Norwegian researchers reviewed large clinical trials of six common cancer screenings, including clinical laboratory tests, but some experts question the findings
Cancer screenings are a critical tool for diagnosis and treatment. But how much do they actually extend the lives of patients? According to researchers at the University of Oslo in Norway, not by much. They recently conducted a review and meta-analysis of 18 long-term clinical trials, five of the six most commonly used types of cancer screening—including two clinical laboratory tests—and found that with few exceptions, the screenings did not significantly extend lifespans.
The 18 long-term clinical trials included in the study were randomized trials that collectively included a total of 2.1 million participants. Median follow-up periods of 10 to 15 years were used to gauge estimated lifetime gain and mortality.
“The findings of this meta-analysis suggest that current evidence does not substantiate the claim that common cancer screening tests save lives by extending lifetime, except possibly for colorectal cancer screening with sigmoidoscopy,” the researchers wrote in their published paper.
The researchers noted, however, that their analysis does not suggest all screenings should be abandoned. They also acknowledged that some lives are saved by screenings.
“Without screening, these patients may have died of cancer because it would have been detected at a later, incurable stage,” the scientists wrote, MedPage Today reported. “Thus, these patients experience a gain in lifetime.”
Still, some independent experts questioned the validity of the findings.
Gastroenterologist Michael Bretthauer, MD, PhD (above), a professor at the University of Oslo in Norway led the research into cancer screenings. In their JAMA Internal Medicine paper, he and his team wrote, “The findings of this meta-analysis suggest that colorectal cancer screening with sigmoidoscopy may extend life by approximately three months; lifetime gain for other screening tests appears to be unlikely or uncertain.” How their findings might affect clinical laboratory and anatomic pathology screening for cancer remains to be seen. (Photo copyright: University of Oslo.)
Pros and Cons of Cancer Screening
The clinical trials, according to MedPage Today and Oncology Nursing News covered the following tests:
Mammography screening for breast cancer (two trials).
As reported in these trials, “colorectal cancer screening with sigmoidoscopy prolonged lifetime by 110 days, while fecal testing and mammography screening did not prolong life,” the researchers wrote. “An extension of 37 days was noted for prostate cancer screening with prostate-specific antigen testing and 107 days with lung cancer screening using computed tomography, but estimates are uncertain.”
The American Cancer Society (ACS) recommends certain types of screening tests to detect cancers and pre-cancers before they can spread, thus improving the chances for survival.
The ACS advises screenings for breast cancer, colorectal cancer, and cervical cancer regardless of whether the individual is considered high risk. Lung cancer screenings are advised for people with a history of smoking. Men who are 45 to 50 or older should discuss the pros and cons of prostate cancer screening with their healthcare providers, the ACS states.
A CNN report about the University of Oslo study noted that the benefits and drawbacks of cancer screening have long been well known to doctors.
“Some positive screening results are false positives, which can lead to unnecessary anxiety as well as additional screening that can be expensive,” CNN reported. “Tests can also give a false negative and thus a false sense of security. Sometimes too, treatment can be unnecessary, resulting in a net harm rather than a net benefit, studies show.”
In their JAMA paper, the University of Oslo researchers wrote, “The critical question is whether the benefits for the few are sufficiently large to warrant the associated harms for many. It is entirely possible that multicancer detection blood tests do save lives and warrant the attendant costs and harms. But we will never know unless we ask,” CNN reported.
Hidden Impact on Cancer Mortality
ACS Chief Scientific Officer William Dahut, MD, told CNN that screenings may have an impact on cancer mortality in ways that might not be apparent from randomized trials. He noted that there’s been a decline in deaths from cervical cancer and prostate cancer since doctors began advising routine testing.
“Cancer screening was never really designed to increase longevity,” Dahut said. “Screenings are really designed to decrease premature deaths from cancer.” For example, “if a person’s life expectancy at birth was 80, a cancer screening may prevent their premature death at 65, but it wouldn’t necessarily mean they’d live to be 90 instead of the predicted 80,” CNN reported.
Dahut told CNN that fully assessing the impact of cancer screenings on life expectancy would require a clinical trial larger than those in the new study, and one that followed patients “for a very long time.”
“From its title, one would have expected this paper to be based on analysis of individual lifetime data. However, it is not,” he wrote in a compilation of expert commentary from the UK’s Science Media Center. “The paper’s conclusions are based on arithmetic manipulation of relative rates of all-cause mortality in some of the screening trials. It is therefore difficult to give credence to the claim that screening largely does not extend expected lifetime.”
He also questioned the inclusion of one particular trial in the University of Oslo study—the Canadian National Breast Screening Study—“as there is now public domain evidence of subversion of the randomization in this trial,” he added.
Another expert, Leigh Jackson, PhD, of the University of Exeter in the UK, described the University of Oslo study as “methodologically sound with some limitations which the authors clearly state.”
But he observed that “the focus on 2.1 million individuals is slightly misleading. The study considered many different screening tests and 2.1 million was indeed the total number of included patients, however, no calculation included that many people.”
Jackson also characterized the length of follow-up as a limitation. “This may have limited the amount of data included and also not considering longer follow-up may tend to underestimate the effects of screening,” he said.
This published study—along with the range of credible criticisms offered by other scientists—demonstrates how analysis of huge volumes of data is making it possible to tease out useful new insights. Clinical laboratory managers and pathologists can expect to see other examples of researchers assembling large quantities of data across different areas of medicine. This huge pools of data will be analyzed to determine the effectiveness of many medical procedures that have been performed for years with a belief that they are helpful.
Though still in trials, early results show tests may be more accurate than traditional clinical laboratory tests for detecting prostate cancer
Within weeks of each other, different research teams in the US and UK published findings of their respective efforts to develop a better, more accurate clinical laboratory prostate cancer test. With cancer being a leading cause of death among men—second only to heart disease according to the Centers for Disease Control and Prevention (CDC)—new diagnostics to identify prostate cancer would be a boon to precision medicine treatments for the deadly disease and could save many lives.
Thus, these are two different pathways toward the goal of achieving earlier, more accurate diagnosis of prostate cancer, the holy grail of prostate cancer diagnosis.
“There is currently no single test for prostate cancer, but PSA blood tests are among the most used, alongside physical examinations, MRI scans, and biopsies,” said Dmitry Pshezhetskiy, PhD (above), Professorial Research Fellow at University of East Anglia and one of the authors of the UEA study. “However, PSA blood tests are not routinely used to screen for prostate cancer, as results can be unreliable. Only about a quarter of people who have a prostate biopsy due to an elevated PSA level are found to have prostate cancer. There has therefore been a drive to create a new blood test with greater accuracy.” With the completion of the US and UK studies, clinical laboratories may soon have a new diagnostic test for prostate cancer. (Photo copyright: University of East Anglia.)
East Anglia’s Research into a More Accurate Blood Test
Scientists at the University of East Anglia (UEA) worked with researchers from Imperial College in London, Imperial College NHS Trust, and Oxford BioDynamics to develop a new precision medicine blood test that can detect prostate cancer with greater accuracy than current methods.
The researchers evaluated their test in a pilot study involving 147 patients. They found their testing method had a 94% accuracy rate, which is higher than that of PSA testing alone. They discovered their test significantly improved the overall detection of prostate cancer in men who are at risk for the disease.
“When tested in the context of screening a population at risk, the PSE test yields a rapid and minimally invasive prostate cancer diagnosis with impressive performance,” Dmitry Pshezhetskiy, PhD, Professorial Research Fellow at UEA and one of the authors of the study told Science Daily. “This suggests a real benefit for both diagnostic and screening purposes.”
The UK scientists hope their test can eventually be used in everyday clinical practice as there is a need for a highly accurate method for prostate cancer screening that does not subject patients to unnecessary, costly, invasive procedures.
Cedars-Sinai’s Research into Nanotechnology Cancer Testing
Researchers from Cedars-Sinai Cancer took a different approach to diagnosing prostate cancer by developing a nanotechnology-based liquid biopsy test that detects the disease even in microscopic amounts.
Their test isolates and identifies extracellular vesicles (EVs) from blood samples. EVs are microscopic non-reproducing protein and genetic material shed by all cells. Cedars-Sinai’s EV Digital Scoring Assay accurately extracts EVs from blood and analyzes them faster than similar currently available tests.
“This research will revolutionize the liquid biopsy in prostate cancer,” said oncologist Edwin Posadas, MD, Medical Director of the Urologic Oncology Program and co-director of the Experimental Therapeutics Program in Cedars-Sinai Cancer in a press release. “The test is fast, minimally invasive and cost-effective, and opens up a new suite of tools that will help us optimize treatment and quality of life for prostate cancer patients.”
The researchers tested blood samples from 40 patients with prostate cancer. They found that their EV test could distinguish between cancer localized to the prostate and cancer that has spread to other parts of the body.
Microscopic cancer deposits, called micrometastases, are not always detectable, even with advanced imaging methods. When these deposits spread outside the prostate area, focused radiation cannot prevent further progression of the disease. Thus, the ability to identify cancer by locale within the body could lead to new precision medicine treatments for the illness.
“[The EV Digital Scoring Assay] would allow many patients to avoid the potential harms of radiation that isn’t targeting their disease, and instead receive systemic therapy that could slow disease progression,” Posadas explained.
Other Clinical Laboratory Tests for Prostate Cancer Under Development
According to the American Cancer Society, the number of prostate cancer cases is increasing. One out of eight men will be diagnosed with the illness during his lifetime. Thus, developers have been working on clinical laboratory tests to accurately detect the disease and save lives for some time.
In “University of East Anglia Researchers Develop Non-Invasive Prostate Cancer Urine Test,” Dark Daily reported on a urine test also developed by scientists at the University of East Anglia that clinical laboratories can use to not only accurately diagnose prostate cancer but also determine whether it is an aggressive form of the disease.
And in “UPMC Researchers Develop Artificial Intelligence Algorithm That Detects Prostate Cancer with ‘Near Perfect Accuracy’ in Effort to Improve How Pathologists Diagnose Cancer ,” we outlined how researchers at the University of Pittsburgh Medical Center (UPMC) working with Ibex Medical Analytics in Israel had developed an artificial intelligence (AI) algorithm for digital pathology that can accurately diagnose prostate cancer. In the initial study, the algorithm—dubbed the Galen Prostate AI platform—accurately detected prostate cancer with 98% sensitivity and 97% specificity.
More research and clinical trials are needed before the new US and UK prostate cancer testing methods will be ready to be used in clinical settings. But it’s clear that ongoing research may soon produce new clinical laboratory tests and diagnostics for prostate cancer that will steer treatment options and allow for better patient outcomes.
Study may lead to clinical laboratory involvement in repurposing hormonal treatments to prevent cancer treatment resistance
Diagnosing prostate cancer and identifying which patients have aggressive forms of the cancer has been a challenge. But new insights into how aggressive cancers become resistant to drug therapies—and the discovery of a way to repurpose hormonal treatment to block or slow aggressive prostate cancer—may lead to clinical laboratories monitoring the progress of patients’ being treated with this new type of therapy.
Instead of treating tumors directly, the new approach developed by an international team of scientists would target proteins that typically regulate a cell’s circadian rhythm, but which have been found to be helping cancerous cells become resistant to treatment therapies.
“Our discovery has shown us that we will need to start thinking outside the box when it comes to new drugs to treat prostate cancer and test medicines that affect the circadian clock proteins in order to increase sensitivity to hormonal therapy in prostate cancer,” said Wilbert Zwart, PhD (above), Lead Researcher and Senior Group Leader Oncogenomics Division at NKI, in a news release. This discovery could give clinical laboratories and anatomic pathology groups an effective way to monitor new forms of cancer hormonal treatments. (Photo copyright: Netherlands Cancer Institute.)
Breakthrough Could Mean New Treatment for Aggressive Cancer
The aim of prostate cancer hormone therapy (AKA, androgen suppression therapy) is to halt signals by male hormones (usually testosterone) that stimulate tumor growth. This approach works until cancer becomes resistant to the drug therapy.
So, the challenge in metastatic prostate cancer treatment is finding a drug that prevents resistance to hormonal therapy.
In addressing the challenge, the researchers made a surprising discovery about what exactly dilutes anti-hormonal therapy’s effectiveness. Proteins that regulate the body’s sleep-wake cycle, or circadian rhythm, were found to also “dampen the effects of the anti-hormonal therapy,” according to the study.
“Prostate cancer cells no longer have a circadian rhythm. But these ‘circadian clock’ proteins acquire an entirely new function in the tumor cells upon hormonal therapy: they keep these cancer cells alive, despite treatment. This has never been seen before,” said Wilbert Zwart, PhD, Lead Researcher and Senior Group Leader Oncogenomics Division, NKI, in the news release.
The research suggests treatment for metastatic prostate cancer requires drugs “which influence the day-and-night rhythm of a cell,” and not necessarily medications that fight cancer, Technology Networks noted.
“Fortunately, there are already several therapies that affect circadian proteins, and those can be combined with anti-hormonal therapies. This lead, which allows for a form of drug repurposing, could save a decade of research,” Zwart added.
Questioning Hormonal Therapy Resistance
In their paper, the Dutch researchers acknowledged that androgen receptor (AR)-targeting agents are effective in prostate disease stages. What they wanted to learn was how tumor cells bypass AR suppression.
For the study, the scientists enrolled 56 patients with high-risk prostate cancer in a neoadjuvant clinical trial. Unlike adjuvant therapy, which works to lower the risk that cancer will return following treatment, the purpose of neoadjuvant therapy is to reduce the size of a tumor prior to surgery or radiation therapy, according to the National Institute of Health (NIH) National Cancer Institute (NCI).
The researchers performed DNA analysis of tissue samples from patients who had three months of anti-hormonal therapy before surgery. They observed that “genes keeping tumor cells alive were controlled by a protein that normally regulates the circadian (body) clock,” said Simon Linder, PhD student and researcher at NKI, in the news release.
“We performed integrative multi-omics analyses on tissues isolated before and after three months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state,” the researchers wrote in Cancer Discovery.
“Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward pro-survival signaling and uncovered the circadian regulator ARNTL [Aryl hydrocarbon receptor nuclear translocator-like protein 1] as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development,” the scientists concluded.
More Research Planned
The scientists expressed intent to follow-up with Oncode to develop a drug therapy that would increase anti-hormonal therapy’s effectiveness in prostate cancer patients.
Given the molecular processes involved in the researchers’ discovery, there may be a supportive role for clinical laboratories and anatomic pathology groups in the future. But that can only happen after more studies and a US Food and Drug Administration (FDA) review of any potential new therapy to combat hormonal treatment resistance in prostate cancer patients.
Access to vast banks of genomic data is powering a new wave of assessments and predictions that could offer a glimpse at how genetic variation might impact everything from Alzheimer’s Disease risk to IQ scores
Anatomic pathology groups and clinical laboratories have become accustomed to performing genetic tests for diagnosing specific chronic diseases in humans. Thanks to significantly lower costs over just a few years ago, whole-genome sequencing and genetic DNA testing are on the path to becoming almost commonplace in America. BRCA 1 and BRCA 2 breast cancer gene screenings are examples of specific genetic testing for specific diseases.
However, a much broader type of testing—called polygenic scoring—has been used to identify certain hereditary traits in animals and plants for years. Also known as a genetic-risk score or a genome-wide score, polygenic scoring is based on thousands of genes, rather than just one.
Now, researchers in Cambridge, Mass., are looking into whether it can be used in humans to predict a person’s predisposition to a range of chronic diseases. This is yet another example of how relatively inexpensive genetic tests are producing data that can be used to identify and predict how individuals get different diseases.
Assessing Heart Disease Risk through Genome-Wide Analysis
Sekar Kathiresan, MD, Co-Director of the Medical and Population Genetics program at Broad Institute of MIT/Harvard and Director of the Center for Genomics Medicine at Massachusetts General Hospital (Mass General); and Amit Khera, MD, Cardiology Fellow at Mass General, told MIT Technology Review “the new scores can now identify as much risk for disease as the rare genetic flaws that have preoccupied physicians until now.”
“Where I see this going is that, at a young age, you’ll basically get a report card,” Khera noted. “And it will say for these 10 diseases, here’s your score. You are in the 90th percentile for heart disease, 50th for breast cancer, and the lowest 10% for diabetes.”
However, as the MIT Technology Review article points out, predictive genetic testing, such as that under development by Khera and Kathiresan, can be performed at any age.
“If you line up a bunch of 18-year-olds, none of them have high cholesterol, none of them have diabetes. It’s a zero in all the columns, and you can’t stratify them by who is most at risk,” Khera noted. “But with a $100 test we can get stratification [at the age of 18] at least as good as when someone is 50, and for a lot of diseases.”
Sekar Kathiresan, MD (left), Co-Director of the Medical and Population Genetics program at Broad Institute at MIT/Harvard and Director of the Center for Genomics Medicine at Massachusetts General Hospital; and Amit Khera, MD (right), Cardiology Fellow at Mass General, are researching ways polygenic scores can be used to predict the chance a patient will be prone to develop specific chronic diseases. Anatomic pathology biomarkers and new clinical laboratory performed genetic tests will likely follow if their research is successful. (Photo copyrights: Twitter.)
Polygenic Scores Show Promise for Cancer Risk Assessment
“It was also striking how results from population-based studies were reproduced using data from electronic health records, a database not ideally designed for specific research questions and [which] is certainly not a population-based sample,” she continued.
The UCSD study highlights one of the unique benefits of polygenic scores. A person’s DNA is established in utero. However, predicting predisposition to specific chronic diseases prior to the onset of symptoms has been a major challenge to developing diagnostics and treatments. Should polygenic risk scores prove accurate, they could provide physicians with a list of their patients’ health risks well in advance, providing greater opportunity for early intervention.
Future Applications of Polygenic Risk Scores
In the January issue of the British Medical Journal (BMJ), researchers from UCSD outlined their development of a polygenic assessment tool to predict the age-of-onset of aggressive prostate cancer. As Dark Daily recently reported, for the first time in the UK, prostate cancer has surpassed breast cancer in numbers of deaths annually and nearly 40% of prostate cancer diagnoses occur in stages three and four. (See, “UK Study Finds Late Diagnosis of Prostate Cancer a Worrisome Trend for UK’s National Health Service,” May 23, 2018.)
An alternative to PSA-based testing, and the ability to differentiate aggressive and non-aggressive prostate cancer types, could improve outcomes and provide healthcare systems with better treatment options to reverse these trends.
While the value of polygenic scores should increase as algorithms and results are honed and verified, they also will most likely add to concerns raised about the impact genetic test results are having on patients, physicians, and genetic counselors.
And, as the genetic testing technology of personalized medicine matures, clinical laboratories will increasingly be required to protect and distribute much of the protected health information (PHI) they generate.
Nevertheless, when the data produced is analyzed and combined with other information—such as anatomic pathology testing results, personal/family health histories, and population health data—polygenic scores could isolate new biomarkers for research and offer big-picture insights into the causes of and potential treatments for a broad spectrum of chronic diseases.
Pathologists around the world will be interested to learn that, for the first time in the UK, prostate cancer has surpassed breast cancer in numbers of deaths annually and nearly 40% of prostate cancer diagnoses occur in stages three and four
Early detection of prostate cancer, and the ability to identify its more aggressive forms, are important goals for every nation’s health system. However, a new study in the United Kingdom (UK) will be of interest to all anatomic pathologists handling prostate biopsies. Researchers determined that late diagnosis of prostate cancer is an issue that should be addressed by healthcare policymakers in the UK.
In 2015, deaths due to prostate cancer surpassed those of breast cancer in the UK. According to data from Cancer Research UK, this trend continued into 2016 with 11,631 deaths from prostate cancer and 11,538 deaths from breast cancer. The trend continued even though breast cancer saw roughly 8,000 more new cases in 2015, according to the same data.
Now, a report from Orchid—a UK male cancer charity—highlights a trend that should interest medical laboratories and histopathology (anatomic pathology in the US) groups that analyze prostate cancer samples. They found that 37% of UK prostate cancer cases involved diagnoses in stages three or four.
Late-Stage Diagnosis of Prostate Cancer: The US and UK Compared
“With prostate cancer due to be the most prevalent cancer in the UK within the next 12 years, we are facing a potential crisis in terms of diagnostics, treatment, and patient care,” stated Rebecca Porta, Chief Executive of Orchid, in a press release. “Urgent action needs to be taken now if we are to be in a position to deliver world class outcomes for prostate cancer patients and their families in the future.”
Orchid Chief Executive Rebecca Porta (far right) and her team are shown above receiving a check from the Industrial Agents Society (AIS) to help fund the charity’s research into male specific cancers, such as prostate cancer. (Photo copyright: AIS.)
The latest data from the Centers for Disease Control and Prevention (CDC) on prostate cancer and mortality rates in the US shows an interesting picture. In 2014, 172,258 men received a prostate cancer diagnosis. However, deaths from prostate cancer were at 28,343.
According to Statista, an international statistics portal, the UK is home to more than 32.3-million males. And, Statista’s data shows the US is home to 159.1-million males. This implies that despite the US having nearly five times the number of males, the number of prostate cancer deaths/year in the UK is significantly higher in relation to population size.
Cancer Research UK notes that despite decreasing by 13% in the last decade, prostate cancer mortality rates are still 21% higher than in the 1970s.
Awareness and Early Detection Key Components in the Fight Against Cancer
A study published in BMC Public Health offers one possible explanation for this disparity.
“Poorer outcomes in the UK are at least in part attributable to later stage diagnoses,” she explained. “Older adults should be vigilant about cancer. Yet, this is not reflected in the news media coverage of cancer risk. Taken together, invisibility, inaccuracy, and information overload build a skewed picture that cancer is a disease which affects younger people.”
While treatment options have improved in the past decade, early detection is a key part of successful treatment—especially as prostate cancer has both aggressive and slow variants. Effective timely health screening also is of critical concern.
Faster diagnosis and the ability to detect whether a prostate cancer is slow or aggressive could help to shift these numbers around the world.
According to BBC News, the NHS hopes to reduce diagnosis times and make the screening process less invasive by using magnetic resonance imaging (MRI). Hashim Ahmed, PhD, Chairman of Urology, Imperial College London, told BBC News, “Fast access to high-quality prostate MRI allows many men to avoid invasive biopsies as well as allowing precision biopsy in those men requiring it to find high-risk tumors much earlier.”
A team from the University of Dundee is trialing a shear wave elastography imaging (SWEI) process to detect prostate tumors as well. Speaking with The Guardian, team leader and Chair of the School of Medicine at The University of Dundee, Dr. Ghulam Nabi, noted, “We have been able to show a stark difference in results between our technology and existing techniques such as MRI. The technique has picked up cancers which MRI did not reveal. We can now see with much greater accuracy what tissue is cancerous, where it is, and what level of treatment it needs. This is a significant step forward.”
Should these tools prove successful, they might help to reverse current trends in the UK and offer greater insight and options for the histopathology groups there, as well as the medical laboratories, oncologists, and other medical specialists helping to treat cancer.
Until then, raising awareness and streamlining both detection and treatment protocols will remain a critical concern, not just in the UK, but around the world as the human population continues to age.
