.
The problem is, about 20 percent of people carry a genetic variation that makes them less likely to respond to it.
In September 2010, Vanderbilt University Medical Center launched a groundbreaking program called PREDICT to help identify these people, to use genetic testing to improve their care, and to include genetic information routinely in patients’ electronic health records. By the end of May 2011, more than 2,000 patients scheduled for cardiac catheterization at Vanderbilt had been tested—or genotyped—for this and other genetic variations that can affect their response to common medications.
The testing may be particularly helpful to heart patients who endure repeated stent procedures because of clotting problems. Stents are tiny tubes placed in coronary arteries to keep the blood flowing to the heart muscle. Clopidogrel is prescribed routinely to prevent blood clots from forming over them.
So far, several patients have been found to be “poor responders” to clopidogrel and have been switched to another drug. The hope is that their new stents will remain open, improving their health and avoiding the $50,000 to $75,000 cost of another stent procedure.
“I’m so excited Vanderbilt is doing this,” said Dennis Condra, executive vice president of Cresent Fine Furniture in Gallatin, Tenn., who received a new set of stents and was switched to another drug in May after genetic tests showed he was not responding to clopidogrel. “It’s a great thing for my personal health. It’s a great thing for Middle Tennessee.”
This summer the PREDICT program began testing patients scheduled for hip and knee joint replacements for genetic variations that may affect their response to warfarin, the most widely used anticoagulant in North America.
The initial dose must be carefully monitored so the drug prevents formation of blood clots without causing dangerous internal bleeding complications. Due largely to genetic factors, patients vary widely in what constitutes a safe, effective initial dose, says Dr. Dan Roden, assistant vice chancellor for personalized medicine and the William Stokes Professor of Experimental Therapeutics at Vanderbilt.
Placing genetic information in the electronic health record before it’s needed can help physicians predict which starting dose of warfarin is best for their patients. “It’s a very attractive way of using genetics to improve outcomes,” says Roden, a nationally known expert on pharmacogenomics—the study of how variations in the human genome affect drug response.
Clopidogrel and warfarin are just the first steps.
By harnessing its expertise in clinical pharmacology, genomics and informatics, Vanderbilt is developing a process for presenting information about genetic markers and drug response in the electronic health record that is clear and useful to physicians. Outcomes will improve because patients will receive the drugs that are right for them and side effects will be avoided.
Not every side effect can be avoided, of course. “We’re just reducing the odds,” Roden says. “That’s what applying genetics at the bedside is all about. It expands what you know about the individual patient.”
Personalized medicine sounds great, but will our health care system embrace it?
One study estimates that by helping physicians choose the right dose of the anticoagulant warfarin, for example, genetic testing could avoid 85,000 serious bleeding events and 17,000 strokes each year, and cut the nation’s annual health care budget by $1 billion.
Personalized medicine won’t yield immediate savings for insurance companies, however, because of high subscriber turnover rates.
According to a 2009 report by the Washington, D.C.-based Deloitte Center for Health Solutions, insurers may cover genetic testing and targeted therapies, only to see their now-healthier members move to a competing health plan. Thus, they may have a “first mover” disadvantage, and they may need to be motivated by convincing clinical comparative effectiveness studies in order to back specific treatment alternatives enthusiastically.
Dr. Jeff Balser isn’t worried. Payment systems already are moving from fee-for-service, covering every test and procedure, to global, quality-based reimbursement that encourages health care providers to keep their patients as healthy as possible.
“What we’re doing, even though it may not look economically attractive today, will be extraordinarily economically attractive down the road, as health care payment systems become a lot more sensible,” says Balser.
Perhaps an even greater challenge is learning how to implement and disseminate the lessons of personalized medicine.
At Vanderbilt, “we’ve learned the importance of making sure all the teams are working together,” says Roden. “We have teams of geneticists, teams of informaticists [specialists in information technology], teams of laboratory science people. And then we have teams of practitioners. At the end of the day, it’s the relationship between the [doctor] and his or her patients that is the target of all this.”
Education of health care providers as well as patients is crucial if personalized medicine is to become a reality.
In the fall of 2010, second-year medical students at Vanderbilt for the first time were given the opportunity to send a sample of their blood or saliva to a private lab for genetic analysis. The students discovered that while everybody had one or two genetic variations, for most everything else they were “in the middle”—average.
“Genetics can contribute to your understanding of what makes a person a person,” says Roden, “but it’s not the be-all and end-all.”
Balser agrees. To achieve truly personalized medicine, Vanderbilt must implement “evidence-based protocols” for all the care it provides, ensure “flawless handoffs” of patients from one caregiver to another, and involve patients more in their own care.
“Just as important,” he continues, “is the warmth and caring we have for each other as individuals and for our patients. Our caring culture is the key ingredient that will make all these things possible.”
© 2014 Vanderbilt University | Photography: “DOCTOR AND THE DOLL” BY NORMAN ROCKWELL, THE SATURDAY EVENING POST © 1929 SEPS LICENSED BY CURTIS LICENSING, INDIANAPOLIS. ALL RIGHTS RESERVED., Victor De Schwanberg / Photo Researchers Inc., John Russell, Susan Urmy
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What does it take to truly personalize cancer medicine?
A longstanding partnership with the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation serves as one key factor in Vanderbilt-Ingram Cancer Center’s successful approach to introducing a new standard of care for patients based on the genetic makeup of the cancer.
Today, Dr. William Pao and his colleagues are routinely testing for known mutations in patients with lung and breast cancer and melanoma so they can prioritize the most appropriate therapy. This advancement is one of the latest developments from nearly two decades of promising discovery science that the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation has supported at Vanderbilt.
Their early support focused on incorporating new technologies to establish programs in genetics-based medicine. Additional investment in molecular imaging led to advancements in early detection and allowed scientists to gauge tumor response to treatment more effectively. Ongoing research is aimed at developing new, targeted therapies to treat cancer patients with fewer side effects.