There is growing interest in tumour markers as aids for the diagnosis, staging and management of cancer. Some are expected to succeed, after several years of evaluation to trials and eventual clinical use. A large number, however, are not likely to make it beyond development. On their part, physicians need to be aware of both opportunities and limitations in the clinical use of tumour markers.
Tumour markers are substances (antigens, proteins, enzymes or hormones) which indicate the presence of cancer or provide information about its likely course of development. They are present in cancerous tissue as well as in the bodily fluids of cancer patients.
Range of applications
Tumour markers have shown their potential for several applications. These range from the differential diagnosis of benign and malignant conditions to prognostic assessments, postoperative surveillance, the prediction of drug response or resistance, and the monitoring of therapy in
advanced disease.
The key advantage of tumour markers in the above applications is convenience. Inexpensive automated assays allow for fast processing of samples.
The case for tumour markers
The best known tumour markers include Her2/neu for breast cancer, which has an established economic case. Her-2/neu is a target for trastuzumab, whose use as an adjuvant has been shown to decrease cancer recurrence rates by 50%. However, up to one in 20 trastuzumab recipients develop cardiac dysfunction. Given that the cost of one year of therapy is close to 100,000 Euros, the need for accurately and precisely assaying every tissue sample is evidently strong.
Work in progress
Tumour markers are, however, still a work in progress and expected to remain so. In the US, the National Cancer Institute (NCI) states that “more than 20 tumour markers are currently in use.” It however lists over 30. The European Group on TumoUr Markers (EGTM) has a list of 16.
Despite the number of tumour markers in development, only ‘traditional’ markers are used in diagnosis, prognosis and monitoring. For example, at least six urine tumour marker kits are approved by the US Food and Drug Administration for bladder cancer. However, none are backed by data from clinical trials that increased survival time, improved quality of life or decreased cost of treatment.
Appropriate use, caution urged
Many experts urge caution with respect to tumour markers. Inappropriate use, according to an article in the ‘British Medical Journal’, can cause patients unnecessary anxiety and distress, and may also delay correct diagnosis and treatment. The authors cite one hospital audit which found “that only about 10% of requests for tumour markers were appropriate.”
The European Group on Tumor Markers attributes part of this problem to the growing availability of automated immunoassays. This makes tumour marker tests available in routine rather than specialist laboratories. “Results are consequently more readily available to non-specialist clinicians, who may be less familiar with their interpretation.”
Challenges of sensitivity and specificity
Only some markers, known as tumour-specific markers, are produced exclusively by a particular tumour As a result, most tumours cannot be detected by a single test, and tests for multiple markers are often required.
Tests are therefore often accompanied by the risk of both false positives and false negatives. The Cancer Information & Support Network (CISN) sums up the picture: False positives may occur because most tumour markers “can be made by normal cells, as well as cancer cells,” and markers “can be associated with noncancerous conditions.” On the other hand, the reason for false negatives is that “tumour markers are not always present in early stage cancers” and because “people with cancer may never have elevated tumour markers.”
For example, the level of CA-125, a marker for ovarian cancer, is also elevated in a variety of non-malignant disorders such as cirrhosis, pancreatitis, endometriosis, and pelvic inflammatory disease. In addition, medications appear to alter the results of a varied range of tests. So too do pregnancy, menstruation, cigarette smoking and various benign disorders.
Biopsy remains only definitive way for diagnosis
The above lack of sensitivity and specificity has been a major limitation facing the use of tumour markers in clinical practice. As with imaging, the use of tumour markers has been limited to supporting the diagnostic process, and the gold standard for diagnosis still remains a biopsy.
Although difficult to access areas such as the brain are likely to result in more use of tumour markers, a biopsy remains “the only definitive way” for diagnosis of a tumour” even in the brain.
NACB Guidelines
In 2008, the National Academy of Clinical Biochemistry (NACB) in the US released updated Laboratory Medicine Practice Guidelines for the use of tumour markers.
The guidelines made cross-referrals to efforts by numerous professional and regulatory best-practices bodies, including the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN), Britain’s National Institute for Health and Clinical Excellence (NICE), the European Group on Tumor Markers (EGTM), the International Federation of Gynecology and Obstetrics (FIGO) and the Gynecologic Cancer Intergroup (GCIG).
The NACB guidelines cover five cancer sites: testicular, prostate, colorectal, breast, and ovarian.
Testicular cancer
For testicular cancer, α-fetoprotein (AFP), human chorionic gonadotropin and lactate dehydrogenase are recommended for diagnosis, staging, prognosis determination, recurrence detection and the monitoring of therapy. AFP is also recommended for the differential diagnosis of tumours
Prostate cancer
Prostate-specific antigen (PSA) is considered to be potentially useful for detecting prostate cancer recurrence and monitoring therapy. Free PSA is considered useful for distinguishing malignant from benign prostatic disease.
Colorectal cancer
In colorectal cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, post-operative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing is considered useful for screening asymptomatic adults who are older than 50 years.
Breast cancer
For breast cancer, estrogen and progesterone receptors predict response to hormone therapy, human epidermal growth factor receptor-2 predicts response to trastuzumab, while urokinase plasminogen activator/ plasminogen activator inhibitor 1 is used for determining prognosis in lymph node-negative patients. CA15-3/BR27–29 or carcinoembryonic antigen can be used for therapy monitoring in advanced disease.
Ovarian cancer
CA125 is recommended (with transvaginal ultrasound) for early detection of ovarian cancer in women at high risk for this disease. CA125 is also recommended for differential diagnosis of suspicious pelvic masses in post-menopausal women, as well as for detection of recurrence, monitoring of therapy, and determination of prognosis in women with ovarian cancer.
Future research to target higher specificity and sensitivity
In the future, research is expected to focus on finding markers which are specific of one pathology, have higher sensitivity with a low cut-off and deliver results which correlate to tumour mass and growth potential. Ideal candidates would also have a short life duration to permit efficient follow-up; in other words, their presence should decrease during treatment and increase before a relapse.
The promise and challenges of screening
Given that tumour markers can aid in assessing the response to cancer treatment and making prognoses, many public health professionals have hoped they might also be used for screening tests which would detect cancer before the presence of symptoms.
Indeed, many tests have both screening and diagnostic uses, with only the context of use determining whether the test is one or the other. “A screening test is done on asymptomatic individuals who receive the test principally because they are of the age or sex at risk for the cancer. A diagnostic test is done on an individual because of clinical suspicion of disease.”
However, no tumour marker identified to date is sufficiently sensitive or specific to be used on its own for screening, demonstrating a survival benefit in randomized controlled trials in the general population.
One of the best known examples is the prostate-specific antigen (PSA) test. Although it is now accepted that most men with elevated PSA levels do not have prostate cancer, the implications of this remain mired in controversy and also illustrate the kind of limitations which other tumour biomarkers may face in the future for use in screening.
PSA screening has been the subject of two large randomized controlled trials in the US and Europe in the 2000s. However, as the Mayo Clinic notes, in spite of the size of the trials, there were “no clear conclusions.” This is because their diversity of methodology allows for significant flexibility in interpretation. As a result, “the decision of whether to screen or not screen – using PSA testing or other means or both – is a decision best made between physicians and their individual patients.”
The two trials were PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) conducted by the National Cancer Institute in the US, and the European Randomized Study of Screening for Prostate Cancer (ERSPC), billed as “the largest randomized trial of screening for prostate cancer” with 162,388 subjects.
In 2011, a US government task-force concluded that healthy men should not be screened for prostate cancer. The finding, which “drastically changed the standard of care for middle-age American men who had grown accustomed to annual screenings,” was largely based on 10 years data from the two studies, which found risk of over-diagnosis and over-treatment.
Problems began when follow-on data from ERSPC two years later showed screening was associated “with a 21% reduction in risk of prostate cancer mortality.” However, this was accompanied by a still-sizeable risk of over-diagnosis and over-treatment. As a result, the authors said that “population-based screening could not yet be recommended.
In April 2015, an article in ‘The Lancet’ re-confirmed “a substantial 21% reduction” from PSA screening. However, due to access restrictions to the ERSPC trial data, the authors called this figure into serious question.
The controversy is unlikely to go away for some time. An Op Ed in The New York Times called the PSA test “hardly more effective than a coin toss.” Although the date of publication was 2010, the author of the commentary was Dr. Richard Ablin, who discovered PSA in 1970.
Such challenges are also likely to accompany screening for other conditions. For instance, data from the PLCO trial show that screening for CA-125 (recommended by the National Academy of Clinical Biochemistry for women with ovarian cancer, along with transvaginal ultrasound), does not reduce ovarian cancer mortality. Instead, false-positive screening test results have been associated with complications.
Molecular diagnostics is seen as the gateway to an era of personalized medicine. It detects DNA and RNA-level abnormalities that provoke and fuel most diseases. As a result, it offers precise diagnosis, determines the susceptibility of a patient to a specific disease and assesses his or her response to therapy. Moelcular diagnostics can also establish a patient’s prognosis over time far more scientifically than what is often no more than a physician’s informed guess.
Tailored therapy, patient convenience
The track record of molecular diagnostics is, on first sight, impressive.
For instance, FoundationOne, a molecular diagnostic test from Foundation Medicine, scans a patient’s tumour sample for changes in 238 genes that drive cancers, helping oncologists to “choose drugs targeted to the genetic profile of a patient’s tumour cells.”
Another example is Cologuard, from Exact Sciences, which screens stool samples for colorectal cancer. Apart from greater accuracy, the technique is far less invasive than colonoscopy. According to The Mayo Clinic, this will enable more people to get tested earlier and ‘revolutionize’ the fight against colorectal cancer.
Convenience in access is also central to tests from TrovaGene, which utilizes urine samples. Priority targets for the company include malignant melanoma, whose rate of spread makes early detection invaluable, but is also an especially difficult cancer to diagnose via traditional means.
Genomic Health: single-product trailblazer
A poster child of the molecular diagnostic revolution is Genomic Health. The company was founded 15 years ago to close the gap between genomic research and real-life benefits for cancer patients.
Based on the success of a single product, Oncotype Dx, the company has reached a market value of about $1 billion. Oncotype Dx predicts relapse rates of women with breast cancer and assesses benefits from different types of chemotherapy. Its scope has also been extended to prostate and colon cancer.
Targeting broad spectrum of diseases
New molecular diagnostic products, however, go beyond cancer to other challenging conditions. Rheumatoid arthritis is the focus for Crescendo Bioscience, which has developed a test for 12 different proteins in a blood sample of patients. Its metrics are the first to measure molecular activity of the disease and permits a quicker decision to screen for antibodies. The test, moreover, can determine the effectiveness of a cheap, generic steroid such as dexamethasone on a particular patient, as it can about the ineffectiveness of biotech drugs – whose costs range from $1,000 to $3,000 a month.
In some cases, research breakthroughs have allowed firms to offer tests for a variety of diseases out of the same platform. The tests from TrovaGene, for example, are based on proprietary cell-free nucleic acid (cf-NA) techniques – and can be used for cancer as well as infectious disease, organ transplantation and prenatal genetic testing.
Regulation holds key to building confidence
In spite of its strong case, the proponents of molecular diagnostics lament that current use is far below potential. Such arguments have reached fever pitch, especially in the US.
The reason seems ironical. The industry has been calling for more government regulation. An Op-Ed piece in ‘The Boston Globe’ in 2011 explains why. Due to the absence of clear approval policies, it notes, both payers and physicians lacked confidence about the reliability and accuracy of molecular diagnostics. The authors of the Op-Ed, Mara Aspinall, then CEO of an IP-rich molecular diagnostics company On-Q-ity, and Brook Byers of venture capital powerhouse Kleiner, Perkins, Caufield & Byers, were especially scathing about the decision by the Food and Drug Administration (FDA) “to regulate diagnostic tests as ‘medical devices’,” and proposed that molecular diagnostics requires both “new expertise and a new regulatory focus.”
These kind of concerns seemed prescient. Within two years, Aspinall’s On-Q-ity had folded. Following its demise, an industry analyst observed that molecular diagnostics faced similar concerns as therapeutics, but was confronted “by larger reimbursement and regulatory uncertainties.”
CLIA certification and reimbursement
Many molecular diagnostic tests on the US market have not been endorsed by the FDA, or been classified as eligible for Medicare. Indeed, tests approved by the FDA largely concern infectious diseases and companion diagnostics.
Most vendors have their products certified under the less stringent Clinical Laboratory Improvement Amendments (CLIA) standard. Some have succeeded in obtaining Medicare reimbursement, with only CLIA certification. However, this has been lengthy. For example, Crescendo’s rheumatoid arthritis test discussed previously was sold for three years, before being approved by Medicare.
Others have fared worse, in spite of successful products on the market. Foundation Medicine’s tumour test (see above) is neither FDA-approved, nor reimbursed by Medicare. As a result, the company has to negotiate with payers to get paid every time a patient is tested with its product.
Multiple, complex challenges
There are several layers in the underlying problem.
The first is the regulation of diagnostic tests as medical devices. As explained by ‘Expert Review of Molecular Diagnostics’, current regulatory systems were written to regulate a broader array of products, and “molecular diagnostics are now being fitted into that existing framework.” Though there will be overlaps, it is “appropriate to treat molecular diagnostics – properly defined – in a different manner to a group consisting of all other IVDs.” This is clearly not yet the case. A certification program at the University of California, San Diego, for example, notes: “Molecular diagnostics, or in vitro diagnostics …”.
A second regulatory challenge is that molecular diagnostics encompasses both test assays as well as instruments and equipment. The latter are more clearly akin to devices, assays far less so. However, a problem arises when instruments used in assay development are specifically referenced for approvals. A Draft Guidance from the FDA in April 2013 acknowledges such a limitation.
The third factor is the linkage between genomics research on biomarkers, which yields masses of data, but does not provide clinically useful information for real-world molecular diagnostics. This can only be achieved in a gray area between a research laboratory and a clinical laboratory.
Research use only versus diagnostics
The FDA regulates (in vitro) diagnostic kits explicitly designed for diagnostic use. In sharp contrast, research use only (RUO) products are unregulated. Their definition in FDA regulations covers labelling only and is sketchy, specifying that they should be “in the laboratory research phase of development and not represented as an effective in vitro diagnostic product.”
Biomarker assays are usually labelled RUO since their clinical use is unknown, until after their diagnostic effectiveness has been evaluated in a clinical laboratory. Some maintain this status indefinitely, staying outside FDA jurisdiction.
The regulatory problem arises once a clinical laboratory evaluation of a biomarker begins to move on its own course.
From in vitro to molecular diagnostics: difference in detail
As explained by Jeffrey Gibbs of the law firm Hyman, Phelps & McNamara, the roots of the RUO challenge date to the 1990s, when many RUO products began to be used by laboratories for clinical applications. At this time, companies labelled their in vitro assays and instruments as RUO but then promoted them for diagnostic use – in some cases, making specific claims too.
In 1997, the FDA sought to curb this practice with a regulation on analyte specific reagents (ASR), targeting the basic chemical components used in diagnostic assays. However, it became clear some years later that the ASR regulation was being used to camouflage sales of more complex products. In 2007, the FDA issued a guidance document on ASRs, prohibiting the combination of more than one active component.
This, as Mr. Gibbs states, was acceptable for in vitro diagnostics. It was clearly not so for molecular diagnostics, where, for example, a primer and probe pair need to be offered together. To cope with this, a number of companies relabelled their ASRs as (unregulated) RUOs.
In a draft guidance in 2011, the FDA proposed sanctioning companies for selling RUO diagnostic products to clinical labs. Of special concerned were ‘high-risk’ laboratory-developed tests (LDTs) impacting on major treatment decisions – attention to which strengthened in 2011 after the prestigious Duke University used faulty genomic markers to select therapy for cancer patients.
FDA steps in, but industry remains uncertain
The end of 2013 saw a series of major moves by the FDA, which will have a bearing on the shape of the molecular diagnostics industry in the years to come.
One was to shut down health-related genetic tests by direct-to-consumer firms, including market leader 23andMe, which has been selling kits and test results for carrier status, health risks, and drug response.
Another was to provide the first-ever FDA clearance of a next-generation sequencing (NGS) instrument and universal reagents, opening the way for tests to be cleared on their own merits. This may encourage a move by companies of their RUO products into the FDA process.
The FDA also issued a Final Guidance on how companies could market RUO and investigational use only (IUO) diagnostic tests and instruments, which several clinical laboratories had been using for LDTs.
In its Guidance, the FDA backed off from its plans two years before to sanction RUO product sales to clinical laboratories. However, it opens the way for enforcement – and another kind of uncertainty for molecular diagnostic companies, for some time to come.
The Guidance notes that if a manufacturer “were to assist in the validation or verification of the performance of a test for clinical diagnostic use that uses its RUO or IUO labelled IVD, that assistance would be considered to be evidence of a non-research or non-investigational intended use.”
The wording of the Final Guidance leaves considerable room for interpreting the marketing and sales behaviour of both vendors and clinical laboratories. These are likely to be taken up for enforcement actions by the FDA on a case-by-case basis.
As another recent commentary by law firm Hyman, Phelps & McNamara observes, the FDA “says it will take enforcement action based on the totality of the circumstances. What that actually means remains to be seen. As with most things with FDA, we will simply have to wait and see.”
Although HIV/AIDS is still the leading cause of death in Africa, and the fourth cause of death globally killing one and a half million people per year, substantial progress has been made in its prevention, diagnosis and treatment in recent years. Thanks particularly to effective antiretroviral drugs requiring less complex dosing regimens, HIV/AIDS is no longer an inevitably fatal disease for the approximately 40% of patients receiving antiretroviral therapy (ART), but rather a chronic condition, albeit one which involves careful and continuous monitoring. However in spite of occasional claims that HIV-positive subjects have been cured of their infection, the so-called ‘Berlin patient’ is still the only person known to have recovered from HIV/AIDS. And he, after eleven years of living with HIV/AIDS, was given bone marrow transplants to treat his acute myeloid leukemia from a donor with a rare mutation affecting the CCR5 HIV co-receptor. Such therapy is, of course, impossible to provide on a large scale; 60% of HIV/AIDS patients are not even receiving ART.
In spite of intensive efforts to develop a safe vaccine, now facilitated by the WHO-UNAIDS HIV Vaccine Initiative, no tested candidates have so far been sufficiently effective to progress beyond clinical trials. Until such a vaccine is available, pre-exposure prophylaxis (PrEP) with the antiretroviral drug ‘Truvada’, approved by the FDA over two years ago for preventing HIV infection, is being prescribed to United States residents at high risk of being infected by HIV. And the US Centers for Disease Control and Prevention recently recommended PrPE for HIV-negative subjects with HIV-positive partners, as well as for people who have had risky, condomless sex or have shared needles when injecting drugs. Even the World Health Organization’s recent HIV prevention guidelines, whilst stressing condom use to prevent infection, recommended the use of PrEP for gay men “as an additional HIV prevention choice”.
So in the face of such endorsements why are the European Medicines Agency (EMA) and the European Centre for Disease Prevention and Control (ECDC) still dragging their feet? Apparently the ECDC, in spite of conceding that the many robust studies using Truvada for PrEP show “encouraging results”, states that insufficient European-specific research has been carried out on the efficacy, cost-effectiveness and side effects of PrEP as well as on possible changes in the sexual behaviour of subjects taking prophylaxis. And indeed it is tragic that so many people with HIV/AIDS are not yet receiving appropriate treatment, but does it really help them to deny PrEP to Europeans who need it?
Although formally defined as recently as the early 2000s, biomarkers have quickly begun to gain acceptance in clinical practice. Many experts believe they will become an indispensable tool for the diagnosis and management of a wide variety of medical conditions in the near future.
Cardiovascular disease now a global priority
One of the priority applications for biomarkers is likely to be for cardiovascular diseases (CVD) – the leading cause of mortality and disability in the Western world. In Europe, CVD causes 1.9 million deaths a year, while the toll in the US is about 1 million.
The prevalence of CVD is also increasing rapidly in newly industrializing countries, especially among the more affluent urban populations adopting Western lifestyles. Indeed, “CVD is now more numerous in India and China than in all economically developed countries in the world added together.”
Mapping the disease progression pathway
It has, for some time, been accepted that CVD follows a relatively clear-cut pathway from subclinical to overt status. The Multi-Ethnic Study of Atherosclerosis (MESA), sponsored in the year 2000 by the US National Institutes of Health, has been seeking to assess the characteristics of subclinical CVD and means to predict its progression to clinically overt cardiovascular disease. More recently, in 2010, Spain’s Banco Santander and the Istituto de Salud Carlos III launched a similar effort in Europe called PESA (Progression of Early Subclinical Atherosclerosis).
Such efforts are targeted at providing clinicians with tools to help assess CVD and identify vulnerable, at-risk patients. In many respects, they complement the world’s most ambitious effort in the area, the Framingham Heart Study, which began in 1948 in a town in Massachusetts in the US with 5,209 adult subjects. The Study, which has now enrolled its third generation of participants, has resulted in the publication of over 1,000 medical papers. It has also provided many commonplace tools for the contemporary understanding of CVD, including the impact of smoking, diet and exercise, medications such as aspirin etc. – as well as the term ‘risk factor’.
The Framingham project: clarifying the role of biomarkers
Biomarkers began to be part of the Framingham project in the 2000s, although initial results were unclear. For instance, enthusiasm about elevated levels of the inflammation marker C-reactive protein (CRP) as an independent risk factor for future CVD events were dispelled in a 2005 study supported by the Framingham sponsors.
In September 2012, a study in the American Heart Association’s journal ‘Circulation’ pointed to one reason for such conflicting assessments, namely the “lack of cardiovascular specificity” in many of the new biomarkers. The authors sought to address such limitations by studying three key CVD biomarkers (soluble ST2, growth differentiation factor-15 and high-sensitivity troponin I) in almost 3,500 patients. The findings were conclusive: “Multiple biomarkers of cardiovascular stress,” they said “add prognostic value to standard risk factors for predicting death, overall cardiovascular events, and heart failure.”
In 2014, another study of 2,680 Framingham participants sought to associate circulating biomarkers with The American Heart Association Cardiovascular Health score (CVH score). The authors concluded there was an “inverse association” between ideal CVH and CVD incidence, and that this was partly attributable to its “favourable impact on CVD biomarker levels and subclinical disease.” The list of CVD biomarkers in the 2014 study includes natriuretic peptides (N-terminal pro-atrial and B-type natriuretic peptide), plasminogen activator inhibitor-1, aldosterone, C-reactive protein, D-dimer, fibrinogen, homocysteine and growth differentiation factor-15.
Identification of at-risk patients
One of the most promising biomarkers seems to be cardiac troponin, first identified in the early 1990s. Changes in cardiac troponin T (cTnT) levels over time appear to correlate with heart failure risk, especially in a major study of elderly subjects.
The potential of circulating cTnT may also extend beyond the heart failure setting. Some argue that circulating cTnT is representative of subclinical myocardial dysfunction. In the general population, studies show that elevated cTnT is associated with subclinical cardiac injury, and marks an increased risk for structural heart disease and all-cause mortality.
Other studies have found that myeloperoxidase (MPO) and high-sensitivity C-reactive protein (hsCRP) in apparently healthy populations can predict risk of coronary disease, allowing for early preventative treatment. Together, MPO and C-reactive protein have also shown promise in prognostic risk assessment for patients with systolic heart failure.
Enabling targeted and timely treatment
While screening the general population is bound to draw considerable attention, the more immediate application of CVD biomarkers is to enable treatment in a risk-stratified and timely fashion.
One of the biggest challenges faced by physicians is to differentiate between patients with unstable angina and acute myocardial infarction (AMI) in an emergency setting. Here too cTnT – as well as cardiac troponin I (cTnI) – have catalysed some of the greatest excitement, due to their high sensitivity and specificity for cardiac damage.
In 2007, the US National Academy of Clinical Biochemistry Laboratory Medicine Practice recommended the use of cardiac troponin as a ‘preferred’ biomarker for MI diagnosis, in conjunction with clinical evidence of myocardial ischemia. Creatine kinase-MB was positioned as an ‘acceptable alternative’. These recommendations were endorsed by the joint European Society of Cardiology/American College of Cardiology/American Heart Association/World Heart Federation task force for the definition of myocardial infarction.
Cardiac troponin ‘the best single marker’
Levels of cardiac troponin are dependent on infarct size, and directly indicate the prognosis following MI. Indeed, in recent years, some experts suggest that CTnI and CTnT have “displaced myoglobin and creatine kinase-MB as the preferred markers of myocardial injury.”
In 2013, a Health Technology Asssessment (HTA) by Britain’s National Institute for Health Research (NIHR) concurred with this view, observing that “high-sensitivity cardiac troponin is the best single marker in patients presenting with chest pain.” Additional measurements of myoglobin or creatine kinase-MB, it noted were “not clinically effective or cost-effective.”
Debate on troponin not over
Nevertheless, considerable debate remains about the utility of troponin in real world CVD management. Although patients with undetectable troponins are considered to have excellent short-term prognosis, levels may be undetectable “for six hours after the onset of myocardial cell injury,” making myoglobin “a preferred early marker” for MI. This limitation, which seems to go against the 2013 NIHR Health Technology Assessment, is also acknowledged by some proponents of troponin, who admit that although it “may be useful for risk assessment and management” in asymptomatic populations, there is no evidence that it confers “an advantage in the context of MI diagnosis.” In addition, they also note that “cTnI assays are not standardized; thus, there can be a substantial difference in values depending on the assay used.”
Defining assay sensitivity, differentiating troponin I and T
One challenge lies in the definition of a ‘high sensitivity’ assay, which can measure cTn in the single digit range of nanograms per litre. The term is used by vendors “for marketing purposes,” and there “is still no consensus” regarding its application. Making matters tougher is the fact that most manufacturers’ claims for assay precision “cannot be achieved in clinical laboratories.”
In effect, the jury on troponin is likely to be out for some time to come, accompanied by continuing uncertainties.
For instance, Britain’s respected health advisory site patient.co.uk suggests that troponin I and T “are of equal clinical value” while a 2010 guideline from NICE (National Institute for Healthcare and Clinical Excellence) advises taking a blood sample for troponin I or T as “preferred biochemical markers to diagnose acute MI.”
However, a very recent study published by the Journal of the American College of Cardiology finds that patients with neuromuscular disease can show elevated levels of troponin T but not I, thus questioning the guidelines which regard both as being “equally sensitive and specific for the diagnosis of myocardial injury.”
These may be some of the reasons why the US Food and Drug Administration (FDA) decided in June 2014 to discuss clarification of claims and protocols with vendors of troponin assays, in order to “modernize the performance evaluation and regulatory review.” In Britain, NICE is currently updating its 2010 guideline.
The role of B-type natriuretic peptide
Once acute MI is confirmed, a variety of other biomarkers are used to help make assessments.
One of the most promising of these is B-type natriuretic peptide or BNP, designated by the FDA in the year 2000 as a Class II diagnostic device.
Nevertheless, it is important to underline that only troponin has been used to direct therapeutic intervention. Though it is evident that the adoption of proven new biomarkers will increase prognostic accuracy, they have yet to be tested to alter outcomes of therapeutic intervention.
Thus, in spite of statements from reputable sources claiming that BNP is “already used to diagnose heart failure,” the truth is somewhat different, with the difference in the details. At the end of 2013, the US Agency for Healthcare Research and Quality (AHRQ), investigated BNP and the related N-terminal proBNP (NT-proBNP) for detecting heart failure (HF). The findings were guarded: “BNP and NT-proBNP had good diagnostic performance for ruling out HF but were less accurate for ruling in HF.” In addition, it found that the “therapeutic value was inconclusive.”
Other biomarkers remain valuable
In the meanwhile, clinicians in emergency settings have recourse to a variety of other established CVD risk markers, such as cholesterol. “Research is also under way on markers with strong predictive value that are not used in the clinic for cardiovascular disease risk prediction, such as fibrinogen, vitamin D, and cystatin C.” Some of these “are of special interest as these may prove to be valuable biomarkers in the future.”
To have clinical utility, however, such biomarkers will need to provide risk assessments independently of other established markers. They also require the presence of standardized assays which are specific and sensitive for the markers, with easy-to-interpret results.
In effect, biomarker-mediated approaches to CVD need to yield superior patient outcomes compared to current standard-of-care management schemes.
Whilst in many less developed countries there is a paucity of diagnostic testing and appropriate therapies, we in the West are suffering from the ‘modern epidemic’ of over-diagnosis and over-treatment. Today’s highly sensitive biomarker and imaging tests increasingly identify asymptomatic or very mild conditions that if left untreated would not cause symptoms or reduce longevity. A recent report on mammography screening in the UK suggested that 19% of breast cancers were over-diagnosed, and a US task force concluded that PSA-based prostate cancer screening over-diagnosed up to 50% of tumours. Other over-diagnosed and over-treated conditions include thyroid cancers as well as a range of cardiovascular diseases, chronic kidney disease and ADHD. At best treating such subjects is an imprudent use of health service funds; at worst ‘patients’ suffer both psychological and physical harm from their diagnosis and subsequent treatment. Of course effective screening for cancer and other serious conditions is vital, but how can the problem of over-diagnosis be at least alleviated when tests (and cut-off values) must be sensitive enough to detect pathologies that really require treatment?
When diagnostic tests are evaluated for accuracy the average sensitivity and specificity are reported. But of course individuals vary, and diseases have stages of severity. What is needed is the identification of those patients for whom treatment will do more good than harm. Similarly average results in therapeutic trials may be positive, so negative effects in some patient groups are not evident, but again the potential benefit of a treatment should be weighed against possible harm according to disease severity. And subjects being screened should surely be informed about the risk of over-diagnosis. Yet in a recent random sample of 500 Australians, only 10% of the women who had had mammography, and 18% of the men who had had prostate cancer screening reported that they had been told about the limitations of these tests.
There is also an urgent need to scrutinize the panels of medical professionals setting disease definitions. Diagnostic thresholds are frequently lowered without considering the balance between good and harm of treating the additional patient group who have a lower risk or milder symptoms. And although it may sound cynical, panels with three quarters of the members having multiple ties to pharmaceutical companies – some of which will directly benefit from an increased number of patients with the disease under discussion – surely can’t be unbiased!
Hopefully appropriate action can be taken before the seemingly inexorable trend towards over-diagnosis makes patients of us all!
November 2025
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The Netherlands
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