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Biomarker testing for harmful genetic mutations provides the opportunity to identify at-risk individuals who might benefit from risk modification strategies and/or enhanced disease screening.
Biomarker testing for harmful genetic mutations provides the opportunity to identify at-risk individuals who might benefit from risk modification strategies and/or enhanced disease screening. This may translate into preventing disease through risk reduction, prevention of advanced disease through earlier detection, and decreased cancer mortality from detection and treatment of localized disease, says Dennis Holmes, MD, breast cancer surgeon and interim director, Margie Petersen Breast Center at John Wayne Cancer Institute at Providence Saint John’s Health Center in Santa Monica, California.
Here’s how biomarkers are currently being used to treat diseases, and what promises they hold.
For more than 40 years, acute myeloid leukemia (AML), a cancer of the blood and bone marrow, has been treated as one disease. “The standard of care, which involved two toxic chemotherapy drugs, has not changed much over that time,” says Ross Levine, MD, director, Memorial Sloan Kettering Center for Hematologic Malignancies, New York, New York. “Most patients, especially older adults, do not respond well or cannot tolerate the treatment. The prognosis for most seniors with AML is very dismal.”
However, an endeavor currently under way could improve patient outcomes. In conjunction with the FDA, the Leukemia & Lymphoma Society (LLS) launched a collaboration of cancer centers, pharmaceutical companies, and a genomics provider to design a protocol for the Beat AML Master Trial in October 2016 that will include multiple clinical sites and multiple treatment arms.
The Beat AML Master Trial is the first-ever precision medicine clinical trial in a blood cancer, where multiple drugs are tested simultaneously at multiple clinical sites. “With a patient-focused neutral party such as LLS at the center, it eases the way for multiple pharmaceutical companies to join the collaboration to test their agents,” Levine says.
Newly diagnosed patients can provide a bone marrow sample to a genomics laboratory and have their specific genetic mutations identified so clinicians can prescribe a more precisely targeted novel therapy matched to their subtype of AML.
“Understanding a patient’s biomarker(s) helps clinicians make better decisions about appropriate drugs for an individual patient by targeting the drivers of the cancer and sparing the healthy cells,” Levine explains. “This trial aims, for the first time, to use these genetic markers to assign first-line therapy in real time, which we believe will accelerate our ability to get molecularly targeted drugs to AML patients at diagnosis and to accelerate drug development.”
Reimbursement for testing is a rapidly moving target. “We are waiting to see how the government handles reimbursement of such tests and hope that genetic testing will soon be covered for all cancer patients,” Levine says.
Clinicians can use different types of biomarkers to better understand how each patient’s cancer is unique. In non-small cell lung cancer, some biomarkers, such as ALK and EGFR, are mutated forms of genes involved in normal cell growth, while others like PD-L1 allow some cells to avoid being detected by the immune system. “By identifying individuals’ tumor biomarkers, clinicians can determine the treatment that is most appropriate for them, whether it's an approved medication or participating in a clinical trial,” says Suman B. Rao, MD, medical oncologist, MedStar Franklin Square Medical Center, Baltimore.
Biomarkers are like pieces to a puzzle that give doctors a more well-defined picture of a patient’s lung cancer, Rao continues. Biomarker test results can also help doctors make informed decisions about the most appropriate treatment. Several different biomarkers can be used to plan treatment in non-small cell lung cancer, including EGFR, ALK, ROS-1, and the recently discovered PD-L1.
Biomarker testing can also help reduce a patient’s exposure to unnecessary treatments-which may reduce healthcare costs.
Massimo Cristofanilli, MD, associate director for precision medicine and translational research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University at Northwestern Memorial Hospital, Chicago, says biomarkers are enabling clinicians to better understand breast cancer as a disease for each individual patient.
“We now understand that breast cancer is not only one disease,” he says. “Studies have shown that there are at least four different disease subtypes. Within these subtypes, new genomic abnormalities sometimes arise during treatment, making them ineffective. Therefore, giving the same treatment to every patient is not beneficial. Improving patient selection and more personalized treatment are key.”
In the past, the only two biomarkers used to determine treatment were estrogen receptor and HER2 oncogene expression. “These two biomarkers provide some discrimination between a distinct type of treatment and two targeted therapies with chemotherapy,” Cristofanilli says. “In the last five years, we have learned that an estrogen receptor positive for breast cancer-which is the most common type-is further divided into two different types of disease-luminal A and luminal B. Luminal A is more sensitive to most hormonal therapy agents than those used in the past. Luminal B is more resistant and sometimes requires a combination of therapies, including chemotherapy.
A1c is the key biomarker for type 2 diabetes management. “This biomarker gives a three-month average of blood sugar control,” says Mohamed Jalloh, PharmD, a spokesman for the American Pharmacists Association and assistant professor at Touro University California, Vallejo, California. “When this number is high, we usually see patients with complications in their eyes, heart, kidneys, hands, and feet. If this number is too high, clinicians can determine which medications are more or less likely to work.”
In fact, the U.S. government looks at the percentage of patients who have a high A1c value to evaluate a health organization’s quality of care. “If the majority of its patients have an A1c above a certain goal, that’s an indicator that the organization might not be the best resource for getting someone to goal,” Jalloh says. This can potentially affect its reimbursement.
But Jalloh notes that some prescribers get too focused on treating a number instead of focusing on the best patient care. For example, insulin is one of the best agents to lower blood glucose. However, if too much insulin is used, patients can get very low blood sugars and have hypoglycemic symptoms (i.e., sweating, shaking). Using too much might not only increase the cost of treatment, but also worsen quality of life.
It can be challenging to assess the level of disease activity in children with chronic conditions. “Children vary in their ability to describe severity and frequency of symptoms, and external signs available on examination do not always correlate with disease activity,” says Steven Spalding, MD, chief clinical integration and medical officer and rheumatologist, Division of Pediatric Rheumatology, Phoenix Children’s Hospital, Phoenix. “Especially in pediatrics, biomarkers offer a unique additional data point to help determine disease activity and make decisions around the need for additional investigation or therapy.”
But how biomarkers are used in treatment decisions for juvenile arthritis is still evolving. “A gap exists between translating biomarker research into clinical practice,” Spalding says. “On the commercial side, not many companies offer laboratory tests that are efficient and effective enough in which to draw conclusions. Right now, biomarker tests are just one data point among magnetic resonance imaging (MRI), sedimentation “sed” rate or erythrocyte sedimentation rate (ESRs), and other diagnostic tools, that help determine if a patient has active disease.”
Given the limited experience with and availability of biomarkers in children with juvenile arthritis, their role in making decisions regarding investigation and therapy is quite small. “There is too much variation across genetics, especially among young children, to tie links from certain genes to functional outcomes,” Spalding says. “We’ve identified modifier genes in some pediatric patients, but we still find plenty of children with the same gene and variation in outcomes. To move to the genetic testing model, we would need to scale to diagnostic, risk-assessment type tools. Right now the jump from genes to smart conclusions is simply too wide. Most decisions for further evaluation or escalation in therapy are still driven by history and physical examination.”
But biomarkers can help to reduce the number of time-consuming and costly tests used to determine a patient’s diagnosis. “They could soon have the ability to rule out false diagnosis, eliminating the need for more assessment from MRIs and other tests,” Spalding says. “These more invasive tests can be especially difficult for children to undergo, with many children requiring sedation. This gives biomarkers an added value in the pediatric arena.”
Nathan Wei, MD, FACP, FACR, director, Arthritis Treatment Center, Frederick, Maryland, says biomarkers have not yet changed treatment decision making for rheumatoid arthritis. “While there is a movement touting the value of peripheral blood biomarkers, they are not an adequate reflection of what’s happening at the level of the joint,” he says. “We need better synovial tissue biomarkers.”
When synovial biomarkers are standardized, a simple synovial biopsy may permit the right type of treatment to achieve remission. A proper biomarker match would prevent the costly approach currently being used, which is to keep trying different biologics-in other words, trial and error.
Karen Appold is a medical writer in Lehigh Valley, Pennsylvania.