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International Clinical Trials

Blood Pressure

In February 2014, the World Health Organization (WHO) warned of an impending cancer ‘tidal wave’. As global populations continue to expand and people live longer, an increasing number will develop cancer. In 2012, an estimated 14.1 million new cases of cancer occurred worldwide, and some 24 million cases per year are predicted by 2035 (1).

While the WHO focuses primarily on cancer prevention, early diagnosis of cancers is critical to disease management and reducing the increasingly unsustainable healthcare costs in both developed and emerging nations. Cancer screening, where available, has a significant positive impact on life expectancy – for example, the Papanicolaou (Pap) smear for cervical cancer and mammography for breast cancer.

Screening Problems

In some cases, however, current technical approaches have questionable benefits – such as the prostate-specific antigen (PSA) test in prostate cancer. In other cases, no screening methods are available. For instance, there is no screening test for lung cancer at present, despite it being the most common cancer worldwide, representing around 13 per cent of all cancer cases (2). The absence of screening programmes makes early diagnosis more difficult, with symptomatic presentation generally preceding a general practitioner visit and eventual referral to a specialist for diagnosis.

Technical solutions are not the only obstacle to implementation of successful screening. Patient compliance can significantly impact the utility of available screening programmes. For example, the faecal occult blood test has a typical compliance rate of below 50 per cent because of the requirement to handle faecal samples (3). Other diagnostic methods are often prohibitively expensive for wide-scale adoption, and are often unpleasant or invasive.

Non-Invasive Testing

Non-invasive blood-based testing remains the ‘holy grail’ for cancer diagnosis. Significant academic, clinical and commercial effort has been focused on this area with some success, although these have yet to reach the mass markets.

Indeed, despite advances in cancer biomarker research over the past 25 years, few successful screening methods have been widely implemented. Current approaches include non-invasive imaging (mammography), invasive imaging (colonoscopy), invasive histology (Pap smear for cervical cancer) and faecal occult blood test (for colon cancer in the EU).

Imaging and histology methods are subjective, and require skilled practitioners to perform and analyse the tests. Similarly, biopsy-based detection (for staging) requires a prior knowledge of the likely location of disease and a high level of skill for sampling.

Blood Markers

The development of blood-based diagnostics has long been seen as a significant goal in cancer R&D. Several promising blood biomarkers are used, despite limited sensitivity and specificity. Perhaps the best known is PSA, which is used in prostate cancer screening alongside the digital rectal exam. However, the test has been criticised for its high false-positive rates (reports suggest up to two in three diagnoses). PSA is raised in other, non-cancer conditions – including benign prostatic hyperplasia and prostatitis – leading to overdiagnosis and subsequent follow-on biopsies.

Other blood markers evaluated in various cancers include: CA 125, an indicator of ovarian and several other cancers; prostatic acid phosphorase, found in testicular cancer; and CA 19-9, associated with advanced pancreatic cancer. In many cases, these biomarkers have been found to perform best when measured across multiple time-points, given their intrinsic lack of specificity.

Furthermore, some biomarkers have shown utility for prognosis, disease progression or treatment response monitoring (for instance, CA 15-3 and CA 27-29 for breast cancer treatment evaluation, and neuron-specific enolase for neuroblastoma or small cell lung cancer treatment evaluation). Such biomarkers can be useful in supporting a diagnosis as part of a panel of tests, but are not definitive. Development of a highly sensitive, cancer-specific diagnostic blood test remains a challenge.

Liquid-Based Biopsies

There is major academic and commercial attention on the development of blood-based singleplex and multiplex diagnostics for cancer. Recently, circulating tumour cells (CTC), circulating cell-free DNA and miRNA have both emerged as promising ‘liquid-based biopsy’ approaches, since they contain tumour-specific genetic and epigenetic information. Genetic sequencing of cell-free DNA can be used to identify specific tumour DNA over background DNA released from healthy cells.

Janssen Diagnostics’ CellSearch is currently the only US Food and Drug Administration (FDA) approved CTC test, used to evaluate prognosis and monitor disease progression, rather than as a first-line diagnostic (4). Rare-cells and academic institutions including the Memorial Sloan-Kettering Cancer Center in New York and Massachusetts General Hospital Cancer Center are also active in this space (5).

Epigenetic Technology

Epigenetic biomarkers hold great promise for the near future. Septin 9, based on tumour-specific methylated DNA, is being developed as a front-line screening test for colorectal cancer – EpiProColon by EpiGenomics (and under licence by Abbott) – with several regional trials completed or under way (6). The test, which is CE marked in Europe, has an overall sensitivity of 71 per cent and specificity of 85 per cent, performing better in stage two and higher cancer. It is available to support a diagnosis in the US via Quest Diagnostics (ColoVantage) and was recently narrowly recommended by an FDA advisory panel (7). A second-line test, EpiProColon 2.0, is also CE marked in Europe, with improved sensitivity of 80.6 per cent and specifi city of 99.3 per cent.

Another epigenetic biomarker-based technology being developed is Nuclesomics®. The approach is based on the quantification and differential structural profiling of tumourderived DNA/protein complexes (nucleosomes) released from dying tumour cells. VolitionRx has developed a range of NuQ® tests, which have shown high diagnostic sensitivity and specificity in pilot studies for colorectal cancer (8). Ongoing development, including a 4,800-individual clinical trial, will be the basis of a CE mark in Europe, under way in conjunction with Hvidovre Hospital, Denmark.

Earlier Diagnosis

It is widely recognised that earlier diagnosis of cancer significantly improves outcomes. Figures cited by the American Cancer Society show that when prostate cancer is caught before stage two, the five-year survival rate is almost 100 per cent; whereas beyond stage four (after it has spread to lymph nodes or other distant parts of the body), five-year survival rate drops to 28 per cent (9). Similarly, for colon cancer, five-year survival is 90 per cent when diagnosed at stages one and two, compared to 12 per cent when diagnosed at stage four. Early diagnosis enables potentially curative surgical intervention, as opposed to expensive chemotherapy with both short- and long-term side-effects.

According to a 2013 survey into attitudes to colorectal cancer screening, 32 per cent of respondents would decline a colonoscopy if recommended by their doctor due to concerns about cost and risks of the procedure (10), but 97 per cent said they would take a blood test. Invasive procedures (colonoscopy or digital rectal exam) or unpleasant or uncomfortable procedures (faecal tests, Pap smear and mammography) reduce patient compliance, whereas a simple blood draw is accepted as a routine procedure. The rate of compliance for the PSA blood test is 85 per cent – compared, for example, with 49 per cent take-up for colonoscopies (11,12).

The regulatory approval process for diagnostics is relatively fast, particularly for European CE marking. However, large cohorts (over 10,000) are required for population-based studies. In terms of implementation, standard format immunoassays can be easily integrated into existing workflow on liquid handling systems, or adapted to run on high-throughput clinical systems found in standard hospital pathology laboratories.

Clinical Implementation

Effective blood tests for major cancer types would enable screening, early diagnosis, improved patient outcomes and more sustainable healthcare costs for cancer. Key issues for effective clinical implementation and uptake include demonstration of high sensitivity and specificity – that is, correctly identifying those with and without a particular cancer in large-scale clinical trials. Cost-benefit analyses are also required in order to demonstrate a clear health economic argument to convince payers.

Currently available blood-based biomarkers are more suited for disease progression and treatment monitoring, rather than first-line diagnosis. Next generation DNA sequencing has opened up the possibility of blood-based tumour sequencing but, again, this is mainly suited to treatment selection – for example, by identifying tumour-specific mutations (KRAS, BRAF, etc) which are addressed by specific therapeutics.

EpiGenomics is pioneering blood-based testing for first-line early diagnosis of colorectal cancer in Europe with its CE-marked EpiProColon tests. The company was expected to receive FDA approval in the US by March 2014, which would set the bar for future blood-based colorectal cancer screening (1). However, the test is not intended to replace colonoscopy for confirmatory diagnosis.

Second generation methylated septin 9 tests have improved negative predictive power (99.9 per cent), but a positive result still only means the patient has a 45 per cent chance of having colorectal cancer, leaving significant room for improvement. Multiplex biomarker-based assays have the potential to address these issues by combining assays that provide high sensitivity and specificity.

1. World Cancer Report 2014, Stewart BW and Wild CP (ed)
2. Cancer Research UK lung cancer incidence statistics. Visit: lung/incidence/#geog
3. Lee JK et al, Improving fecal occult blood testing compliance using a mailed educational reminder, J Gen Intern Med 24(11): pp1,192-1,197, November 2009
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9. American Cancer Society survival rates for prostate cancer. Visit:
10. Attitudes into colorectal cancer screening survey, Racepoint Group/ VolitionRx, November 2013
11. Prostate cancer screening (PDQ), National Cancer Institute. Visit: healthprofessional/page1/allpages
12. Taylor et al, Comparison of compliance for colorectal cancer screening and surveillance by colonoscopy based on risk, Genet Med 13(8): pp737-743, 2011

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Dr Mark Eccleston is Managing Director of OncoLytika Ltd, a life sciences consultancy with an internal pipeline of innovative imaging and drug delivery solutions. He is also the Collaborations Manager for cancer diagnostic development company, VolitionRx. Mark has founded several start-ups and held senior technical roles in both UK and US listed companies, with responsibilities ranging from preclinical biotherapeutic development and validation to coordinating antibody and assay development.
Dr Mark Eccleston
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