F  5184Significant advances in diagnostics


       Genetic testing is opening up new possibilities for diagnosis and treatment, particularly in oncology. Along with new options for procedures and technology, however, come challenges. In this article, industry experts discuss obstacles and successes.

       The use of genetic testing for cancer represents a major advance in diagnosing and treating the disease. But like any new technology, it presents questions and challenges.
       According to Muin J. Khoury, MD, PhD, founding director, Office of Public Health Genomics, Centers for Disease Control and Prevention (CDC), one such challenge is that, like other newer technologies, the use of genetic testing has implications when it comes to effective and responsible use for achieving the maximum public health impact.
 KhouryMuin J. Khoury, MD, PhD      This entails what some might call “ethical questions,” such as whether or not the new technology’s benefits outweigh any potential harm, he says. “While we do a lot of studies around discoveries, we do fewer studies to assess whether or not a new technology will lead to improved health outcomes, or to overdiagnoses, or unrealistically raised expectations on the part of patients,” Khoury says.
      And there is also the issue of implementation, he adds. For the CDC, that means having enough evidence that the new technology can improve the public health. “It’s a major public health challenge to disseminate information and interventions to all patients who will benefit from this new technology,” Khoury says.
       Having said that, Khoury acknowledges that the use of DNA testing to find and diagnose many kinds of diseases is in a rapid-growth stage. DNA testing is available for more than 2,000 health conditions, and this number continues to expand. The use of whole-genome sequencing for even more diseases should only increase, he says.
       Oncology is leading the way. Since 2009, 521 new genomic tests have been developed for various diseases—and two-thirds are cancer-related, more than for any other disease, Khoury says, citing statistics from the Genomic Applications in Practice and Prevention Knowledge Base, a CDC database that tracks the emerging scope of genomic testing. Cancer is the predominant area for genetic testing.
       Genetic testing for cancer can measure, among other things, the gene expression of tumors, and can determine the risk of occurrence and, thus, what type of therapy may be indicated. This development is also being explored for other areas such as detection of infectious diseases such as influenza, Khoury says.
       Along with the success and wider use of genomic testing have come challenges. Khoury says there are not enough trained laboratory and health care practitioners to keep up with the testing’s increased usage. “Many are still inadequately prepared, and aren’t trained in the many nuances between different kinds of genetic tests and their interpretation,” he says. “The science is so rapidly moving and has only been in existence for about 20 years, so labs need a new pipeline of trained technicians. In addition, with over 500 new tests developed in the last few years, most techs don’t have enough evidence yet in order to make informed decisions on whether to use the tests in practice or not.
       “The technology is moving much more rapidly than evidence for its utility and workforce, and consumer education is not keeping up,” Khoury adds.
       And there’s another pitfall: that of raised expectations for genetic testing among the public, especially in the area of oncology, which is fueled by the media, he says. “It’s been too hyped up and can’t possibly keep pace with predictions,” Khoury says. “Studies will take time, and a clearer picture will emerge in the long term.”

  F  5069Tanya Quint, senior research associate II, loads one of the instruments used to run the Exact Sciences colorectal cancer screening test.      BRCA testing is now considered a preventive service under the Affordable Care Act. Women who have no symptoms of breast cancer, but have a family history of the disease, may even be able to receive BRCA testing for free if they maintain the type of health insurance coverage spelled out in the law.
“We view the clarification of BRACAnalysis as a preventive service as an important win for patients,” says Pete Meldrum, president and CEO, Myriad Genetics Inc, Salt Lake City. “This designation ensures that women at high risk for hereditary cancer can now have access to the life-saving information provided by BRACAnalysis without worrying about out-of-pocket costs.”
       A blood test from Myriad Genetics can help determine a woman’s risk of developing breast cancer, as well as help physicians and their patients choose the right treatment options and measure the risk of the cancer’s advance or return for women who develop the disease.
       Risk factors for hereditary breast cancer mutations in the BRCA1 and BRCA2 genes are found using the company’s BRACAnalysis® sequencing test. Mutations in these genes cause most cases of inherited breast cancer—women who harbor just one of these mutations face an 87% chance of being diagnosed with breast cancer by the time they are 70, according to the company. The broader process of calculating a woman’s risk factors includes compiling an in-depth personal and family history.
 F  5172Theran Myers, senior director, Exact Sciences’ clinical lab, running one of the multiplex assays that is a part of the company’s colorectal cancer screening test.       The company offers myriad other cancer detection tests that help assess hereditary risk factors, including COLARIS, which evaluates a patient’s risk for colorectal cancer and a woman’s risks for uterine cancer; COLARISAP, which finds gene mutations that cause adenomatous polyposis colon cancer syndromes; MELARIS, which determines risks for melanoma; PANEXIA, which tests for pancreatic cancer risk; and Prolaris, which tests for prostate cancer. The OnDose test helps physicians make treatment decisions for patients who have colorectal cancer; TheraGuide 5-FU helps physicians tailor chemotherapy to best battle a patient’s cancer and limit debilitating side effects; and PREZEON evaluates a gene (PTEN) that triggers fierce cancer progression and proliferation. The BRACAnalysis Large Rearrangement Test (BART), which helps find substantial genomic rearrangements in BRCA1 and BRCA2 that are not found in the BRACAnalysis test, can be included with the BRACAnalysis for no extra change if patients meet certain criteria.
       The company also plans to introduce new tests for lung cancer and melanoma this year. The lung cancer test will fill a void in helping to guide the use of postsurgical chemotherapy, and the melanoma test will be a tool in diagnosing skin biopsies that do not yield definitive results through pathology testing. Another new test, in the long-term pipeline, aims to single-handedly take the place of BRCA and COLARIS, and would feature added driver mutations.

 Oncology BergerBarry Berger, MD, FCAP      Cancer of the colon or rectum is highly treatable when discovered early, says Barry Berger, MD, FCAP, chief medical officer and senior vice president of medical affairs, Exact Sciences, Madison, Wis. Since precancerous polyps may take 10 years to transform from benign to malignant, screening and early detection are keys to survival.
       The company completed patient enrollment in its DeeP-C pivotal trial for its stool-based DNA colorectal cancer screening test in November 2012. Results of this pivotal study of more than 10,000 patients at 90 sites in the United States and Canada are expected to form the basis for submitting the noninvasive test application for possible FDA approval. While Exact Sciences’ DNA test is an investigational device and is not available for sale in the United States, the company plans to complete its PMA submission to the FDA in the second quarter of 2013.
       “We are the first company to participate in the new parallel review process with the FDA and CMS (Centers for Medicare and Medicaid Services),” Berger says. “Both agencies will be reviewing our submissions and data at the same time.”
       More than 80 million Americans are at average risk for colorectal cancer and eligible for screening. That number is expected to grow to 100 million by 2020. In the United States, the market potential is greater than $2 billion.
       The American Cancer Society recommends that all Americans age 50 and older be regularly screened for colorectal cancer, but unfortunately, only about half of this population has been screened, according to the guidelines using the currently available methods. The American College of Gastroenterology includes sDNA in its guidelines and has recommended an interval of 3 years.
       Testing for colorectal cancer by use of a colonoscopy is recommended for those between 50 and 75 years of age. After age 75, it is thought to be less desirable because of its invasiveness. However, with the Exact Sciences assay, the need for an invasive procedure factor is avoided. Patients can simply collect a stool sample at home, pour a buffer solution onto it, and then mail the container to a lab for processing.
Stool-based DNA (sDNA) testing is designed to detect altered human DNA associated with colorectal cancer in a person’s stool. If the test result is negative, the patient returns to the screening pool until it is time to be screened again. However, if the test is positive, a diagnostic colonoscopy will be recommended for follow-up.
GrahamGraham Lidgard, PhD       Enrollment in DeeP-C has been completed, and the topline study data comparing the test to a FIT (fecal occult blood test) using colonoscopy as a reference method will be available soon. The company recently presented results of a 1,003-patient, case-control study at a meeting of the American Association for Cancer Research and included patients at 36 study centers. Among the study population, there were 93 cases of colorectal cancer, 114 cases of advanced precancers, and 796 controls. At a nominal specificity of 90%, the test detected 98% of colorectal cancers and 83% of precancers with high-grade dysplasia, the majority of which progress to cancer. The test demonstrated 57% sensitivity in the detection of advanced precancers equal to or larger than 1 centimeter. The test’s sensitivity increased with the size of the precancers, rising to 83% for precancers larger than 3 centimeters.
       “The use of DNA analysis in the field of colorectal cancer in general is increasing,” says Graham Lidgard, PhD, senior vice president of research and development and chief science officer, Exact Sciences. “It has become increasingly possible to predict response to certain cancer treatments using genetic information from the cancer tissue. This allows therapies to be targeted to the patients where they will be the most  effective.”
       The company’s test identifies mutations in the KRAS gene and aberrant methylation in two other genes, biomarkers that have been shown to be associated with colorectal cancer and premalignant lesions. “Compared to normal colorectal epithelial cells, this pattern of methylation is aberrant, and we can use that finding to help identify patients with colorectal neoplasia who need additional diagnostic investigation,” Lidgard says.
       While genetic testing today is still more the province of cancer centers and large labs, Lidgard says, in the next 5 years he expects the process will be entering more routine labs. Lidgard notes that genetic testing based on sequencing has actually been routine for a long time, but was a manual process that is increasingly becoming automated.

      The Pathwork® Tissue of Origin Test from Pathwork Diagnostics, Menlo Park, Calif, was the subject of a recent study using a third-party payor perspective.
      With increasing emphasis on providing optimal care for patients while holding down health care costs—and beset by technological obstacles in pinpointing the primary site for challenging tumors—the study found this gene-profiling test to be a cost-effective diagnostic option.
      Used for patients who have difficult-to-diagnose cancers—such as tumors found in several locations, or those that are poorly differentiated or undifferentiated—this molecular test uses tumor genomic information to help pathologists and oncologists determine the tumor of origin.
      The study, titled “Cost-Effectiveness of Gene-Expression Profiling for Tumor-Site Origin,” published in Value in Health, the journal of the International Society for Pharmacoeconomics and Outcomes Research, was conducted by Cedar Associates, Stanford University, University of Texas MD Anderson Cancer Center, Memorial University of Newfoundland, and the University of Washington.
      The researchers found that the test “significantly altered clinical practice patterns and is projected to increase overall survival, quality-adjusted life-years, and costs, resulting in an expected cost per quality-adjusted life-year of less than $50,000.”
The company says the test could potentially affect more than 4% of new cancer cases.

Gary Tufel is a contributing writer for CLP. For more information, contact Editor Judy O’Rourke, [email protected]


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