 |
 CHAPEL HILL, N.C. — Selecting the best treatment based on the unique features of a particular patient is the goal of personalizing cancer care, says Richard Schilsky, MD, this year’s recipient of the Award for Clinical Service from the UNC Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina at Chapel Hill “We are moving into the frontier of personalized medicine and are treating patients not just by the site of their tumor but by the genetic composition of their disease and of their normal DNA,” Schilsky told the U.S. House of Representatives in March, “This enables us to determine which patients will benefit from a treatment, and just as importantly, which patients will not benefit from a treatment.” The IPIT Award for Clinical Service annually honors a person who has made significant direct contributions to the advancement of individualized therapy in clinical practice. The award acknowledges Schilsky’s long-standing efforts to further the notion and practice of individualizing care for cancer. “Dr. Schilsky has been directly responsible for shifting the discussion from ‘should we’ to ‘how do we’ pursue individualized cancer therapy,” said Howard McLeod, director of IPIT and Fred Eshelman Professor of Pharmacy at the UNC Eshelman School of Pharmacy. Schilsky is president of the American Society of Clinical Oncologists and section chief of hematology/oncology at the University of Chicago Medical Center. He will receive the award and present a seminar entitled “Personalized Cancer Care: Research, Policy, and Practice” on November 19, at 3 p.m. in the Joseph Pagano Conference Room in the Lineberger Comprehensive Cancer Center on the UNC-Chapel Hill campus. “As ASCO president last year, Dr Schilsky chose the emerging science of personalized cancer care based on pharmacogenetics as his flagship issue,” said Richard Goldberg, MD, chief of the Division of Hematology/Oncology at the UNC School of Medicine and physician-in-chief of the new North Carolina Cancer Hospital. “His advocacy for practicing medicine based on individual patients rather than a generic approach has helped to move the field forward.” Since 1995 Schilsky has served as chair of Cancer and Leukemia Group B, a cooperative group sponsored by the National Cancer Institute that conducts clinical trials in cancer treatment, biology, prevention, and health outcomes. His laboratory and clinical research have been continuously funded by the NCI since 1987. As the current president of ASCO, he champions the clinical-trials model to ensure that high quality, evidence-based practices for the prevention, diagnosis, and treatment of cancer are available to each individual American citizen. Richard M. Schilsky, M.D. Schilsky earned his M.D. at the University of Chicago Pritzker School of Medicine in 1975. Following a residency in Internal Medicine at the University of Texas Southwestern Medical Center and Parkland Memorial Hospital, he received training in medical oncology and clinical pharmacology at the National Cancer Institute from 1977 to 1981. He then served as assistant professor of medicine at the University of Missouri-Columbia School of Medicine from 1981 to 1984 when he returned to the University of Chicago where he is presently professor of medicine (tenured). Schilsky previously served as director of the University of Chicago Cancer Research Center from 1991 to 1999 and as associate dean for clinical research from 1999 to 2007. As an international expert in gastrointestinal malignancies and cancer pharmacology, he has served on a number of peer-review and advisory committees for the NCI and previously served as chair of the Oncologic Drugs Advisory Committee for the FDA.. Schilsky currently serves as chair of the NCI Board of Scientific Advisors and as a member of the Clinical and Translational Research Advisory Committee. Schilsky has served as a member of the board of directors of the American Society of Clinical Oncology. CHAPEL HILL, N.C. — The best way to advance personalized medicine is by encouraging patient choice and practicing evidence-based medicine, says Mark McClellan, MD, PhD, this year’s recipient of the Award for Public Service from the Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina at Chapel Hill. This annual award from the institute honors a person who has made significant contribution to the advancement of rational drug-therapy initiatives across society. The award acknowledges McClellan’s advocacy of pharmacogenomics and personalized medicine throughout his career. Currently the director of the Engelberg Center for Health Care Reform at the Brookings Institution, he has also served as commissioner of the Food and Drug Administration and administrator of the Centers for Medicare & Medicaid Services. McClellan, who is both a medical doctor and economist, will receive the award and present a seminar on November 5 at 4:00 p.m. in the Blue Cross Blue Shield Auditorium of the UNC Gillings School of Global Public Health on the Chapel Hill campus (click for a map). A reception will immediately follow. “Dr. McClellan has been willing to lead by example, making policy that puts the individual patient in a place of priority,” says Howard McLeod, PharmD, director of IPIT, “The fact that the FDA and CMMS take pharmacogenomics seriously has caused medical practice to follow suit.” McClellan’s work at the Engelberg center focuses on developing practical policy solutions for health-care reform that will reduce the growth of health-care spending and improve quality. He also continues to be a driving force for personalizing the health care that Americans receive. Under his leadership, a range of center initiatives are focused on improving the development of and regulatory science for more personalized therapies in cancer and neuro-degenerative diseases, as well as effectively implementing comparative effectiveness research that advances individualized care. “If we do it right, health-care reform can have a positive impact on medical innovation and our overall ability to deliver the best, most targeted care to patients,” McClellan says. As FDA commissioner, McClellan oversaw efforts to establish a new regulatory approach for using pharmacogenomic information in product development and the creation of electronic data systems that would enhance the analysis of collected pharmacogenomics data. “We believe that better analysis of pharmacogenomics data can close the information gaps as to why people respond differently to the same drug,” he says. “These steps toward developing better, more comprehensive information on treatments at a lower cost are especially important to patients so that we can do a better job of telling patients exactly which treatments are best for them.” Mark McClellan, MD, PhD Mark McClellan is senior fellow, director of the Engelberg Center for Health Care Reform, and Leonard D. Schaeffer Chair in Health Policy Studies at the Brookings Institution. Established in 2007, the Engelberg Center provides practical solutions to achieve high-quality, innovative, affordable health care with particular emphasis on identifying opportunities on the national, state, and local levels. A doctor and economist by training, McClellan has a highly distinguished record in public service and academic research. He is a former administrator of the Centers for Medicare & Medicaid Services and former commissioner of the Food and Drug Administration. McClellan served as a member of the President’s Council of Economic Advisers and senior director for health-care policy under President George W. Bush. He also served in the Clinton administration as deputy assistant secretary of the Treasury for economic policy where he supervised economic analysis and policy development on a range of domestic policy issues. Previously, McClellan was an associate professor of economics and associate professor of medicine with tenure at Stanford University where he directed Stanford’s Program on Health Outcomes Research; served as associate editor of the Journal of Health Economics, and was coprincipal investigator of the Health and Retirement Study, a longitudinal study of the health and economic status of older Americans. He has twice received the Kenneth J. Arrow Award for Outstanding Research in Health Economics. In his capacity as a health-policy expert, McClellan is the codirector of the Bipartisan Policy Center’s Leaders’ Project on the State of American Health Care; cochair of the Robert Wood Johnson Foundation Commission to Build a Healthier America; and chair of the FDA’s Reagan-Udall Foundation. He is also cochair of the Quality Alliance Steering Committee, sits on the National Quality Forum’s Board of Directors, is a member of the Institute of Medicine of the National Academy of Sciences, and is a research associate at the National Bureau of Economic Research. McClellan holds an MD from the Harvard University–Massachusetts Institute of Technology ] Division of Health Sciences and Technology, a PhD in economics from MIT, an MPA from Harvard University, and a BA from the University of Texas at Austin. He completed his residency training in internal medicine at Brigham and Women's Hospital in Boston, is board certified in internal medicine, and has been a practicing internist during his career. UNC Institute for Pharmacogenomics and Individualized Therapy The institute was formed in the UNC Eshelman School of Pharmacy as a collaborative effort with the School of Medicine, Gillings School of Global Public Health, and the School of Nursing and with support from the UNC Lineberger Comprehensive Cancer Center and the Carolina Center for Genome Sciences. Pharmacogenomics is the study of how genetic variation among individuals contributes to differences in the way people respond to medicines. Leadership in key areas of pharmacogenomic research is fostered by contiguous office and laboratory space that bolster collaboration and enable the development of comprehensive research investigations and treatment tools. IPIT also offers the services of core facilities in molecular genomics, cellular phenotyping and bioinformatics to add to the excellent core facilities already existing at UNC.  One is a powerful number. At Carolina, the work of an individual faculty or staff member, student or alumnus can reach thousands of people across North Carolina. Take Howard McLeod, for example. A professor and research in the Eshelman School of Pharmacy, McLeod directs the UNC Institute for Pharmacogenomics - the study of how people's gens affect the way they respond to drug threapies. read more at: http://gazette.unc.edu/10-28-web/10-28-lo-res.pdf Entrepreneur Ryan Phelan spoke Tuesday to a packed room of medical clinicians and researchers about the benefits of personalized medical care and genetic testing. Phelan was the recipient of the UNC Institute for Pharmacogenomics and Individualized Therapy’s 2009 award in patient service. The award recognizes her work as an advocate for genetic testing. “This is the direction health care is going, and UNC is at the frontier of this research,” she said. Phelan spoke at the UNC Lineberger Comprehensive Cancer Center, which recently received an award of more than $12 million dollars to conduct further research into genetic testing and DNA mutations. Doctors use genetic testing to reveal changes in DNA that can cause diseases and illnesses. Genetic testing can also predetermine a patient’s reaction to certain drugs. Phelan is the founder and CEO of DNA Direct, a San Francisco-based company that serves as an online and personal resource for patients, physicians and health care providers about genetic testing. “I’ve been at this for 30 years, and how patients make health care choices and who pays for them has always been at the forefront of my work,” she said. Phelan said her background in business improves her understanding of all sides of the issue of genetic testing. In 1995, Phelan founded Direct Medical Knowledge, a Web site dedicated to helping patients sift through medical literature to find the information that applies to them. Four years later, the company was acquired by the medical Web site WebMD, and her research became the foundation for the site’s database. “People used to say that my service was only for the worried well,” she said. “But I like to say it’s for the rightly worried.” Phelan estimated there are fewer than 2,000 doctors specializing in genetics, which she said emphasizes the need for creating an accessible database of genetic information. “Our mission is to act as a link between patients, physicians and health care providers to ensure that the patient receives personalized medical care,” she said. She added that too often patients are tested for the wrong illness — and that leads to mistrust from insurance companies who pay for the tests. Through genetic testing, patients can obtain access to drugs that specifically target their disease. “Patients have a role to be their own advocate and we’re here to help.” CHAPEL HILL, N.C. (October 5, 2009) — Ryan Phelan, CEO and founder of DNA Direct, is this year’s recipient of the Award for Patient Service from the Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina at Chapel Hill. When Phelan launched DNA Direct in 2005, she believed that genomics would transform health care, she says. “My promise at that time was to start with the people we knew would benefit most, and evolve our offerings as the landscape unfolded,” Phelan says. ”So we began with services for consumers. By helping consumers access state-of-the-art genetic testing and interpretation, we knew we could make a difference in their health care.” DNA Direct delivers guidance and decision support for genomic medicine to patients, providers and payers. DNA Direct’s clinical leadership team includes two medical geneticists and a national call center of board-certified genetic counselors. The company has developed a technology platform to provide Web-based decision support solutions that enable individuals and health-care professionals to understand the appropriateness, implications and interpretation of genetic and molecular diagnostic testing, ultimately resulting in more informed decisions. The incorporation of pharmacogenomics into the work of DNA Direct recognizes the increase in the use of genetics in medical practice. The IPIT patient-service award honors a person who has made significant contributions to empowering patients and who champions patient focus in the advancement of rational drug therapy. “Ms. Phelan’s work has dramatically improved patient access to genetic information,” says Howard McLeod, Pharm.D., director of IPIT. “Her vision to empower patients by providing them with the information about their own genetics ultimately makes these consumers more informed participants in their own health-care choices.” The award also acknowledges Phelan’s earlier work to empower patients with the founding of Direct Medical Knowledge, an extensive consumer health Web site highly regarded for its unique content depth and innovative search interface. DMK developed proprietary software that enabled users to drill down through the most current medical literature and retrieve personalized health and medical information. In 1999 Direct Medical Knowledge was acquired by WebMD, and DMK's content became the backbone of WebMD's consumer health site. As the founding director of Planetree, a nonprofit consumer health-care organization, Phelan helped create a national model for humanizing hospitals and a national model for providing health information to the public. McLeod will present the award to Phelan during a ceremony on Oct. 6 at 4 p.m. in seminar room CG222, Level G, in the newly opened North Carolina Cancer Hospital. Phelan will present a seminar entitled “Integrating Genomic Medicine into Patient Care” with a reception immediately following. UNC Institute for Pharmacogenomics and Individualized Therapy The institute was formed in the UNC Eshelman School of Pharmacy as a collaborative effort with the School of Medicine, Gillings School of Global Public Health, and the School of Nursing and with support from the UNC Lineberger Comprehensive Cancer Center and the Carolina Center for Genome Sciences. Pharmacogenetics is the study of how genetic variation among individuals contributes to differences in the way people respond to medicines. Leadership in key areas of pharmacogenomic research is fostered by contiguous office and laboratory space that bolster collaboration and enable the development of comprehensive research investigations and treatment tools. IPIT also offers the services of core facilities in molecular genomics, cellular phenotyping and bioinformatics to add to the excellent core facilities already existing at UNC. For more information, please visit: www.ipit.unc.edu. # # # Media Contacts: David Etchison Director of Communications UNC Eshelman School of Pharmacy (919) 966-7744 david_etchison@unc.edu IPIT Contacts: Tejinder Rakhra-Burris Associate Director for Research UNC Institute for Pharmacogenomics and Individualized Therapy (919) 843-1961 teji_rakhraburris@unc.edu Science and Medicine - Genes determine blood thinner dosage ... By savery “The promise of genetic testing is getting the right drug in the right amount to the right person at the right time every time,” said Howard McLeod, director of UNC-CH's Institute for Pharmacogenomics and Individualized Therapy. ... "The American Enterprise Institute hosted a panel discussion on pharmaceutical price regulation. Co-authors John Vernon and Joseph Golec discussed the argument made in their book, "Pharmaceutical Price Regulation: Public Perceptions, Economic Realities, and Empirical Evidence," that price controls lead to a trade-off between low drug prices and innovative breakthroughs." In addition to Dr. Vernon's presentation, of the additional speakers on the panel, included is Mark McClellan, former FDA Commissioner and head of Medicare and Medicaid Services. Some of the panel discussion touched on personalized medicine. To view the live presentation, please copy and paste this URL in your browser: http://www.c-span.org/Watch/watch.aspx?MediaId=HP-A-15547 Jim Crowley, Patrick Sullivan and Howard McLeod have editorials in the recent issue of Pharmacogenomics: Pharmacogenomic genome-wide association studies: lessons learned thus far James J Crowley†, Patrick F Sullivan and Howard L McLeod Request article: http://www.futuremedicine.com/doi/abs/10.2217/14622416.10.2.161 Genome-wide association studies: powerful tools for improving drug safety and efficacy David Gurwitz† and Howard L McLeod Request article: http://www.futuremedicine.com/doi/abs/10.2217/14622416.10.2.157 In the College of American Pathologists' publication, CAP Today, the January 2009 Feature Story: PGx tests for warfarin dosing—how soon? Selected portions of Howard McLeod and Karen Weck's comments: Dr. Weck points out two subtle but important aspects of PGx algorithms for warfarin dosing. First, they are mostly based on studies of Caucasians, with a few exceptions (Limdi NA, et al. Pharmacogenomics. 2008;9:1445–1458; Wu AH, et al. Pharmacogenomics. 2008;9:169–178). “Those two algorithms performed somewhat better in our patient population,” Dr. Weck says, perhaps because African-Americans make up 30 percent of UNC patients. Second, “All algorithms so far have looked at prediction of final stable warfarin dose. It is unclear at this time how well those algorithms will do at predicting optimal initial dose. More work needs to be done in this area.” Dr. Weck and her colleagues at the University of North Carolina Medical Center have started a single-center study of initial warfarin dosing guided by an algorithm incorporating PGx information compared with the same clinical algorithm without genotyping. “We are asking specifically what is the effect of adding genotyping to an algorithm rather than comparing PGx to current practice,” she says. They are enrolling all inpatients started on warfarin as well as patients seen at the Doppler clinic for workup of deep vein thrombosis. The goal is to recruit 100 patients in each arm and to follow them for three to six months. Outcomes measures include the number of therapeutic-range INRs, time needed to get to a stable INR, and number of INRs greater than four, a surrogate for adverse bleeding events. They are asking, too, whether genotype-guided warfarin dosing will be cost-effective. Parameters for cost are the number of visits to the coagulation clinic, number of hospitalizations for anticoagulation, number of procedures for over or undercoagulation, and the cost of laboratory testing. Dr. Weck is using the Idaho Technology kit, which she validated in-house. One reason for this choice is its rapid turnaround time. “It has never been demonstrated that a rapid turnaround time is required,” Dr. Weck says, “but our experience has been that clinicians are not willing to wait to start a patient on this important therapy. In principle, you would want to know about genetic variants that will affect a patient’s response prior to putting them on therapy, so a fast turnaround time could be a crucial factor.” Some of the clinicians at UNC have been enthusiastic about PGx and others are more reluctant. “But all of them have agreed that there needs to be evidence, so they are enthusiastic for us to do this trial,” Dr. Weck says. “That’s why we decided to do a clinical trial rather than simply bringing the test online. Clinicians want to find out more about the test’s clinical utility.” She describes as “great” the collaboration in this trial among the laboratory, geneticists, coagulation specialists, internal medicine physicians, and cardiologists—and particularly with the clinical pharmacy. “We do genotyping and pharmacy runs the algorithm and makes dosing recommendations. With pharmacogenomics in general, collaboration with pharmacy is key,” Dr. Weck says. “There is more acceptance by clinicians for pharmacists to make dosage and drug recommendations than the laboratory.” Howard L. McLeod, PharmD, is director of UNC’s Institute for Pharmacogenomics and Individualized Therapy, which is coordinating the trial, and it is he who has been “crucial in forging these collaborations,” Dr. Weck says. “We took a close look at what has gone right and wrong with personalized therapy,” Dr. McLeod says, “particularly in the use of genetic markers. We found a number of bottlenecks. It’s not only that there was not data from large clinical trials. In addition, some people who normally get involved in the process were missing.” For instance, health economists and people experienced at changing behavior at the policy and practice level hadn’t participated. “This institute draws across the entire university to pull those people together,” Dr. McLeod says. About warfarin PGx specifically, Dr. McLeod says, “We found that the endpoints most exciting to academic physicians would not necessarily move the field.” Severe cerebral bleeds are one egregious example. “From community physicians’ viewpoint they are costly but rare, so they are not a big mover,” he explains. “The health system is much more interested in clinical efficiency. We need to manage warfarin with fewer INRs and 6 PM urgent calls, better dosing from the start. That is something they will adopt right away.” Dr. McLeod says very few physicians understand whether CYP2C9*3 is good or bad. “That information needs to be put into a clinical decisionmaking algorithm using pharmacists as intermediaries. We spent a fair amount of time looking at what will happen when this is a routine test,” he says. They found that the group most equipped to apply information and asked to do it in normal practice is clinical pharmacists. “So we decided even in the context of the clinical trial to include them. They already individualize drug dosages based on drug levels or drug interactions or organ function. It is not a big deal for them to add genetics.” “A more efficient research enterprise ensures the translation of scientific discoveries into medical treatments in a safe and predictable manner, allowing oncology patients faster access to needed therapies,” said Howard McLeod, PharmD, chair of the ASCO-FDA Alternative Design Working Group, and director of the Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina-Chapel Hill. A review of 293 studies that assessed 12 commonly prescribed second-generation antidepressants found no significant differences between the drugs for the treatment of acute-phase depression, according to a report by the RTI International-University of North Carolina at Chapel Hill Evidence-based Practice Center. However, side effects among the drugs varied, causing many patients to have to try more than one before settling on long-term therapy. The drugs reviewed were bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone and venlafaxine. The studies included randomized controlled trials with active or placebo controls, observational studies and systematic reviews. "Based on our review of the available research, we found very little difference in the effectiveness of various antidepressants," said Dr. Gerald Gartlehner, lead author of the report and a research associate at UNC's Sheps Center for Health Services Research. Despite their similarities, the drugs create different side effects that lead only about 60 percent of patients to respond to an initial treatment regimen, said Linda Lux, an RTI researcher. And, she said, 61 percent of patients in efficacy trials experienced at least one adverse side effect, including constipation, diarrhea, dizziness, headache, insomnia and vomiting. "Because of the high incidence of side effects, many patients try more than one medication before finding an effective treatment," Lux said. "Predicting which one will be most effective or best tolerated by any individual is not yet possible." "This study highlights the important issue that side effects happen to patients, not doctors, and we need to take them a bit more seriously," said Dr Howard McLeod, director of the UNC's Institute for Pharmacogenomics and Individualized Therapy. McLeod, who was not part of this study, and others at UNC are trying to solve this drug-prescribing dilemma by using a patient's DNA to help direct the selection of treatment. Gartlehner and Lux said more research is also needed to determine the effects that dosage and duration of second-generation antidepressant treatment have on efficacy, and to see if efficacy differs in patients who also suffer from anxiety, insomnia, pain or fatigue. The project was supported by the Agency for Healthcare Quality Research, and is posted on the agency's Web site: http://www.ahrq.gov. Chapel Hill, N.C. — When it comes to prescribing medicine, doctors are learning one size does not fit all patients. A pilot trial at UNC Hospitals uses a patient's genetic profile to prescribe tamoxifen for breast cancer... Howard Mcleod Feature Interview in Fall 2008 Issue of Prospective Health Care09/01/2008 - Kevin Chen Feature interview: Dr. Howard McLeod on pharmacogenomics Fall 2008 / Volume 3, Issue 1 Interview: Howard McLeod, Director, University of North Carolina at Chapel Hill Institute for Pharmacogenomics and Individualized Therapy by Kevin Chen Prospective Health Care Fall 2008 www.prospectivehealthcare.com Everyone's genes spell out a risk for some disease, and an imminent anti-discrimination law is about to give genetic testing a boost. But discrimination is just one hurdle. The bigger quandary: Doctors don't yet know how many of the genetic tests being pushed for dozens of conditions are truly useful - and how many are misleading at best. "Some of these tests are complete rubbish," warns Dr. Howard McLeod, a personalized medicine specialist at the University of North Carolina. "The big challenge for a consumer is figuring out which data is real or not, without having to go to medical school." Soon, President Bush is expected to sign into law federal protection against genetic discrimination, a bill barring employers and insurers from using test results against patients. First to benefit will be people who have put off learning whether they have inherited genes responsible for diseases that run in their families - breast cancer, colon cancer, Huntington's, early-age Alzheimer's - for fear of losing insurance coverage or a job. No one knows how many people that encompasses. The National Institutes of Health estimates 30 percent of potential volunteers for gene studies cite discrimination fears in backing out. At the same time, states have adopted a patchwork of protections, and steadily growing use of two of the best-proven tests - for the BRCA1 and BRCA2 gene mutations linked to breast and ovarian cancer - suggests that lingering concern hasn't been a huge deterrent for people with strong family histories of disease. But until now, most genetic testing has been for conditions linked to single genes gone wrong, typically rare ones. That's changing. Most diseases - including diabetes and the No. 1 killer, heart disease — are caused by complex interactions of multiple genes and environmental factors, such as diet, exercise and smoking. With scientists rapidly discovering gene variants for these more common conditions, genetic testing in turn is poised to boom. Yet laboratories can market tests for those newly discovered DNA glitches before scientists prove how risky they are, or whether knowing you have one will make any difference in your health care. So while the pace of discoveries makes for a thrilling time, genetic testing in some ways is science's Wild West - with more than 1,200 different genetic tests available, but only a fraction accepted by mainstream medical groups, McLeod notes. Just last week, government health advisers called for more oversight of genetic testing, citing "significant gaps" in validating the tests' usefulness, especially those sold directly to consumers. Specialists advise anyone considering a gene test to: • Consult a doctor or one of the nation's 3,000 genetic counselors, to weigh pros and cons. • Ask what the results will mean for siblings or children. How big is their risk, and do they want to know? • Ask how accurate the test is, and if knowing you've got a risky gene allows you to take steps for better health or just worry. "It's not of value unless you're going to do something to modify your health behavior," cautions Angela Trepanier of Wayne State University, president of the National Society of Genetic Counselors. SILVER SPRING, MD. — Howard McLeod, PharmD, a professor at the University of North Carolina School of Pharmacy and director of the UNC Institute for Pharmacogenomics and Individualized Therapy, will deliver the 2008 William B. Abrams Lecture titled, “Personalized Medicine: This Gene’s for You.” ... Last week, the Critical Path Institute, the Arizona Center for Education and Research on Therapeutics, and the American Medical Association issued a new brochure to help educate physicians about gene-based warfarin dosing. The brochure, called: Personalized health care report 2008: Warfarin and genetic testing, “is designed for physicians and other healthcare providers who commonly prescribe warfarin but who may not have had exposure to pharmacogenomics and genetic testing,” the AMA states on its website. The pamphlet discusses how variations in the genes CYP2C9 and VKORC1 affect patients’ ability to metabolize and respond to the anticoagulant; mentions the US Food and Drug Administration’s request for drug makers to update the drug’s label with genetic-testing information; and notes that an FDA-approved genetic test is available to determine which patients carry the gene variations. In August, the FDA had pharmas update warfarin’s label to say that people with variations in the CYP2C9 and VKORC1 genes may respond differently to the drug. The agency, however, stopped short of including stronger language in the label that would require physicians to genetically test patients, noting the need for additional outcomes studies [see PGx Reporter 9-5-2007]. The brochure states that while genotyping patients for the CYP2C9 and VKORC1 variants may account for between 45 percent and 60 percent of the variation in their response to warfarin, “a large part of the variation is still unknown.” For this reason, genotyping patients should not be thought of as a panacea for warfarin’s dose variability between patients. “’Is genetic testing ready to replace what we’re doing today?’ That’s never been the question,” noted Raymond Woosley, president of the Critical Path Institute. “The question is, ‘Can genetic testing provide important, additional information?’” “It’s just another very important piece of information that for some people can be life saving. And for others it won’t be as important,” he added. Several academic and government institutions, including the University of Washington in Seattle, the University of Utah, the FDA in partnership with the principal investigators of the Harvard Creating an Optimal Warfarin Nomogram Trial, and the Warfarin Pharmacogenomics Consortium, are working to develop their own PGx-based dosing algorithm for warfarin. Additionally, as reported in Pharmacogenomics Reporter’s sister publication BioInform, PGx Labs is developing a decision support system that combines a patient’s clinical and genotype information to determine the most appropriate maintenance dose for warfarin for a given patient. While the AMA/Critical Path’s brochure doesn’t suggest a particular algorithm to dose warfarin, it does point physicians to visit www.warfarindosing.org, a website to help doctors initiate patients on warfarin therapy based on clinical factors and genotypes of the CYP2C9 and VKORC1 genes. The recommendations on warfarindosing.org are based on data from more than 1,000 patients. Doctors enter patient information into the free site and immediately receive an initial estimate of a therapeutic dose that “explains 53 percent of the variability in a warfarin dose,” according to information on the site. “If you return to the website and enter an INR value after 3 and/or 4 warfarin doses, the dose refinement is even more accurate.” Woosley noted that the Critical Path and the AMA plan to issue a second brochure on warfarin that will concentrate on dosing, drug interactions, or both. However, he noted that recommending “good dosing guidelines” for warfarin is challenging because there are so many clinical factors that can alter the dose from patient to patient. The Critical Path Institute “and the FDA have gone back and forth on this,” Woosley said. “When you come right down to it, you can’t really give good dosing guidelines on warfarin.” According to Woosley, even the distance a patient lives from the clinic factors into the dosing regimen. “For instance, if you’re seeing a patient who lives 20 miles from the clinic, and someone else lives one mile from the clinic, you may give them a different dose and a different regimen when they come back for INR,” he said. “You have to weigh in age and body weight. … If you don’t have any nurses or pharmacists to help the patient, and it’s just the doctor writing a prescription, it would be good if they weigh in the genetic information, but how much they weigh it in depends on how many resources they have to manage the patient. “Every case is so different,” said Woosley. “It’s truly personalized medicine.” Reimbursement Reservations Meanwhile, although there have been numerous published studies and two FDA-approved genetic tests to gauge warfarin sensitivity [see PGx Reporter 01-30-2008], insurers remain uncertain about whether to reimburse for genetic tests designed to help doctors dose the commonly prescribed anticoagulant. Recently, when a controversial PGx warfarin study, called Couma-Gen, by Anderson et al., failed to meet its endpoint, some payors interpreted it as a negative mark against genotyping to dose warfarin. However, in the latest issue of Personalized Medicine, Lawrence Lesko, director of FDA’s Office of Pharmacology, and Brian Gage, associate professor of medicine at Washington University and the creator of warfarindosing.org, published an evaluation of Couma-Gen and how the study might improve the design of future PGx warfarin studies (see related article, this issue). “Numerous studies have confirmed that a significant proportion of the variability in individual dose requirements and anticoagulation response to warfarin can be linked causally to polymorphisms in VKORC1 and CYP2C9,” Lesko and Gage wrote in the article, entitled “Couma-Gen: implications for future randomized trials of pharmacogenetic-based warfarin therapy.” Woosley added: “Those who … are deciding whether they are going to pay for something really need to start thinking about patients. Really, the science is overwhelming.” On the heels of his recent $9 million gift to the School of Pharmacy at the University of North Carolina at Chapel Hill, Fred Eshelman has contributed another $1 million to support the School's Educational Renaissance initiatives, which attracted $1 million in matching funds from the Pharmacy Network Foundation. Eshelman is CEO and founder of Wilmington-based PPD Inc., a leading global contract research organization providing discovery, development and postapproval services as well as compound partnering programs to the biopharmaceutical industry. The Educational Renaissance is the School's plan to address the needs of the next generation of students who are expected to learn very differently from the students of the past, said Bob Blouin, PharmD, dean of the School of Pharmacy. "We're on the brink of falling into a generation gap between educators and learners," Blouin said. "Children who grew up in the '90s have never known life without the World Wide Web and the instant access to information that it affords. They are going to thrive in an educational environment that mirrors that access." Gary Pollack, PhD, the School's executive associate dean, is leading the group working to develop and implement the principles and technology behind the School's educational initiatives. Pollack has been teaching at the School for more than 20 years and is the recipient of a number of its teaching awards. "The students we will be teaching in the very near future are used to finding information on their own," Pollack said. "They find it more interesting and stimulating to seek out the information rather than wait for someone to give it to them. They are increasingly intolerant of a traditional lecture." The Educational Renaissance will move the knowledge transfer aspect of education - such as a traditional lecture - out of the classroom and put it online. Students would come to class fully prepared to learn to apply that knowledge, which is the key to developing the critical thinking skills so important to a pharmacist, Pollack said. In January Eshelman pledged $9 million to support cancer research at the School of Pharmacy. He made a $20 million gift to the school in 2003. He said that he made his most recent gift to help the School of Pharmacy reach its potential. "The UNC School of Pharmacy has the opportunity to be the leading pharmacy school in the nation," Eshelman said. "The ideas behind the Educational Renaissance promise to revolutionize pharmacy education, and I felt it was important for the School to be able to move quickly to implement them." The gift was matched by the Pharmacy Network Foundation, which works to promote and enhance pharmacy service in order to improve the health and welfare of the general population. "The Foundation's board is happy to support the development of the School of Pharmacy's Educational Renaissance," said Mitchell Watts, chairman of foundation's board of directors. "We believe this program will offer students the best educational tool yet developed for modern-day learning. This translates into having the most qualified pharmacists to serve the health-care needs of North Carolina. " Dr. Howard McLeod is a Fred N. Eshelman Distinguished Professor and Director of the UNC Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina Chapel Hill School of Pharmacy. He received his Doctor of Pharmacy from Philadelphia College of Pharmacy and Science and went on to complete research fellowship training in cancer pharmacology at St. Jude Children's Research Hospital in Memphis and at the University of Glasgow in Scotland. Dr. McLeod is an internationally recognized expert in the pharmacogenomic analysis of cancer therapeutics and is a member of the FDA Subcommittee on Clinical Pharmacology. download audio in a new window http://www.patientpower.info/audio/hrn/PatientPower_hrn012807.mp3 On May 19, Sharon Terry, MA, president and CEO of Genetic Alliance, was honored with the Institute for Pharmacogenomics and Individualized Therapy (IPIT) at the University of North Carolina at Chapel Hill Award for Patient Service. This award is given to an individual who has made significant contributions to empowering patients and who champion a focus on patient in the advancement of individualized therapy. "The completion of the Human Genome Project brought the promise of new tools for choosing the safest and most beneficial medicines for patients," said Howard McLeod, director of the UNC institute. "But realizing these tools requires great dedication and leadership by experts from diverse areas of health sciences, leaders such as Sharon Terry." "Scientific discovery does not automatically become clinically useful," McLeod said. "It takes extraordinary effort to convert an idea into better patient care." "I am immensely honored to be given this first patient award. The UNC Institute for Pharmacogenomics and Individualized Therapy is sharply focused on the patient, bringing together researchers and clinicians across the University to create personalized therapies. Like us, they ask, what matters for the patient? Everything they do is through that lens. I am proud to stand as an award recipient with these dedicated professionals." Sharon Terry receiving the Award for Patient Service at the University of North Carolina at Chapel Hill Sharon Terry receiving the Award for Patient Service at the University of North Carolina at Chapel Hill . Also honored were: Janet Woodcock, MD, chief medical officer of the Food and Drug Administration, was named the recipient of the IPIT Award for Clinical Service. Her award honors a person who has made significant direct contributions to the advancement of individualized therapy in clinical practice. Larry Lesko, PhD, director of the FDA Office of Clinical Pharmacology and Biopharmaceutics, received the IPIT Award for Public Service. His award honors a person who has made a significant impact on the advancement of individualized therapy across society. Howard McLeod has a passion to reduce the amount of drug-related deaths in the United States. "Adverse drug reactions are the fifth-leading cause of death in the United States," said McLeod, the director of the new Institute for Pharmacogenomics and Individualized Therapy at the School of Pharmacy. "It's really inexcusable that we have so many people dying." McLeod's desire to alter this trend was one of the main factors in the decision to bring his talents, and his grant money, to UNC. McLeod previously was a professor at Washington University in St. Louis before coming to UNC. He brought with him a $10 million grant he earned from the National Institutes of Health during his tenure at Washington, which will be used to fund startup operations at the new center. A new facility - to be located at the Genetics Medical Building on Mason Farm Road - will house that program, which officials say will endeavor to find new ways to better tailor medicines to its individual recipients. The institute will consist of an interdisciplinary team from UNC's schools of pharmacy, medicine and public health, as well as the Lineberger Cancer Center. Research in this area is important, McLeod said, because of the immense amount of options Americans have when it comes to drug choices. "We now have some very difficult choices to make, and we need tools to do that," he said. "Even our rich country can't afford to give them to everybody." The institute, the first of its kind to take such a broad look at the issue, will address the scientific problems and the legal and logistical issues involved with individualizing medicine to remove the different obstacles that get in the way of this progress. "We looked at the main bottlenecks to getting individualized therapy," McLeod said. "We put the institute together to change them." As part of the institute's legal pursuit of more tailored pharmaceuticals, its leaders will work with the offices of U.S. Sens. Richard Burr, R-N.C., and Barack Obama, D-Ill., to draft legislation promoting this practice. "The idea of putting together individualized therapy legislation is one thing, making sure it's going to help people is another," McLeod said, adding that it was for that reason Obama came to him for help with the initiative. McLeod added that the key to removing these bottlenecks is to work with multiple disciplines. "The key thing about individualized therapy is that it can't be done by any one discipline," McLeod said. Because of UNC's strength in a variety of disciplines for this research including business, law, public health and information science, McLeod said the University is a great place to carry the program out. "You have to go to a place that has all of those elements," he said. "It's going to be places like UNC that have all the elements at a very high level." http://www.newsobserver.com/104/story/563207.html Researchers at UNC Lineberger are advancing beyond onesize-fits-all treatments for cancer to prescribe personalized therapies based on each patient's genetics. "The big clinical need we're trying to serve is which of the many cancer drugs is right for each patient, and how we can avoid the unacceptable level of side affects," explains Lineberger member Howard McLeod, Fred N. Eshelman Distinguished Professor in the UNC School of Pharmacy. Pharmacogenomics, the study of inherited DNA variations, enables clinicians to design treatments that are more effective, have fewer adverse effects and stand to improve patient outcomes. "Differences in our genetic makeup can affect how individuals metabolize and respond to drugs, including cancer therapy," says Karen Weck, associate professor of pathology and laboratory medicine, and director of molecular genetics in UNC Hospitals’ McLendon Laboratories. Her work includes developing and validating clinical tests that can be used to target the right therapy for individual patients based on a patient's genotype. "The hope," she says, "is that personalized diagnostics and therapies will result in better response to cancer therapies and less toxicity." Two centers at UNC are exploring the link between genetics and drug therapies: The UNC Institute for Pharmacogenomics and Individualized Therapy (IPIT): McLeod runs this new research institute that is the first of its kind in the nation. IPIT will work to create effective therapies and precise treatment options for individual patients diagnosed with a wide range of conditions. Faculty and staff from the Schools of Pharmacy, Medicine, Public Health, Nursing and College of Arts & Sciences are actively involved, with planned integration of investigators from the Schools of Business, Law and Journalism. The goal is to use the multidisciplinary nature of the institute to more efficiently bring individualized therapy to routine clinical practice. Initial efforts will focus on cancer therapy with planned expansion into cardiovascular disease, psychiatric disorders and global health. The Bryson Center for Human Genetics: James Evans, director of clinical cancer genetics and a Lineberger member, heads this center which integrates basic science investigation with clinical care. Part of this effort is a campus-wide "Phenotyping Core" that collects DNA samples and clinical information from a broad array of investigators in order to gain maximum amounts of information from genetic studies; to facilitate such studies; and to protect subjects of research. Identifying Markers A deeper understanding of the human genome allows scientists to better predict a person's response to a particular drug or dosage. "If all we had was one drug, all that would matter was the dosage," McLeod notes. "But now with so many kinds of drugs available, there's a real choice to make about what drug and what dose. One-size-fits-all is better than nothing and has helped a lot of people, but as we refine the choices, you want the first therapy to be the right one." McLeod is currently working with several large national clinical trials groups-such as Cancer and Leukemia Group B (CALGB) to confirm that findings from small institutional studies will actually translate into better therapy across the nation. Most large CALGB studies now collect a specific blood sample for DNA analysis as part of the trial. CALGB is a program of the National Cancer Institute. "Right now, we're working hard to answer whether a marker is a good predictor," he says. "We're working with an NCI-funded clinical trials group, so instead of being able to look at only 50 patients from North Carolina, for instance, we can look at 1,500 patients from across North America to find out if a marker really does predict the risk of side-effect or bad outcome -- or not." In some cases, the Food and Drug Administration will change drug package inserts to identify patient groups that are genetically predisposed to experience severe side effects or inadequate benefit. McLeod and his team have successfully pushed for changes in packaging for drugs used to treat advanced colorectal cancer (Irinotecan), solid tumors (5-FU) and childhood leukemias (thiopurines such as mercaptopurine). From the Lab to the Patient Findings such as this can help physicians make better treatment decisions for their patients. After all, there are more than 70 FDA-approved drugs that might be useful for a particular tumor, so anything that helps narrow down the choices to a handful of very effective options is a significant improvement. For instance, later this year Evans, Weck and members of the Lineberger Breast Cancer Program will undertake a study of how breast cancer patients respond to Tamoxifen. Most breast cancer development is dependent on estrogen, and Tamoxifen blocks the estrogen receptor that allows the hormone to work. Women who have a genetic variant in the enzyme that converts Tamoxifen into its active form may not respond as well to the drug. "If we can identify women who aren't responding well to the treatment," Evans says, "we can adjust their treatment and achieve better outcomes." Extended Benefits Genetics also help researchers understand how someone might respond to all kinds of medicine, not solely chemotherapy regimens, McLeod adds. "We need to do a better job at matching patients with the right pain meds, anti-nausea meds and drugs that stimulate red or white blood cells. Personalized medicine lets us looks at patients and their treatments in a more comprehensive way." And these more effective treatments have benefits beyond the health care realm. There's also an economic benefit. "In many cases right now, we have to treat all patients with expensive drugs to find out which 10 percent of patients actually benefit from the treatment," McLeod explains. "Or, with very expensive drugs, the access is limited. Knowing more about who will respond well to what will help us prescribe the expensive treatments only to the people who will actually benefit from them. That will create a decrease in costs to the state as we choose better. Being more rational means we can be more responsible to taxpayers." The Bottom Line Our increasing knowledge of the human genome will have a far-reaching positive impact on medicine as scientists learn - and apply - more of what they know. "Medicine as we've practiced it has been inefficient because we didn't treat individuals," Evans says. "We're entering a new era of medicine where we can treat people as individuals and not just their diseases. It's our hope that through the application of this knowledge and technology, we'll be able to treat better, prevent better and avoid adverse reactions. We can stop using the same screening and treatments for all and start improving the quality and effectiveness of care while lowering the cost and of treatment." CHAPEL HILL — Todd Auman, Ph.D., has joined the Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina at Chapel Hill as a member of its research team... “We wouldn't buy a car based solely on the outward appearance, neither should we select therapy without a more thorough understanding of the probability of receiving benefit.” Oncology Issues recently interviewed Howard McLeod, PharmD, about Genzyme’s in-vitro diagnostic test that helps identify patients with a greater risk for irinotecan toxicity. McLeod, who is Fred N. Eshelman Distinguished Professor and director of the UNC Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina, Chapel Hill, N.C., and Lineberger Cancer Center, had this to say about the FDA-approved genetic test. Q. How does the UGT1A1 genetic test work? What is the test’s significance in terms of identifying risk of irinotecan toxicity in colorectal cancer patients? A. Unfortunately most anticancer drugs are associated with some type of adverse event. These events are usually unpredictable and undesirable and interfere with the therapeutic intent of the treatment. Irinotecan is certainly a drug that has those features. We have been able to manage some of irinotecan’s side effects, such as acute diarrhea, through changing the drug infusion or through the use of other medications, such as Lomotil. Other aspects of irinotecan have been difficult to predict. Neutropenia, for example, is a common blood disorder that occurs in many patients undergoing chemotherapy. While this condition is not a big deal for many individuals, patients with more severe neutropenia can require hospitalization and run the risk of sepsis. Early in the development of irinotecan, researchers observed that the active metabolite of the drug, SN-38, was cleared from the body through a process called glucuronidation. A gene called UGT1A1 was responsible for sticking that glucoronide group onto the drug. Once glucoronide was on a compound, it was easily excreted by the bile. So, for example, bilirubin and a number of estrogen molecules in the body are glucuronidated. Irinotecan is one of several anticancer drugs that also undergo this process. Researchers found that a subset of the population, about 10 percent, have a genetic change in the UGT1A1 gene that hinders their ability to perform this glucuronidation process. This change does not have an apparent phenotype; it is not something that can be detected by the usual bilirubin test or by some outward manifestation of the patient. However, when patients with the genetic change in UGT1A1, called UGT1A1*28, receive a standard dose of irinotecan, they have a very high risk of severe, or in some cases fatal, neutropenia. In late 2004, the U.S. Food and Drug Administration (FDA) reviewed the data on UGT1A1*28 and decided that this genetic change should be included in the FDA packet insert for irinotecan as a risk factor for severe toxicity to the drug alongside the other standard risk factors: pelvic irradiation, performance status of 2 or greater, and age greater than 70 years. Thus, UGT1A1*28 is one of the first examples of genetics identifying a patient population that would be predisposed to a risk of toxicity. Q. What is the current status of the UGT1A1 test? Is the test available for use in the community care setting? A. The package insert for irinotecan was changed in June 2005, and the FDA-approved UG1A1 test was released in August 2005, by Third Wave Technologies. Today, the UGT1A1 test is widely available from most reference labs, including Genzyme, Quest Diagostics, and LabCorp, as well as several local labs. Many hospitals and major medical centers are offering UGT1A1 testing; the genetic test often takes a day or two to get the results. Q. What does the test cost? Is the cost covered by insurance? A. The test costs about $250, depending on the particular laboratory’s overhead. The test is currently covered by most public and private insurers because it is an FDA identified risk factor. Q. Should every patient with colorectal cancer be offered this test? A. I can offer you my opinion based on the literature. In November 2004, the FDA considered the dosing of irinotecan as part of its deliberations. At that time the FDA-approved dose of irinotecan was 300-350mg/m2 every 28 days. Today many people are receiving several lower regimens, 180-200mg/m2 every 2 weeks or 100 -125mg/m2 weekly for four out of six weeks, and other regimens as well. Since November 2004, the literature has grown. Data are now available on a number of different dose levels, including studies that were presented at the June 2006 ASCO meeting.1 Looking across the spectrum of data— ranging from extremely low doses at 20mg/m2 all the way up to 350mg/m2 over different regimens—here’s what I recommend to my clinical colleagues when asked: * For patients receiving single agent irinotecan or irinotecan combined with a nonmyelotoxic drug, for example irinotecan plus cetuximab, if the patient is getting a dose greater than 150mg/m2, the UGT1A1 test is useful for identifying patients at risk for severe neutropenia. * For patients receiving a combination of irinotecan with another marrow-toxic agent, for example irinotecan plus oxaliplatin (the IROX regimen), then I suggest using 100 mg/m2 as the threshold for when testing would be useful. My opinion is based on about 10 literature publications to date over a range of dosing regimens that seem to define a conservative but useful threshold for testing. * For patients receiving doses below those levels, the relative impact of UGT1A1 appears to be very small. So, even though patients with the UGT1A1 genetic variant—the so-called 7/7 genotype or *28—might have an increased risk, it is neither statistically nor clinically signficant. It is also my opinion that we will never have clear data (e.g., prospectively designed randomized trial data) to tell practitioners exactly when testing should and should not be conducted. Simply put: there is not enough desire in the clinical community nor is there enough funding through either the National Institutes of Health or any other interested body to conduct studies to de ne exactly the right dosing based on genotype for this drug. That being said, prospective studies are being conducted to try and help. The CALGB cooperative group has a study gearing up in which different doses of irinotecan will be given based on UGT1A1 genotype. When completed, this study data should offer some guidance for practitioners. But the real level of evidence that most clinicians would like to know, that is, exactly when and when not to use this test, in my mind, will never be produced. This situation is unfortunate and less than ideal, but it is reality. Q. Is there any downside to offering a patient this test? A. The UGT1A1 test was designed to avoid toxicity, so we don’t really know whether the test has a downside. One theoretical downside exists: too much of a dose reduction, while it certainly could mean that the dose is safe, may also mean that the dose is no longer as effective. And this theoretical scenario is the main concern of practitioners. For clinicians at community cancer centers, the balance of trying to make the drug safe for patients yet still effective can be tricky. The decision comes down to a true risk/benefit analysis. Right now, data are available on the risk side, but not a great deal of data can be found on the benefit side. Data from the N9741 clinical trial and some of the other trials suggest that when practitioners dose reduce for other reasons, they do not see a big diminishing in the drug’s effectiveness. (In the N9741 trial, irinotecan was dose reduced because of an observed high mortality rate in the first 60 days of therapy. And the paper that was recently published in the Journal of Clinical Oncology clearly showed that that dose reduction did not result in an inferior outcome. Because there currently is not, and may never be, clear data to measure the effect of dose reduction on outcome, practitioners should discuss with their patient what level of side effect risk he or she is willing to assume. For patientswhowant full-press therapy, regardless of toxicity risk, genotyping does not really serve a purpose. If, however, a patient is on the fence about the issue, testing might be quite useful. Additionally, if a patient wants therapy that has low toxicity risk regardless of the ef cacy, testing might be useful to dial in a therapy with a low risk of toxicity. Certainly, patients in all of those categories are routinely seen in the clinic setting. Q. For community-based clinicians, is there a particular learning curve for working with the UGT1A1 test or with the test results? A. In my mind this test is very similar tomany other tests that are used in oncology care today. If a patient has poor renal function and a clinician wants to give a drug that is excreted by the kidneys, then the practitioner either knows what to do or looks up what to do. Genetic testing for side effects is similar in nature. The decision is not a case of choosing to treat or not to treat with irinotecan. If a practitioner has selected irinotecan as the right drug for a patient, he or she is not going to change that choice based on UGT1A1 genotype. The practitioner may, however, change the dose or the particular regimen based on the genetic test. In my opinion, the community-based oncologist with a busy clinical practice is not going to have to become a molecular biologist or a genetics counselor. Instead he or she will have to know how to respond to the results of genetic tests. And practitioners will respond the same way they have responded to most of the other lab results they order. Just as with patients with low white counts and patients with low kidney functions, the clinician will gather the information that a patient has a UGT1A1 mutation and factor it into the patient’s treatment algorithm. Q. How has the status of the UGT1A1 test changed since your 2004 editorial in the Journal of Clinical Oncology? Is there any new evidence in terms of the test retaining its predictive power when irinotecan is administered as part of combination therapy? A. I want to highlight several points. First, the data for the test being associated with severe diarrhea have really come out in favor of a lack of prediction for that particular endpoint. So, severe diarrhea does not appear to be predicted in most patients by this test. The data for irinotecan and neutropenia have expanded, however. Data can now be put together from different dose levels and used to come up with some guidelines for when testing is going to most useful and when it appears to be of less value. Another point that I want to emphasize is that many clinicians may suggest simply measuring bilirubin. If a practitioner is ordering fasting bilirubin (where the patient fasts and then takes the bilirubin challenge assessment), the data for UGT1A1 function is fairly reasonably defined and, in some cases, might even be more useful than genotype because it’s a functional readout. Fasting bilirubin is rarely done in routine practice, however, and most clinicians do not plan for a long enough visit to do fasting bilirubin. The standard bilirubin test that is typically ordered has been shown now in several trials not to be a useful predictor of irinotecan toxicity. While I would support a functional analysis over a genetic analysis, a bilirubin test, in the way clinicians typically order the test, does not meet that criteria. Bottom line: even though some clinicians may want to forgo to genotype and use the standard bilirubin test, a more high-powered test (fasting bilirubin or the UGT1A1 test) is the better choice. Q. When in the treatment process would the UGT1A1 test be offered? A. The test is most useful in a patient-centered orientation. Clinicians should first decide if irinotecan is the best drug for the patient and then talk to the patient about the level of side effect risk he or she is willing to endure. If, as mentioned previously, a patient wants aggressive therapy, and he or she is willing to endure whatever side effects may occur, practitioners probably don’t need to order the test. In patients who are a little more nuanced, the test may help tailor a specific regimen based on the patients’ level of toxicity tolerance. Additionally, for oncologists that prescribe only one regimen of irinotecan and for patients receiving doses less than 150mg/m2 as a single agent, the test is probably not going to be all that valuable. On the other hand, if a practitioner is using several different regimens, depending on the patient’s wishes, the test could be quite useful. Q. Does the data on UGT1A1 testing apply only to colorectal cancer? A. To date, data are primarily from colon cancer and non-small cell lung cancer and suggest that the dosing guidance that I mentioned earlier are relevant regardless of the tumor type. It's really a patient bone marrow issue as opposed to a tumor type issue. Q. In conclusion, what's your take home message on UGT1A1 testing for the community-based program? Almost everything in life is a gene/environment interaction. Genetics is most important when there is lots of environment—in this case, when there’s a large dose of an anticancer drug. With UGT1A1 testing, clinicians should think beyond "testing" or "not testing" in patients and focus in on the drug dose and which dose is most appropriate for each patient. |
To view an article, simply click on the title.
To download an article's associated file, simply click on the icon in the right corner of the article.
To minimize an article, either click on the title again or click on the "collapse article" link at the bottom of an article.