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.
Studies into use of population-level genomic cancer screening show promising results while indicating that such testing to find evidence of increased cancer risk among non-symptomatic people may be beneficial
In another example of a government health system initiating a program designed to proactively identify people at risk for a serious disease to allow early clinical laboratory diagnosis and monitoring for the disease, cancer researchers at Monash University in Australia have receive a $2.97 million grant from the Medical Research Future Fund (MRFF) to study ways to “identifying people who are living with a heightened cancer risk who would ordinarily be informed only after a potentially incurable cancer is diagnosed.”
According to a Monash news release, the researchers, led by Associate Professor Paul Lacaze, PhD, Head of the Public Health Genomics Program at Monash University, plan to use the award to develop a “new low-cost DNA screening test which will be offered to 10,000 young Australians. The new approach, once scaled-up, has the potential to drastically improve access to preventive genetic testing in Australia, and could help make Australia the world’s first nation to offer preventive DNA screening through a public healthcare system.”
Called DNACancerScreen, the clinical genetic test will be offered to anyone between the ages of 18 and 40, rather than to a select group of people who have a family history of cancer or who present with symptoms. The Monash scientists hope to advance knowledge about the relationship of specific genes and how they cause or contribute to cancer. Such information, they believe, could lead to the development of new precision medicine diagnostic tests and anti-cancer drug therapies.
Gap in Current Cancer Screening Practices
The DNACancerScreen test will look for genes related to two specific cancer categories:
Hereditary Breast and Ovarian Cancer Syndrome is associated with an increased risk of developing breast, ovarian, prostate, and pancreatic cancers, as well as melanoma. Lynch Syndrome is associated with colorectal, endometrial, ovarian, and other cancers.
Currently, screening practices may miss as many as 50-90% of individuals who carry genetic mutations associated with hereditary breast and ovarian cancer, and as many as 95% of those at risk due to Lynch Syndrome, according to the Monash news release.
But currently, only those with a family history of these cancers, or those who present with symptoms, are screened. By targeting younger individuals for screening, Lacaze and his team hope to give those at risk a better chance at early detection.
“This will empower young Australians to take proactive steps to mitigate risk, for earlier detection, surveillance from a younger age, and prevention of cancer altogether,” Lacaze said in the news release.
Along with the possibility of saving lives, Associate Professor Paul Lacaze, PhD (above), Head of the Public Health Genomics Program at Monash University, expects that the screening program will have an economic impact as well. “This type of preventive DNA testing will not only save lives, but also save the Australian public healthcare system money by preventing thousands of cancers,” he said. There’s evidence to back up his statement. In 2019 he led a team that published a study, titled, “Population Genomic Screening of All Young Adults in a Healthcare System: A Cost Effectiveness Analysis.” That study concluded, “Preventive genomic screening in early adulthood would be highly cost-effective in a single-payer healthcare system, but ethical issues must be considered.” (Photo copyright: Monash University.)
Similar Genetic Studies Show Encouraging Results
Although the DNACancerScreen study in Australia is important, it is not the first to consider the impact of population-level screening for Tier 1 genetic mutations. The Healthy Nevada Project (HVN), a project that combined genetic, clinical, environmental, and social data, tested participants for those Tier 1 conditions. The project was launched in 2016 and currently has more than 50,000 participants, a Desert Research Institute (DRI) press release noted.
In 2018, HVN began informing participants who had increased risk for hereditary breast and ovarian cancer, Lynch Syndrome, and a third condition called Familial Hypercholesterolemia. There were 27,000 participants, and 90% of those who had genetic mutations associated with the three Tier 1 conditions had not been previously identified.
“Our first goal was to deliver actionable health data back to the participants of the study and understand whether or not broad population screening of CDC Tier 1 genomic conditions was a practical tool to identify at-risk individuals,” said Joseph Grzymski, PhD, lead author of the HVN study in the DRI press release.
Grzymski is Principal Investigator of the Healthy Nevada Project, Director of the Renown Institute for Health Innovation, Chief Scientific Officer for Renown Health, and a Research Professor in Computational Biology and Genetics at the Desert Research Institute.
“Now, two years into doing that it is clear that the clinical guidelines for detecting risk in individuals are too narrow and miss too many at risk individuals,” he added.
A total of 358, or 1.33% of the 26,906 participants in the Healthy Nevada Project were carriers for the Tier 1 conditions, but only 25% of them met the current guidelines for screening, and only 22 had any previous suspicion in their medical records of their genetic conditions.
Another project, the MyCode Community Health Initiative conducted at Geisinger Health System, found that 87% of participants with a Tier 1 gene variant did not have a prior diagnosis of a related condition. When the participants were notified of their increased risk, 70% chose to have a related, suggested procedure.
“This evidence suggests that genomic screening programs are an effective way to identify individuals who could benefit from early intervention and risk management—but [who] have not yet been diagnosed—and encourage these individuals to take measures to reduce their risk,” a Geisinger Health press release noted.
Realizing the Promise of Precision Medicine
Studies like these are an important step in realizing the potential of precision medicine in practical terms. The Tier 1 genetic conditions are just a few of the more than 22,000 recognized human genes of which scientists have a clear understanding. Focusing only on those few genetic conditions enables clinicians to better help patients decide how to manage their risk.
“Genomic screening can identify at-risk individuals more comprehensively than previous methods and start people on the path to managing that risk. The next step is figuring out the impact genomic screening has on improving population health,” said Adam Buchanan, MPH, MS, Director of Geisinger’s Genomic Medicine Institute.
These are positive developments for clinical laboratories and anatomic pathology group practices. The three examples cited above show that a proactive screening program using genetic tests can identify individuals at higher risk for certain cancers. Funding such programs will be the challenge.
At the current cost of genetic testing, screening 100 people to identify a few individuals at high risk for cancer would probably not be considered the highest and best use of the limited funds available to the healthcare system.
Many other healthcare systems also are partnering with private genetic testing companies to pursue research that drive precision medicine goals
It is certainly unusual when a major health network announces that it will give away free genetic tests to 10,000 of its patients as a way to lay the foundation to expand clinical services involving precision medicine. However, pathologists and clinical laboratory managers should consider this free genetic testing program to be the latest marketplace sign that acceptance of genetic medicine continues to move ahead.
Notably, it is community hospitals that are launching this
new program linked to clinical laboratory research that uses genetic tests for
specific, treatable conditions. The purpose of such genetic research is to
identify patients who would benefit from test results that identify the best
therapies for their specific conditions, a core goal of precision medicine.
Clinical laboratory leaders will be interested in this
initiative, as well other partnerships between healthcare systems and private
genetic testing companies aimed at identifying and enrolling patients in
research studies for disease treatment protocols and therapies.
The Future of Precision Medicine
Modern Healthcare reported that data from the WholeMe DNA study, which was funded through donations to the AdventHealth Foundation, also will be used by the healthcare network for research beyond FH, as AdventHealth develops its genomics services. The project’s cost is estimated to reach $2 million.
“Genomics is the future of medicine, and the field is rapidly evolving. As we began our internal discussions about genomics and how to best incorporate it at AdventHealth, we knew research would play a strong role,” Wes Walker MD, Director, Genomics and Personalized Health, and Associate CMIO at AdventHealth, told Becker’s Hospital Review.
“We decided to focus on familial hypercholesterolemia
screening initially because it’s a condition that is associated with
life-threatening cardiovascular events,” he continued. “FH is treatable once
identified and finding those who have the condition can lead to identifying
other family members who are subsequently identified who never knew they had
the disease.”
The AdventHealth Orlando website states that participants in the WholeMe study receive information stored in a confidential data repository that meets HIPAA security standards. The data covers ancestry and 22 other genetic traits, such as:
Asparagus Odor Detection
Bitter Taste
Caffeine Metabolism
Cilantro Taste Aversion
Circadian Rhythm
Coffee Consumption
Delayed Sleep
Earwax Type
Endurance vs Power
Exercise Impact on Weight
Eye Color
Freckling
Hair Curl and Texture
Hand Grip Strength
Height
Lactose Tolerance
Sleep Duration
Sleep Movement
Sleeplessness
Sweet Tooth
Tan vs. Sunburn
Waist Size
Those who test positive for a disease-causing FH variant will be referred by AdventHealth for medical laboratory blood testing, genetic counseling, and a cardiologist visit, reported the Ormond Beach Observer.
One in 250 people have FH, and 90% of them are undiagnosed,
according to the FH Foundation,
which also noted that children have a 50% chance of inheriting FH from parents
with the condition.
AdventHealth plans to expand the free testing beyond central
Florida to its 46 other hospitals located in nine states, Modern Healthcare
noted.
Other Genetics Data Company/Healthcare Provider Partnerships
Helix (above) is one of the world’s largest CLIA-certified, CAP-accredited next-generation sequencing labs. The partnership with AdventHealth offered study participants Exome+: a panel-grade medical exome enhanced by more than 300,000 informative non-coding regions; a co-branded ancestry + traits DNA product for all participants; secure storage of genomic data for the lifetime of the participant; infrastructure and data to facilitate research; and in-house clinical and scientific expertise, according to Helix’s website. (Photo copyright: Orlando Sentinel.)
Business Insider noted that Helix has focused on clinical partnerships for about a year and seems to be filling a niche in the genetic testing market.
“Helix is able to sidestep the costs of direct-to-consumer
marketing and clinical test development, while still expanding its customer
base through predefined hospital networks. And the company is in a prime
position to capitalize on providers’ interest in population health management,”
Business Insider reported.
Ochsner’s program is the first “fully digital population
health program” aimed at including clinical genomics data in primary care in an
effort to affect patients’ health, FierceHealthcare
reported.
Hereditary breast and ovarian cancer due to
mutations in BRCA1 and BRCA2 genes;
Lynch
syndrome, associated with colorectal and other cancers; and
FH.
Color also offers genetic testing and whole genome sequencing services to NorthShore’s DNA10K program, which plans to test 10,000 patients for risk for hereditary cancers and heart diseases, according to news release.
And, Jefferson Health offered Color’s genetic testing to the healthcare system’s 33,000 employees, 10,000 of which signed up to learn their health risks as well as ancestry, a Color blog post states.
“Understanding the genome warning signals of every patient will be an essential part of wellness planning and health management,” said Geisinger Chief Executive Officer David Feinberg, MD, when he announced the new initiative at the HLTH (Health) Conference in Las Vegas. “Geisinger patients will be able to work with their family physician to modify their lifestyle and minimize risks that may be revealed,” he explained. “This forecasting will allow us to provide truly anticipatory healthcare instead of the responsive sick care that has long been the industry default across the nation.”
It will be interesting to see how and if genetic tests—free
or otherwise—will advance precision medicine goals and population health
treatments. It’s important for medical laboratory leaders to be involved in health
network agreements with genetic testing companies. And clinical laboratories should
be informed whenever private companies share their test results data with
patients and primary care providers.
In recent weeks, company representatives began informing physicians at cancer centers and hospitals about a problem with a specific variant in the MSH2 gene
Invitae Corporation (NYSE:NVTA), a genetic testing company in San Francisco, has told some physicians and clinicians in recent weeks that it has reported false-negative results. Clinical laboratory professionals with knowledge of the facts in this case believe the cause of the false negative results may have gone undetected for months and that genetic tests for a large number of patients may be involved.
For several weeks, Invitae has reported to its ordering physicians that it knows about a small number of false-negative reports that affect an estimated two to 10 patients who have a rare genetic variant in the MSH2 gene. The variant is known as the Boland Inversion and the gene is associated with Lynch syndrome (AKA, hereditary nonpolyposis colorectal cancer).
This episode may be a watershed event in the evolution of the genetic testing industry. Evidence indicates that genetic tests for a large number of patients were done incorrectly, and that the problem was systemic and went undetected by the lab company’s staff for as long as 11 months. Because these genetic tests were laboratory-developed tests (LDTs), the problem at Invitae could be used by some to argue that FDA regulation of LDTs is needed.
Invitae provided two written statements to The Dark Report, Dark Daily’s sister publication. The full statements can be read at the end of this story. The Dark Report is preparing a detailed intelligence briefing about this matter in its upcoming August 28 issue.
False Negative Reports for Some Genetic Tests
In one statement, the company wrote, “For the past several weeks Invitae has been working with clinicians to address an issue related to our analysis of a rare genetic variant in the MSH2 gene associated with Lynch syndrome (0.007% of inherited cancer tests), also known as the Boland inversion, which we believe could have led to a false negative report for a small number of patients (estimated 2-10 patients impacted).”
Invitae Corporation, founded in 2010, is a clinical laboratory company based in San Francisco that provides genetic testing services and has used aggressive pricing to fuel fast growth in specimen volume in recent years. According to the company’s 2017 second quarter earnings report, for the first six months of 2017 Invitae reported revenue of $27.7 million. Its net loss before taxes for the first six months of 2017 was $57.3 million. (Photo copyright: Yelp.)
After detecting the problem, the company began a root-cause analysis to determine the extent of the problem. “We would expect to observe the MSH2 Boland inversion event in 0.007% of patients undergoing hereditary cancer testing and approximately one in every 1,250 in patients with Lynch syndrome-spectrum cancers,” the company stated. “Based on these estimates, we expect this to impact a very small number of patients.”
Limited Number of Patients with False Negatives, but How Many Tests Involved?
The number of patients whose test results may have been affected is the subject of speculation among medical laboratory professionals who refer genetic tests to Invitae. Two medical directors at genetic testing laboratories pointed out that—based on the lab company’s estimate that false negatives were reported on just two to 10 patients—the problem could involve 3,000 to 12,500 patients.
The photo above taken Feb. 12, 2015, is of the Invitae management team at a happier time when the company’s shares began trading on the New York Stock Exchange (NYSE). (Photo copyright: Invitae.)
The company’s internal quality systems did not identify this problem. They learned about the problem from an outside source. Invitae said, “A client recently reported a discrepancy between an Invitae report and a report issued by another laboratory for the presence of a single rare mutation in MSH2, known as the Boland inversion. As soon as we learned of the discrepancy, we quickly identified and rectified the issue.”
The company confirmed that the problem with the Boland Inversion had gone undiscovered for 11 months, stating “We have identified all samples impacted by this issue, which were processed between September 2016 and July 2017. We are reanalyzing all previous results over the next several weeks to ensure their accuracy.”
Quality Control Checks for Omission of Assay Components
In its statement, Invitae referenced the quality-control issue, saying, “Because of the unique characteristics of how we were testing for the MSH2 Boland inversion, our quality control checks did not catch omission of the components of the assay. As soon as the omission was recognized and relevant components returned to the assay, it once again performed properly. We have added two separate quality controls to ensure this issue will not reoccur.”
The statement continued, saying, “We have identified all samples that could have been impacted by this error and are in the process of reanalyzing them free-of-charge.” The company also said, “Our ability to detect this specific MSH2 mutation has been fully restored and is functioning properly …. Moving forward, the new assay incorporates a quality check for successful capture and sequencing of the region around both ends of the Boland inversion so that the absence of the inversion gives a positive signal and the presence of the inversion gives a separate and different signal, while failure or absence of successful capture of these regions gives a third and different signal.”
To comply with federal and state clinical laboratory regulations, Invitae confirmed that it had conducted a root cause analysis (RCA) and was addressing the problem, notifying physicians and patients as necessary.
“We have been reaching out to all customers with patients who could have been impacted by this issue. We have samples to conduct reanalysis for all patients and will reach out to individual clinicians if any of those samples are deemed ‘quantity not sufficient’ (QNS) and new ones are required. However, the assay developed and validated for reanalysis is designed to use very small amounts of DNA, so we anticipate the number of new samples needed will be small.”
Retesting may be a greater challenge for Invitae than is indicated by its statement. Several pathologists told The Dark Report that such retesting comes with several problems. For example, certain states require patient samples used in genetic testing to be destroyed within a set time period. In such cases, the lab would need to work with the physician to have the patient provide a new sample for the retest. Also, it is common for genetic testing to use so much of a sample that the amount remaining is inadequate for a retest. In these cases, a new sample must be collected.
Another issue for Invitae will involve both the time to retest and the cost to retest. One lab executive pointed out that Invitae’s lab accessions had almost tripled from 12,500 in the second quarter of 2016 to 30,500 in second quarter of 2017. “Their lab is already straining to stay up with that volume increase. If Invitae must retest, say, 10,000 or more patient samples because of the MSH2 Boland inversion problem, this can seriously overload their lab and cause significant delays in turnaround time for all samples,” he explained.
A point of interest for pathologists and laboratory directors is whether any clinicians have filed a complaint or notified Invitae’s laboratory accreditation organizations, and the federal and state lab regulators, about the problems they had with this specific MSH2 mutation in their genetic tests and genetic test panels. Invitae has not commented on that situation.
Finally, the consequences for the patients whose genetic tests were performed by Invitae during this 11-month period should be considered. One executive from a large genetic testing lab in the Northeast said it best: “Every lab that performs genetic testing is in the rare mutation business!” he declared. “The mission is specifically to test for rare mutations and accurately identify the 1-in-1,000,000 mutation to enable that patient to get the right treatment that is invariably life-changing.
“Thus, for any lab like Invitae to tell its physicians that ‘only a few patients’ may have been given a false negative result from their genetic test betrays the quality and accuracy that all physicians, patients, and their families expect of our labs,” he continued. “Remember that what physicians and patients do with these results is very drastic! I consider it a massive failure anytime a genetic lab—whether large or small—misses rare mutations in even a small number of patients because of problems at the bench.”
—The Dark Report Editorial Team
Invitae provided two statements to The Dark Report. Here is the first statement, in full, dated Aug. 24 from Invitae, titled, “Statement on Boland Inversion Testing.”
“For the past several weeks Invitae has been working with clinicians to address an issue related to our analysis of a rare genetic variant in the MSH2 gene associated with Lynch syndrome (0.007% of inherited cancer tests), also known as the Boland inversion, which we believe could have led to a false negative report for a small number of patients (estimated 2-10 patients impacted).
“Our immediate priority has been getting accurate and actionable information to patients and clinicians about what happened and the steps we are taking to address the situation. We have identified all samples that could have been impacted by this error and are in the process of reanalyzing them free-of-charge. We have been personally reaching out to clinicians whose patients may have been impacted to discuss the issue, outlining what we have done to correct it and explaining the timeframe for receiving updated information. We are also offering no-cost family variant testing for the immediate families of any patient who tests positive for the Boland inversion variant, something we do for all our patients who test positive for a pathogenic variant.
“Our ability to detect this specific MSH2 mutation has been fully restored and is functioning properly. The corrected assay has been revalidated and shown to have regained its previous high sensitivity for the Boland inversion for all samples currently in the lab. Dual quality control checks specific to this issue have been added and are performing properly. We have also reviewed all of our other testing and are confident that this was an isolated error. Our ability to detect other MSH2 mutations or mutations in any other genes in our testing panels was not affected.
“Because of the unique characteristics of how we were testing for the MSH2 Boland inversion, our quality control checks did not catch omission of the components of the assay. As soon as the omission was recognized and relevant components returned to the assay, it once again performed properly. We have added two separate quality controls to ensure this issue will not reoccur.
“We take the reliability and validity of our test results extremely seriously. Nothing is more important to our company than ensuring that the information we provide is accurate. It is extremely rare that we find an error, but when we do we will quickly to correct it and share information with clinicians, in keeping with the medical community’s standards for error reporting.”
This is the second written statement, in full, provided to The Dark Report on Aug. 24. Invitae said:
“A client recently reported a discrepancy between an Invitae report and a report issued by another laboratory for the presence of a single rare mutation in MSH2, known as the Boland inversion. As soon as we learned of the discrepancy, we quickly identified and rectified the issue.
“We have identified all samples impacted by this issue, which were processed between September 2016 and July 2017. We are reanalyzing all previous results over the next several weeks to ensure their accuracy.
“We would expect to observe the MSH2 Boland inversion event in 0.007% of patients undergoing hereditary cancer testing, and approximately one in every 1,250 in patients with Lynch syndrome-spectrum cancers. Based on these estimates, we expect this to impact a very small number of patients.
“Moving forward, the new assay incorporates a quality check for successful capture and sequencing of the region around both ends of the Boland inversion so that the absence of the inversion gives a positive signal and the presence of the inversion gives a separate and different signal, while failure or absence of successful capture of these regions gives a third and different signal.
“We have been reaching out to all customers with patients who could have been impacted by this issue. We have samples to conduct reanalysis for all patients and will reach out to individual clinicians if any of those samples are deemed ‘quantity not sufficient’ (QNS) and new ones are required. However, the assay developed and validated for reanalysis is designed to use very small amounts of DNA, so we anticipate the number of new samples needed will be small.”
