Wait times blamed on the Irish National Health System’s ‘overstretched’ services and ‘under-resourced’ commitment to cancer genetic testing done by medical laboratories
Histopathologists in the UK and anatomic pathologists in the US understand the important role predictive genetic testing can play in helping patients understand their risk for certain types of breast, bowel, and ovarian cancers. While timely access to cancer testing may be routine in the United States, a report out of Ireland reveals patients in that country’s government-run healthcare system may have to wait up to two years or more for genetic counseling and testing.
UK Patients in Need of Genetic Services Are Switching from Public to Private Healthcare
While early access to genetic testing can provide opportunities for preventative treatments or earlier diagnosis of cancer, many patients in Ireland with a family history of cancer must wait months or years for genetic services. UCC Nursing Professor and Physiologist Josephine Hegarty, PhD, lead author of the ICS report, stated in a news release that “public cancer genetic services are overstretched. Waiting lists exist at every point on the pathway for people who need genetic services.”
She added, “Many patients spoken to seemed to abandon the waiting for overstretched public services in favor of paying for private testing and treatment.”
While the ICS report’s survey sample size was small—154 patients, family members, or members of the public—the data revealed:
One in seven respondents waited 13-24 months and one in 27 waited over 24 months for counseling and testing appointments.
Many people had changed from the public health system to private healthcare to speed up access to genetic testing.
The cumulative waiting time from referral to counseling, testing, receipt of genetic test results, and onwards to screening, surveillance, or prophylactic treatments [aka, preventive healthcare] can be up to four years, which patients see as time lost in terms of cancer prevention and early intervention.
Barriers to Genetic Services Affect Treatment Decisions
A separate survey of 52 healthcare professionals highlighted barriers for accessing services with six in 10 respondents saying they are under-resourced and four in 10 concerned about access to follow-up surgery for patients deemed to be at high risk.
In the ICS news release, breast cancer patient Margaret Cuddigan said genetic testing was not available to her at diagnosis.
“In those 13 months waiting for a result, I went through chemotherapy, a lumpectomy, and radiotherapy on my breast, only for a double mastectomy to be required once the BRCA mutation was known. Had I known this earlier, my course of treatment could have been very different,” Cuddigan said.
“I had to postpone a radiation treatment to go up to Dublin from Cork to do the genetic test, as it would have taken up to another 12 months in Cork, and then I waited over four months for the results. Once I received the news of the gene mutation, I had to navigate a path of risk-reducing surgeries,” she noted, adding, “I researched and sought out a surgeon myself.”
Long Waits for Genetic Testing Are Common in Single-Payer Healthcare
Meanwhile, it is cancer patients and their families who pay the price for underinvestment because delays in their cancer test results then delay timely treatment decisions. This is particularly true when an immediate start of therapy for an aggressive form of cancer is imperative.
ICS Executive Director, Advocacy and External Relations, Rachel Morrogh, argues the solution is prioritizing cancer prevention within the Health Service Executive, which runs Ireland’s national healthcare system.
“The reality is the focus must be on urgent care, but we’re missing chances to keep people healthy (through genetic testing),” Morrogh told the Irish Independent. “We can prevent four in 10 cancers, but we have to prioritize prevention. There needs to be a significant investment and the expansion of capacity across all the follow-on services that someone with a genetic risk of cancer may need, focusing on the development of a dedicated and resourced pathway for them.
The ICS report found that limited access to timely genetically-guided health and oncology services is the result of multiple barriers to care.
“It is apparent from engaging directly with service users that waiting lists exist at every point on the pathway for people who need genetic [cancer testing] services,” the report states. “For those who may have a genetic risk of cancer, the wait times for access to [genetic cancer] testing alone (before counselling treatment, prophylactic surgery, etc.) can be up to two years. Barriers to accessing cancer genetic services include costs of tests, long processing time for referrals to tests, restrictive referral criteria, and difficulty in accessing information on cancer genetic services.”
In the forward she wrote for the ICS report, ICS Chief Executive Officer Averil Power said her organization would continue its push for improved access to genetic testing services. “Government needs to not only expand capacity for testing and counselling, but also ensure that the follow-on services that are needed by people diagnosed with a genetic risk of cancer are in place and can be accessed swiftly.”
The ICS report is another reminder to histopathologists in the UK—as well as anatomic pathologists in the US—that a single-payer healthcare system comes with its own flaws and access-to-care issues.
Results of the UK study confirm for clinical laboratory professionals the importance of fully understanding the design and function of SNP chips they may be using in their labs
Here is another example of a long-established clinical laboratory test that—upon new evidence—turns out to be not as accurate as once thought. According to research conducted at the University of Exeter in Devon, UK, Single-nucleotide polymorphism (SNP) chips (aka, SNP microarrays)—technology commonly used in commercial genetic testing—is inadequate at detecting rare gene variants that can increase breast cancer risk.
A news release announcing the results of the large-scale study states, “A technology that is widely used by commercial genetic testing companies is ‘extremely unreliable’ in detecting very rare variants, meaning results suggesting individuals carry rare disease-causing genetic variants are usually wrong.”
Why is this a significant finding for clinical laboratories? Because medical laboratories performing genetic tests that use SNP chips should be aware that rare genetic variants—which are clinically relevant to a patient’s case—may not be detected and/or reported by the tests they are running.
UK Researchers Find ‘Shockingly High False Positives’
The conclusion reached by the Exeter researchers, the BMJ study states, is that “SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.”
Leigh Jackson, PhD, Lecturer in Genomic Medicine at University of Exeter and co-author of the BMJ study, said in the news release, “The number of false positives on rare genetic variants produced by SNP chips was shockingly high. To be clear: a very rare, disease-causing variant detected using [an] SNP chip is more likely to be wrong than right.”
Large-Scale Study Taps UK Biobank Data
The Exeter researchers were concerned about cases of unnecessary invasive medical procedures being scheduled by women after learning of rare genetic variations in BRCA1 (breast cancer type 1) and BRCA2 (breast cancer 2) tests.
“The inherent technical limitation of SNP chips for correctly detecting rare genetic variants is further exacerbated when the variants themselves are linked to very rare diseases. As with any diagnostic test, the positive predictive value for low prevalence conditions will necessarily be low in most individuals. For pathogenic BRCA variants in the UK Biobank, the SNP chips had an extremely low positive predictive value (1-17%) when compared with sequencing. Were these results to be fed back to individuals, the clinical implications would be profound. Women with a positive BRCA result face a lifetime of additional screening and potentially prophylactic surgery that is unwarranted in the case of a false positive result,” they wrote.
Using UK Biobank data from 49,908 participants (55% were female), the researchers compared next-generation sequencing (NGS) to SNP chip genotyping. They found that SNP chips—which test genetic variation at hundreds-of-thousands of specific locations across the genome—performed well when compared to NGS for common variants, such as those related to type 2 diabetes and ancestry assessment, the study noted.
“Because SNP chips are such a widely used and high-performing assay for common genetic variants, we were also surprised that the differing performance of SNP chips for detecting rare variants was not well appreciated in the wider research or medical communities. Luckily, we had recently received both SNP chip and genome-wide DNA sequencing data on 50,000 individuals through the UK Biobank—a population cohort of adult volunteers from across the UK. This large dataset allowed us to systematically investigate the performance of SNP chips across millions of genetic variants with a wide range of frequencies, down to those present in fewer than 1 in 50,000 individuals,” wrote Wright and Associate Professor of Bioinformatics and Human Genetics at Exeter, Michael Weedon, PhD, in a BMJ blog post.
The Exeter researchers also analyzed data from a small group of people in the Personal Genome Project who had both SNP genotyping and sequencing information available. They focused their analysis on rare pathogenic variants in BRCA1 and BRCA2 genes.
The researchers found:
The rarer the variant, the less reliable the test result. For example, for “very rare variants” in less than one in 100,000 people, 84% found by SNP chips were false positives.
Low positive predictive values of about 16% for very rare variants in the UK Biobank.
Nearly all (20 of 21) customers of commercial genetic testing had at least one false positive rare disease-causing variant incorrectly genotyped.
SNP chips detect common genetic variants “extremely well.”
Advantages and Capabilities of SNP Chips
Compared to next-gen genetic sequencing, SNP chips are less costly. The chips use “grids of hundreds of thousands of beads that react to specific gene variants by glowing in different colors,” New Scientist explained.
Common variants of BRCA1 and BRCA2 can be found using SNP chips with 99% accuracy, New Scientist reported based on study data.
However, when the task is to find thousands of rare variants in BRCA1 and BRCA2 genes, SNP chips do not fare so well.
“It is just not the right technology for the job when it comes to rare variants. They’re excellent for the common variants that are present in lots of people. But the rarer the variant is, the less likely they are to be able to correctly detect it,” Wright told CNN.
SNP chips can’t detect all variants because they struggle to cluster needed data, the Exeter researchers explained.
“SNP chips perform poorly for genotyping rare genetic variants owing to their reliance on data clustering. Clustering data from multiple individuals with similar genotypes works very well when variants are common,” the researchers wrote. “Clustering becomes more difficult as the number of people with a particular genotype decreases.”
Clinical laboratories Using SNP Chips
The researchers at Exeter unveiled important information that pathologists and medical laboratory professionals will want to understand and monitor. Cancer patients with rare genetic variants may not be diagnosed accurately because SNP chips were not designed to identify specific genetic variants. Those patients may need additional testing to validate diagnoses and prevent harm.
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 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
Cilantro Taste Aversion
Endurance vs Power
Exercise Impact on Weight
Hair Curl and Texture
Hand Grip Strength
Tan vs. Sunburn
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
Other Genetics Data Company/Healthcare Provider Partnerships
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.
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.
Clinical labs and pathology groups know how advances in targeted therapies and genomics far outpace providers’ and patients’ ability to know how best to use and pay for them.
One fascinating development on the road to precision medicine is that many new cancer drugs now in clinical trials will require a companion genetic test to identify patients with tumors that will respond to a specific therapeutic drug.
This implies more genetic testing of tumors, a prospect that challenges both the Medicare program and private health insurers because they already struggle to cope with the flood of new genetic tests and molecular diagnostic assays. However, even as this genetic testing wave swamps payers, some pharmaceutical companies have cancer drugs for rare types of cancers and these companies would like to see more genetic testing of tumors.
Pathologists and clinical laboratory managers will find this to be precisely the dilemma facing specialty pharma company Loxo Oncology (NASDAQ:LOXO), a biopharmaceutical company located in San Francisco and Stamford, Conn.
Loxo is developing larotrectinib (LOXO-101), a “selective TRK inhibitor.” According to a Loxo press release, Larotrectinib is “a potent, oral, and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRK receptors).” In short, the drug is designed to “directly target TRK, and nothing else, turning off the signaling pathway that allows TRK fusion cancers to grow.”
How to Find Patients for This Cancer Drug
While a powerful, new, targeted cancer drug will be a boon to cancer therapy, it is only intended for a relatively small number of patients. Loxo estimates that between 1,500 and 5,000 cases of cancer are caused by TRK mutations in the United States each year. Conversely, according to the National Cancer Institute, the total number of new cancer diagnoses in the US in 2016 was 1,685,210.
An article in MIT Technology Review on larotrectinib notes, “To find patients, Loxo will need to convince more doctors to order comprehensive tests that screen multiple genes at once, including TRK.” And that is where things get complicated.
“These advanced genetic tests, which can cost $5,000 or more, are offered by companies like Foundation Medicine, Caris Life Sciences, and Cancer Genetics. The problem is, insurers still consider the tests ‘experimental’ and don’t routinely cover them, meaning patients are often stuck picking up the bill,” notes MIT Technology Review.
Data for the graph above comes from theNational Human Genome Research Institute. The graph illustrates the steep decline in cost for whole genome sequencing over the past 17 years. As the cost of genetic testing drops, development of targeted-drug cancer therapies increases. Clinical laboratories and anatomic pathology groups can expect to be performing more such tests in the future. (Graphic copyright: National Human Genome Research Institute/Simple English Wiki.)
To further confuse the market, the National Cancer Institute states that “Insurance coverage of tumor DNA sequencing depends on your insurance provider and the type of cancer you have. Insurance providers typically cover a DNA sequencing test if there is sufficient evidence to support that the test is necessary to guide patient treatment. Tests without sufficient evidence to support their utility may be considered experimental and are likely not covered by insurance.”
That, however, leads to a different conundrum for drug makers such as Loxo: the majority of doctors are not keeping up with the rapid-fire pace of discovery in the realm of genetics and targeted therapies. Some genes like BRCA1 and BRCA2 are familiar enough to doctors that they know how and why they are important. However, most other genes are less known, and critically, less understood by doctors who must also focus on all the other myriad aspects of patient care.
Further complicating the issue, there is an enormous lack of information on how multipanel screenings will affect individuals, public health, and the cost of healthcare in general. Several studies are underway, but they are so new it could be years before any real results become available.
Five years ago, it cost about $20,000 to sequence the whole human genome. Now the average price is $1,500, though there are more and less expensive types of genetic tests. As the cost continues to decline, however, more people will undergo the testing and scientists will learn more about how to identify the best therapy to treat cancers caused by genetic mutations.
New discoveries about the genetics of prostate cancer could lead to better tools for diagnosing the disease and selecting effective therapies based on each patient’s specific physiology
In recent decades, the biggest challenge for urologists, and for the pathologists who diagnosed the prostate tissue specimens they referred, has been how to accurately differentiate between non-aggressive prostate cancer, which can exist for decades with no apparent symptoms, and aggressive prostate cancer that kills quickly.
Thus, a research study that has identified unique genetic features within prostate cancer that can help determine if the cancer is aggressive or not, and whether certain drugs may be effective, is good news for men, for urologists, and for the clinical laboratories that will be called upon to perform testing.
These types of breakthroughs bring precision medicine ever closer to having viable tools for effective diagnosis of different types of cancer.
Genetic Fingerprints of Cancer Tumor Types
One such study into the genetic pathways of prostate cancer is bringing precision medicine ever-closer to the anatomic pathology laboratory. Researchers from the Princess Margaret Cancer Centre, which is associated with the University of Toronto Faculty of Medicine, have discovered that some tumors in prostate cancer have a genetic fingerprint that may indicate whether or not the disease will become more aggressive and less responsive to treatment.
Robert Bristow, MD, PhD, and Paul Boutros, PhD, conducted a study of nearly 500 Canadian men who had prostate cancer. Published in the journal Nature, the researchers examined the genetic sequences of those tumors, looking for differences between those that responded to surgery or radiation and those that did not.
In the video above, Dr. Robert Bristow, clinician-scientist at Princess Margaret Cancer Centre, discusses the findings of a key piece in the genetic puzzle that explains why men born with a BRCA2 mutation develop aggressive prostate cancer. (Caption and photo copyright: University Health Network/Princess Margaret Cancer Centre.)
According to a FierceBiotech article, approximately 30% of men who have a type of prostate cancer thought to be curable eventually develop an aggressive metastatic type of the disease. About half of the men who developed a metastatic form of cancer had mutations to three specific genes:
“This information gives us new precision about the treatment response of men with prostate cancer and important clues about how to better treat one set of men versus the other to improve cure rates overall,” stated Bristow in a University Health Network (UHN) press release.
In another study, researchers looked at 15 patients with BRCA2-inheritied prostate cancer and compared the genomic sequences of those tumors to a large group of sequences from tumors in less-aggressive cancer cases. According to a ScienceDaily news release, they found that only 2% of men with prostate cancer have the BRCA2-inherited type.
Knowing what type of cancer a man has could be critically important for clinicians tasked with prescribing the most efficient therapies.
“The pathways that we discovered to be abnormal in the localized BRCA2-associated cancers are usually only found in general population cancers when they become resistant to hormone therapy and spread through the body,” noted Bristow in the ScienceDaily release. If clinicians knew from diagnosis that the cancer is likely to become aggressive, they could choose a more appropriate therapy from the beginning of treatment.
Genetic Mutations Also Could Lead to Breast and Brain Cancer Treatments
BRCA mutations have also been implicated in breast, ovarian, and pancreatic cancers, among some other types. The knowledge that BRCA1 and BRACA2 mutations could indicate a more aggressive cancer is likely to spark investigation into whether poly ADP ribose polymerase (PARP) inhibitors could be used as an effective therapy.
According to the UHN press release, the next step in using the knowledge that BRCA1 and BRCA2 may indicate a more aggressive prostate cancer is for researchers to create a diagnostic tool that can be used to determine what type of prostate cancer a man has. They expect the process to take several years. “This work really gives us a map to what is going on inside a prostate cancer cell, and will become the scaffold on which precision therapy will be built,” Boutros stated in a Prostate Cancer Canada news release.
Unlocking Knowledge That Leads to Accurate Diagnoses and Treatments
Research that furthers precision medicine and allows clinicians to choose the most appropriate treatment for individuals shows how quickly scientists are applying new discoveries. Every new understanding of metabolic pathways that leads to a new diagnostic tool gives clinicians and the patients they treat more information about the best therapies to select.
For the anatomic pathology profession, this shows how ongoing research into the genetic makeup of prostate cancer is unlocking knowledge about the genetic and metabolic pathways involved in this type of cancer. Not only does this help in diagnosis, but it can guide the selection of appropriate therapies.
On the wider picture, the research at the Princess Margaret Cancer Centre is one more example of how scientists are rapidly applying new knowledge about molecular and genetic processes in the human body to identify new ways to more accurately diagnose disease and select therapies.