A Quiet Evolution
P4 medicine promises to promote wellness, lower healthcare costs and improve treatment outcomes.
BY DAVE SLAYBAUGH
Recent and emerging technologies and several decades of research are transforming the practice of medicine from the primarily disease-based care of today to a wellness-based care model of the future. This new approach is called P4 medicine: It provides care that is predictive, preventive, personalized and participatory (see sidebar).
The principles of P4 medicine are being applied to oncology with a growing emphasis on the use of genomics and other "-omic" sciences to predict cancer risk, prevent cancer development, and develop and guide use of personalized therapy. Along with this, there is growing emphasis on encouraging patients to participate more in treatment decisions and to adhere to survivorship care plans (see "Survivorship 2012," page 14).
The Ohio State University Medical Center and Ohio State's Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) are at the forefront of the P4 medicine movement with research that is advancing clinical care and offering training in P4 medicine for the physicians of tomorrow.
"The OSUCCC – James is committed to personalized health care through research to improve diagnosis and develop targeted therapies, identify clinically useful biomarkers and evaluate new cancer prevention and control strategies," says Michael A. Caligiuri, MD, director of Ohio State's Comprehensive Cancer Center and chief executive officer of The James Cancer Hospital and Solove Research Institute.
Why P4 medicine is important
CLAY MARSH, MD
executive director, Ohio State's Center for Personalized Health Care
In a presentation at the 2011 Annual Systems Biology Symposium: Systems Biology & P4 Medicine, Clay Marsh, MD, executive director of Ohio State's Center for Personalized Health Care, cited these factors in discussing health care's "need for transformation":
• In 2009, the overall cost of health care in the United States totaled $2.5 trillion, accounting for 17.6 percent of the American economy.
• An estimated 75 to 90 percent of that amount was spent managing and treating preventable chronic illnesses.
• On a per-person basis, U.S. healthcare costs are 50 percent higher than in the nation with the second-highest costs.
• Drugs prescribed for patients are effective in less than 60 percent of treated patients, but development costs have skyrocketed.
Marsh and other P4 medicine advocates say that by engaging patient participation, predicting and preventing disease, facilitating health and creating a personalized wellness plan for each patient, P4 medicine can eliminate much of the labor and cost of treating preventable illnesses while enhancing quality of care.
"We believe that by increasing the precision of health care and ultimately trying to reverse our paradigm from disease to health, from reactive to proactive care, there's a tremendous opportunity to both lower costs and improve outcomes," says Marsh, who is also vice dean and senior associate vice president for research at Ohio State's College of Medicine.
P4M for Cancer Patients
"Cancer is a genetic disease," Caligiuri says, "but the kinds of genetic changes that occur can be different in each patient—even those with the same type of cancer— and they influence how that patient responds to treatment. We want to learn how those changes affect outcome and which ones we should target with existing or new drugs."
Researchers, physicians, geneticists and others at the OSUCCC – James are contributing to each area of the P4 medicine transformation.
As recently as the 1980s, the existence of major hereditary forms of cancer was not universally accepted. Then groundbreaking research by Albert de la Chapelle, MD, PhD, co-leader of the OSUCCC – James Molecular Biology and Cancer Genetics Research Program, and others in the 1990s established that hereditary nonpolyposis colorectal cancer
(HNPCC), commonly called Lynch syndrome, is inherited.
Further research led by de la Chapelle on Lynch syndrome mutations showed the following:
• All colon tumors requiring surgery should be tested for Lynch syndrome mutations, and that prescreening for the mutations could be done economically using immunohistochemistry. The study was published in the New England Journal of Medicine.
• About one in 50 newly diagnosed endometrial cancer patients have Lynch syndrome mutations, suggesting that women with endometrial cancer should be screened for the syndrome.
• Some rare skin cancers – sebaceous adenomas, sebaceous adenocarcinomas and keratoacanthomas – may be a sign of Lynch syndrome. The study confirmed that Muir Torre
syndrome is a variant of Lynch syndrome.
Because Lynch syndrome carries an almost 100 percent lifetime risk of cancer, patients or their relatives with the mutation require close monitoring for early cancer detection.
Additional studies have shown that testing for tumor genomics or patient genomics may help predict a susceptibility to other types of cancer, including breast and lung.
"We know that about 5 to 10 percent of all cancers are caused by a genetic mutation that runs in the family and causes an increased susceptibility to cancer," says Heather Hampel, a certified genetic counselor and associate director of Ohio State's Division of Human Genetics.
"If we can identify the gene mutation that is responsible, we can offer predictive testing to at-risk relatives. Those who are found to have a high risk for cancer can follow intensive
cancer surveillance and prevention recommendations to either prevent the cancer altogether or to diagnose it early when it is most treatable."
The Division of Human Genetics has counseled nearly 5,000 patients since 1996, and about 2,800 have undergone genetic testing, Hampel says. The testing has identified several hundred individuals with Lynch syndrome and several hundred with hereditary breast and ovarian cancer syndrome, enabling their physicians to prescribe appropriate observation and prevention protocols.
Although Lynch syndrome and hereditary breast and ovarian cancer syndrome are the two most common inherited cancer syndromes, Hampel adds, "There are many other hereditary cancer syndromes, and we can evaluate families for any of them."
Because so many people are diagnosed with cancer every year, cancer prevention is an area of P4 medicine that holds tremendous potential for progress. Researchers continue to learn more about cancer-causing genetic mutations, but much is yet to be discovered.
Read about the OSUCCC – James Clinical Cancer Genetics Program here.
"The history of research in cancer-related genetics at the OSUCCC – James spans studies in acute and chronic leukemia that have improved patient stratification and led to new
treatments and more individualized treatment," says Caligiuri. Therapies— and clinical trials testing new therapies—for these and other cancers are being personalized based on the genetic profile of patients' cancer cells.
Gregory Otterson, MD, a lung cancer specialist and a member of the Molecular Biology and Cancer Genetics Program at the OSUCCC – James, says that lung-cancer clinical
trials at The James and elsewhere are matching specific drugs and approaches with specific patients according to the genetic signature of the patient's tumor cells.
"Instead of talking about 200,000
patients per year with lung cancer,
we will be talking about 20,000 to
30,000 patients per year with
EGFR-mutant lung cancer, 8,000
patients with EML4-ALK translocated
lung cancer and 60,000 to
70,000 patients with KRAS mutant
The treatments for each type
can be quite different, he says.
"Approaches that affect the specific
molecular defects of the cancer
may be much more effective than
the 'old-fashioned' concept of
adding Drug A to Drug B to see
if it improves treatment."
Acute Myeloid Leukemia
Guido Marcucci, MD, director
of the OSUCCC – James Myeloid Malignancy Program, focuses on
drug development and discovery of
molecular prognostic biomarkers in
acute myeloid leukemia (AML).
"Morphologically, patients with
this disease all look the same," he says,
"but genetically, they are much
different. Every patient is characterized
by certain gene mutations or
changes in genetic expression, and
these impact treatment outcome
according to which alterations are
present. In other words, a particular
mutation may have more or less
impact on a patient's prognosis
according to whether other
mutations are present.
"This is important because we now make treatment decisions based on the mutations that are present," Marcucci says.
Researchers at the OSUCCC –
James and elsewhere have associated
scores of genetic alterations with
tumors, leading to a wave of novel
agents that target specific mutations
involved in the growth of particular
tumors. However, the mutation is
carried by only a portion of patients
with a specific cancer.
"This is where pharmacogenomics becomes important," says Wolfgang Sadée, PhD, chair and professor of Pharmacology and director of Ohio State's Program in Pharmacogenomics. "The goal is to optimize therapy for each individual patient, rather than applying the same treatment regimen to all. This approach
has considerable potential to improve the success of therapy, and it is particularly pertinent to cancer chemotherapy."
Tests that measure gene variation,
gene-expression profiles, protein
abnormalities and other molecular
changes are being used increasingly
at the OSUCCC – James to determine
therapy. For example, the targeted
breast-cancer drug Herceptin is
effective only in patients who highly
express the growth factor receptor
HER2-neu, Sadée says.
To be successful, proponents say, P4 medicine will require active patient participation. Here are some of the most important facets of this fourth "P":
• Ongoing collection of
patients' data – everything from
family health history, genetic
screenings and personal medical
records to information about
lifestyle and environment. Such
data helps stratify patients into
risk groups enabling more precise
care and more effective treatments,
• Health literacy – patients must understand their medical information well enough to make appropriate health decisions and to follow prescribed disease prevention and treatment protocols. One study estimates that between $106 billion and $238 billion is lost annually because adults are unable to obtain, process and understand health information.
• Clear and continued
communication from healthcare
providers to patients. "We must
say things in terms patients
understand," Marsh says. "This is
also about continuity of care and
communicating in a variety of ways
that include phone, videoconferencing
and email, so that patients
can continue the conversation with
members of their health team. We
must make sure patients understand
that initial burst of information,
and then we must work with them
throughout their illness to provide
the help they need when they
"As the emphasis of health care shifts to prediction and prevention, health and wellness, and engagement and empowerment," says Marsh, "we want people to go beyond participation based on just following instructions. We want to give people the capacity to drive their lives in ways that will keep them healthy.
"Through personalized medicine, we can transform health care so that it costs less, provides higher quality outcomes and yields better patient satisfaction."