Half of the people tested were unaware of their genetic risk for contracting the disease
Existing clinical laboratory genetic screening guidelines may be inadequate when it comes to finding people at risk of hereditary breast-ovarian cancer syndromes and Lynch syndrome (aka, hereditary nonpolyposis colorectal cancer). That’s according to a study conducted at the Mayo Clinic in Rochester, Minn., which found that about half of the study participants were unaware of their genetic predisposition to the diseases.
Mayo found that 550 people who participated in the study (1.24%) were “carriers of the hereditary mutations.” The researchers also determined that half of those people were unaware they had a genetic risk of cancer, and 40% did not meet genetic testing guidelines, according to a Mayo Clinic news story.
The discoveries were made following exome sequencing, which the Mayo Clinic news story described as the “protein-coding regions of genes” and the sites for most disease-causing mutations.
“Early detection of genetic markers for these conditions can lead to proactive screenings and targeted therapies, potentially saving lives of people and their family members,” said lead author Niloy Jewel Samadder, MD, gastroenterologist and cancer geneticist at Mayo Clinic’s Center for Individualized Medicine and Comprehensive Cancer Center.
“This study is a wake-up call, showing us that current national guidelines for genetic screenings are missing too many people at high risk of cancer,” said lead author Niloy Jewel Samadder, MD (above), gastroenterologist and cancer geneticist at Mayo Clinic’s Center for Individualized Medicine and Comprehensive Cancer Center. New screening guidelines may increase the role of clinical laboratories in helping physicians identify patients at risk of certain hereditary cancers. (Photo copyright: Mayo Clinic.)
Advancing Personalized Medicine
“The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC (hereditary breast and ovarian cancer) and LS (Lynch syndrome),” the authors wrote in JCO Precision Oncology.
For the current study, Helix, a San Mateo, Calif. population genomics company, collaborated with Mayo Clinic to perform exome sequencing on the following genes:
BRCA1 and BRCA2 genes (hereditary breast and ovarian cancer).
Mayo/Helix researchers performed genetic screenings on more than 44,000 study participants. According to their published study, of the 550 people who were found to have hereditary breast cancer or Lynch syndrome:
387 had hereditary breast and ovarian cancer (27.2% BRCA1, 42.8% BRCA2).
163 had lynch syndrome (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM).
Participants recruited by researchers hailed from Rochester, Minn.; Phoenix, Ariz.; and Jacksonville, Fla.
Minorities were less likely to meet the NCCN criteria than those who reported as White (51.5% as compared to 37.5%).
“Our results emphasize the importance of expanding genetic screening to identify people at risk for these cancer predisposition syndromes,” Samadder said.
Exome Data in EHRs
Exomes of more than 100,000 Mayo Clinic patients have been sequenced and the results are being included in the patients’ electronic health records (EHR) as part of the Tapestry project. This gives clinicians access to patient information in the EHRs so that the right tests can be ordered at the right time, Mayo Clinic noted in its article.
“Embedding genomic data into the patient’s chart in a way that is easy to locate and access will assist doctors in making important decisions and advance the future of genomically informed medicine.” said Cherisse Marcou, PhD, co-director and vice chair of information technology and bioinformatics in Mayo’s Clinical Genomics laboratory.
While more research is needed, Mayo Clinic’s accomplishments suggest advancements in gene sequencing and technologies are making way for data-driven tools to aid physicians.
As the cost of gene sequencing continue to fall due to improvement in the technologies, more screenings for health risk factors in individuals will likely become economically feasible. This may increase the role medical laboratories play in helping doctors use exomes and whole genome sequencing to screen patients for risk of specific cancers and health conditions.
Liquid biopsy tests hold much promise. But inconsistencies in their findings provoke scrutiny and calls from researchers for further development before they can be considered reliable enough for diagnostic use
Many commercial developers of liquid biopsy tests tout the accuracy and benefits of their diagnostic technology. However, there are an equal number of medical laboratory experts who believe that this technology is not yet reliable enough for clinical use. Critics also point out that these tests are being offered as Laboratory Developed Tests (LDTs), which are internally developed and validated and have not undergone regulatory review.
Dark Daily has published several e-briefings on researchers who have sent the same patient samples to different genetic testing labs and received back materially different test results. Now, a new study by Johns Hopkins University concludes that liquid biopsy technology “must improve” before it should be relied upon for diagnostic and treatment decision making.
‘Certification for Medical Laboratories Must Improve’
Liquid Biopsy is the term for drawing whole blood and looking for cancer/tumor cells circulating in the blood stream. This is one factor in the imprecision of a liquid biopsy. Did the blood sample drawn actually have tumor cells? After all, only a limited number of tumor cells, if present, are in circulation.
Gonzalo Torga, MD (above left), and Kenneth J. Pienta, MD (above right), are the two Johns Hopkins Medicine doctors who conducted the recent study into the efficacy of liquid biopsy laboratory developed tests (LDTs) offered by different medical laboratory companies. They published their findings in JAMA Oncology. (Photos copyright: Johns Hopkins.)
In reporting the DNA findings and results from the two medical laboratory companies, researchers discovered that the results completely matched in only three of the 40 patients! The Johns Hopkins researchers are concerned that patients could be prescribed certain cancer treatments based on which lab company’s liquid biopsy test their physician orders, instead of an accurate identification of the unique mutations in their tumors.
“Liquid biopsy is a promising technology, with an exceptional potential to impact our ability to treat patients, but it is a new technology that may need more time and experience to improve,” Gonzalo Torga, MD, Postdoctoral Fellow and Instructor at Johns Hopkins, and the lead author of the study, told Forbes. “We can’t tell from these studies which laboratory’s panel is better, but we can say that certification for these laboratories must improve.”
Unlocking New View of Tumors
Two commercial tests were used for the study:
Guardant360 from Guardant Health, Inc., uses digital sequencing to analyze genomic data points at the single molecular level. It examines 73 genes, including all National Comprehensive Cancer Network (NCCN) listed genes. The test searches for DNA fragments among billions of cells and digitally tags each fragment. This process unlocks a view of tumors that is not seen with tissue biopsies, which helps doctors prescribe the best treatment options for a particular patient.
“As a simple blood test, it provides physicians with a streamlined, cost-effective method to identify genomic alterations that can comprehensively influence a patient’s therapy response,” Helmy Eltoukhy, PhD, co-founder and Chief Executive Officer at Guardant Health, told MDBR.
“The only way of keeping ahead of those diseases and tracking those mutations has been through surgery, through doing a tissue biopsy and physically cutting a piece of the tumor out and sequencing it,” Eltoukhy noted in an interview with Xconomy. “What we’re able to do is essentially get the same, or sometimes better performance to tissue biopsy, but through two teaspoons of blood.”
According to the Guardant Health website, it takes just 14 days for a full report from Guardant360 to reach the ordering physician. In addition, the blood test provides samples with an adequate level of cell-free DNA to test 99.8% of the time and reduces errors and false positives found in standard sequencing methods by 1,000 times. It is common for samples used for tissue sequencing to have insufficient DNA for testing 20% to 40% of the time.
“We believe that conquering cancer is at its core a big data problem, and researchers have been data-starved,” explained Eltoukhy in VentureBeat. “Our launch of the world’s first commercial comprehensive liquid biopsy sparked a boom in cancer data acquisition. Every physician who orders one of our tests, and every patient whose tumor DNA we sequence, adds to this larger mission by improving our understanding of this complex disease.”
PlasmaSELECT-R64, manufactured by Personal Genome Diagnostics (PGDx), evaluates a targeted panel of 64 genes that have biological and functional relevance in making treatment decisions. PGDx announced the expanded version of its PlasmaSELECT assay in March of 2017.
“We are proud to launch the revolutionary PlasmaSELECT 64 expanded assay just six months after we introduced the most accurate, clinically actionable liquid biopsy tumor profiling assay to the market,” said Doug Ward, Chief Executive Officer at PGDx, in a press release. “This update is the first liquid biopsy assay that includes MSI (microsatellite instability) testing as a biomarker for high tumor mutational load, thereby providing cancer patients and their oncologists with information on whether they might be candidates for immuno-oncology therapies. The ability to generate DNA tumor profiling non-invasively using blood or plasma offers many advantages and makes genomic testing more accessible and usable.”
Regulations of LDTs Could be Needed to Improve Liquid Biopsy Tests
There are pathologists and clinical laboratory professionals who believe the technology behind liquid biopsies is not yet reliable enough for clinical use. The tests are being offered as LDTs, which are internally developed and validated, and the Food and Drug Administration (FDA) allows LDTs to be sold without regulatory reviews at this time. However, there are discussions regarding if and how to regulate LDTs, the outcome of which could impact how clinical laboratories are allowed to market the LDTs they develop.
Clearly, liquid biopsies are still in their relatively early stages of development. More testing and evaluation is needed to determine their efficacy. However, their potential to revolutionize cancer detection and care is obvious and a strong motivator for LTD developers, which means there will be future developments worth noting.
OPKO Health’s 4Kscore test predicts the rate of high-risk prostate cancer and may become a useful business case study for other labs developing proprietary diagnostic tests
Clinical laboratories and biotech companies with new medical laboratory tests are struggling to win coverage by Medicare and private payers. How big is this problem? There are currently tens of thousands of molecular diagnostic assays and genetic tests offered for clinical use.
Any lab company seeking to obtain an appropriate Current Procedural Terminology (CPT) code, favorable coverage guidelines, and adequate reimbursement from health insurers for its new lab test faces three big challenges, and they are related. First, payers are simply overwhelmed with requests to review new genetic tests. The flood of new test submissions exceeds the capability of payers to respond.
Most Payers May Not Have Right Scientific Expertise to Evaluate Genetic Tests
Experts at National Comprehensive Cancer Network conference voice opinions
It may surprise many pathologists and clinical laboratory managers to learn that a number of prominent healthcare leaders recently voiced significant reservations about the current status of molecular genetics testing. In their view, clinical pathology laboratory testing that incorporates genetic and molecular technologies needs further refinement, improved billing codes, and additional regulation before it can fulfill its potential to be a precise diagnostic tool.
That was the conclusion reached by a panel of distinguished physicians representing healthcare organizations, pharmaceutical giants, insurance companies, and the government at this year’s annual National Comprehensive Cancer Network (NCCN) conference. (more…)
Appropriate use of clinical pathology laboratory tests to detect and treat cancer will be a scorecard factor
One primary goal of pay-for-performance programs is to reduce or eliminate the variability of care that physicians provide to their patients. Getting physicians to follow the recommended care protocols 100% of the time with 100% of their patients would contribute to improved outcomes, while reducing overall healthcare costs.
Pathologists and clinical laboratory professionals are well positioned to see this variability in care, since they regularly handle the laboratory test requests from client physicians. Over time, they can recognize the good and bad practice patterns of individual doctors, since it is reflected in both the lab test orders and the laboratory test results for that doctor’s patients.
