Should their research result in new ways to identify and diagnose disease, doctors and clinical laboratories would do confirmatory testing and then initiate a precision medicine plan.
Dan Roden, MD, Senior Vice President for Personalized Medicine at VUMC and Senior Author of the Circulation study, said in a VUMC news release that the findings support the growing use of genetic information in clinical care.
“The questions we asked were: How many people who had no previous indication for cardiac genetic testing had pathogenic or likely pathogenic variants, and how many of those people actually had a phenotype in the electronic health records?” he explained.
Arrhythmia More Common than Previously Thought
The VUMC researchers drew data for their reports from the eMERGE Phase III study, which investigated the feasibility of population genomic screening by sequencing 109 genes across the spectrum of Mendelian diseases—genetic diseases that are caused by a mutation in a single gene—in more than 20,000 individuals. The scientists returned variant results to the participants and used EHR and follow-up clinical data to ascertain patient phenotypes, according to a Northwestern University Feinberg School of Medicine news release.
The research team looked specifically at the 120 consortium participants that had disease-associated pathogenic or likely pathogenic (P/LP) variants in the arrhythmia-associated genes. An analysis of the EHR data showed that 0.6% of the studied population had a variant that increases risk for potentially life-threatening arrhythmia, and that there was overrepresentation of arrhythmia phenotypes among patients, the VUMC news release noted.
The research team returned results to 54 participants and, with clinical follow-up, made 19 diagnoses (primarily long-QT syndrome) of inherited arrhythmia syndromes. Twelve of those 19 diagnoses were made only after variant results were returned, the study’s authors wrote.
Carlos G. Vanoye, PhD, Research Associate Professor of Pharmacology at Northwestern University (NU), said the study suggests arrhythmia genes may be more common than previously thought.
“A person can carry a disease-causing gene variant but exhibit no obvious signs or symptoms of the disease,” he said in the NU news release. “Because the genes we studied are associated with sudden death, which may have no warning signs, discovery of a potentially life-threatening arrhythmia gene variant can prompt additional clinical work-up to determine risks and guide preventive therapies.”
“The take-home message is that 3% of people will carry a pathogenic or likely pathogenic variant in a disease-causing gene and many others will carry variants of uncertain significance,” said Dan Roden, MD (above), Senior Vice President for Personalized Medicine at VUMC and Senior Author of the Circulation study in the VUMC news release. “We can use genetic testing, electronic health record phenotypes, and in vitro technologies to evaluate and find people who have unrecognized genetic disease and save lives by making earlier diagnoses.” Clinical laboratories will play a key role in making those early diagnoses and in managing personalized medical treatment plans. (Photo copyright: Vanderbilt University.)
Variants of Uncertain Significance
According to the NU news release, the scientists determined the functional consequences of the variants of uncertain significance they found and used that data to refine the assessment of pathogenicity. In the end, they reclassified 11 of the variants: three that were likely benign and eight that were likely pathogenic.
In the JAMA Oncology study, the VUMC scientists and other researchers conducted a phenome-wide association study to find EHR phenotypes associated with variants in 23 hereditary cancer genes. According to the VUMC news release, they identified 19 new associations:
The VUMC study findings could improve disease diagnosis and management for cancer patients and help identify high-risk individuals, the researchers noted in their published report.
In an editorial published in Circulation, titled, “First Steps of Population Genomic Medicine in the Arrhythmia World: Pros and Cons,” the professors noted that using genomic information in the case of potentially lethal inherited arrhythmia syndromes could be “lifesaving,” but questioned the benefits of reporting such secondary findings when patients are undergoing genome sequencing for other indications such as cancer.
“The likelihood that these ‘genetic diagnoses’ are translated into clinical diagnoses have not been completely evaluated,” they wrote. “In addition to the challenge of accurately identifying disease-causing genetic variants, defining the penetrance of such variants is critical to this process, i.e., what proportion of individuals in the general population with apparently pathogenic variants will develop the associated phenotype? If penetrance is low for particular gene/phenotype combinations, the costs associated with clinical screening and the psychological effects on individuals informed that they have potentially life-threatening variants may outweigh the benefits of the few new clinical diagnoses.”
These latest studies provide further evidence of the value of big data in healthcare and offer another lesson to clinical laboratories and pathologist about the future role data streaming from clinical laboratories and pathology assays may have in the growth of personalized medicine.
Number of patients eligible for genome-driven oncology therapy is increasing, but the percentage who reportedly benefit from the therapy remains at less than 5%
Advances in precision medicine in oncology (precision oncology) are fueling the need for clinical laboratory companion diagnostic tests that help physicians choose the best treatment protocols. In fact, this is a fast-growing area of clinical diagnostics for the nation’s anatomic pathologists. However, some experts in the field of genome-based cancer treatments disagree over whether such treatments offer more hype than hope.
Prasad and his colleagues evaluated 31 US Food and Drug
Administration (FDA) approved drugs, which were “genome-targeted” or
“genome-informed” for 38 indications between 2006 and 2018. The researchers
sought to answer the question, “How many US patients with cancer are eligible
for and benefit annually from genome-targeted therapies approved by the US Food
and Drug Administration?”
They found that in 2018 only 8.33% of 609,640 patients with
metastatic cancer were eligible for genome-targeted therapy—though this was an
increase from 5.09% in 2006.
Even more telling from Prasad’s view, his research team concluded
that only 4.9% had benefited from such treatments. Prasad’s study found the
percentage of patients estimated to have benefited from genome-informed therapy
rose from 1.3% in 2006 to 6.62% in 2018.
“Although the number of patients eligible for genome-driven treatment has increased over time, these drugs have helped a minority of patients with advanced cancer,” the researchers concluded. “To accelerate progress in precision oncology, novel trial designs of genomic therapies should be developed, and broad portfolios of drug development, including immunotherapeutic and cytotoxic approaches, should be pursued.”
The graph above is based on data from a study published in Science titled, “Estimation of the Percentage of US Patients With Cancer Who Benefit from Genome-Driven Oncology,” co-authored by Vinay Prasad, MD, MPH, et al. (Image copyright: Science.)
A Value versus Volume Argument?
Hyman, who leads a team of oncologists that conduct dozens
of clinical trials and molecularly selected “basket studies” each year,
countered Prasad’s assertions by noting the increase in the number of patients
who qualify for precision oncology treatments.
As reported in Science, Hyman said during his AACR
presentation that Sloan Kettering matched 15% of the 25,000 patients’ tumors it
tested with FDA-approved drugs and 10% with drugs in clinical trials.
“I think this is certainly not hype,” he said during the
conference.
Hyman added that another 10% to 15% of patient tumors have a
DNA change that matches a potential drug tested in animals. He expects “basket”
trials to further increase the patient pool by identifying drugs that can work
for multiple tumor types.
The US National Institute of Health (NIH) describes “basket studies” as “a new sort of clinical studies to identify patients with the same kind of mutations and treat them with the same drug, irrespective of their specific cancer type. In basket studies, depending on the mutation types, patients are classified into ‘baskets.’ Targeted therapies that block that mutation are then identified and assigned to baskets where patients are treated accordingly.”
Are Expectations of Precision Medicine Exaggerated?
A profile in MIT Technology Review, titled, “The Skeptic: What Precision Medicine Revolution?,” describes Prasad’s reputation as a “professional scold” noting the 36-year-old professor’s “sharp critiques of contemporary biomedical research, including personalized medicine.” Nevertheless, Prasad is not alone in arguing that precision oncology’s promise is often exaggerated.
“Like most ‘moonshot’ medical research initiatives,
precision medicine is likely to fall short of expectations,” Joyner wrote.
“Medical problems and their underlying biology are not linear engineering
exercises and solving them is more than a matter of vision, money, and will.”
“Although some niche applications have been found for
precision medicine—and gene therapy is now becoming a reality for a few rare
diseases—the effects on public health are miniscule while the costs are astronomical,”
they wrote.
Hope for Precision Medicine Remains High
However, optimism over precision oncology among some industry leaders has not waned. Cindy Perettie, CEO of molecular information company Foundation Medicine of Cambridge, Mass., argues genome-directed treatments have reached an “inflection point.”
“Personalized cancer treatment is a possibility for more patients than ever thanks to the advent of targeted therapies,” she told Genetic Engineering and Biotechnology News. “With a growing number of new treatments—including two pan-tumor approvals—the need for broad molecular diagnostic tools to match patients with these therapies has never been greater. We continue to advance our understanding of cancer as a disease of the genome—one in which treatment decisions can be informed by insight into the genomic changes that contribute to each patient’s unique cancer.”
Prasad acknowledges genome-driven therapies are beneficial for some cancers. However, he told MIT Technology Review the data doesn’t support the “rhetoric that we’re reaching exponential growth, or that is taking off, or there’s an inflection point” signaling rapid new advancements.
“Right now, we are investing heavily in immunotherapy and heavily in genomic therapy, but in other categories of drugs, such as cytotoxic drugs, we have stopped investigating in them,” he told Medscape Medical News. “But it’s foolish to do this—we need to have the vision to look beyond the fads we live by in cancer medicine and do things in a broader way,” he added.
“So, I support broader funding because you have to sustain
efforts even when things are not in vogue if you want to make progress,” Prasad
concluded.
Is precision oncology a fad? Dark Daily has covered the advancements in precision medicine extensively over the past decade, and with the launch of our new Precision Medicine Institute website, we plan to continue reporting on further advancements in personalized medicine.
Time will tell if precision oncology can fulfill its
promise. If it does, anatomic pathologists will play an important role in
pinpointing patients most likely to benefit from genome-driven treatments.
One thing that the debate between proponents of precision
medicine in oncology and their critics makes clear is that more and better
clinical studies are needed to document the true effectiveness of target
therapies for oncology patients. Such evidence will only reinforce the
essential role that anatomic pathologists play in diagnosis, guiding
therapeutic decisions, and monitoring the progress of cancer patients.
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.
News reports state that Anthem and Cigna have denied payment for some multigene panel tests, saying that the tests are unproven. Other insurers, such as UnitedHealthcare and Priority Health, pay for such tests but only for certain patients
A conflict is building between patients and health insurers over the reluctance among health plans to pay for new, expensive molecular diagnostic assays and genetic tests that clinical laboratory companies offer.
This conflict has caught the attention of the nation’s media. That is probably because it makes a great story, for example, to interview parents who can assert that their sick child suffered because their health insurance plan would not pay for a genetic test the parents believed would make a difference in their child’s clinical care. Of course, pathologists and medical laboratory professionals know that there are a significant number of expensive genetic tests being offered by various lab companies that lack extensive data to support their clinical efficacy. (more…)
