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European Biopharmaceutical Review

Companion Diagnostics


In the shift from broad-based treatments to more targeted applications, the development of new diagnostic testing platforms has become an essential factor in the success and adoption of new therapeutics, bringing a host of medical, clinical and administrative challenges that must be overcome to deliver a fi t-forpurpose service for patients. Cancer treatment is evolving as the concept of personalised medicine is fast becoming a reality. Traditionally, cancer treatment regimens evolved by combining drugs that showed in vitro activity in the lab against specific tumour types, followed by clinical trials to prove activity in the real world. However, as our understanding of the molecular biology of tumours grows, researchers have been able to discover new molecular targets to enable cancer treatments to be tailored to patients most likely to respond. The hope is that by focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than other types of treatment, including chemotherapy and radiotherapy, and less harmful to normal cells.

The majority of current R&D of anticancer medicines is focused on targeted therapies that are directed toward specific pathways involved in tumour growth and progression, such as antigens, growth factors and the cell signal transduction pathways, where the aim is to moderate, control or kill cancer cells. In a recent update to their seminal paper on the so called hallmarks of cancer, Hanahan and Weinberg describe how their unifying, simplified concept has made all cancers understandable in terms of a few underlying principles, the so called hallmarks, and how the effects of targeted therapies can be linked to their hallmark capabilities (1). They predict that in the future, the selective co-targeting of multiple core and emerging hallmark capabilities of cancer cells will result in more effective and durable therapies for cancer. Targeted cancer therapies are being developed for use alone, in combination with other targeted therapies and in combination with chemotherapy.

A New Genetic Testing Paradigm

In order to exploit the growing knowledge of molecular targets and targeted agents, new detection and diagnostic techniques have had to be developed, proven and introduced into clinical practice.

In an ideal world, genetic testing for common mutations specific to each tumour type, for example KRAS in colorectal cancer patients and EGFR in lung cancer patients, would be built into the diagnostic pathway along with the more usual tests such as pathology and imaging, so that when the multi disciplinary team (MDT) meet to plan a patient’s treatment they are armed with all information needed for an entire treatment plan.

However, achieving this new paradigm is by no means straightforward. As an example, in the UK the National Health Service (NHS) does not routinely offer or fund the testing needed for many new targeted therapies licensed by the European Medicines Agency (EMA). An entirely new genetic diagnostic service will therefore be needed to meet the demand for testing for biomarkers associated with new medicines. These new genetic tests are currently beyond the capabilities of hospital pathology laboratories, and external providers are needed. In the UK this has led to a combination of solutions based around existing regional genetic services and private laboratories offering a commercial solution.

Both of these options are not without challenges. Existing genetic testing services are mainly set up for diagnosis of hereditary cancers and rare genetic diseases. They do not have the capacity to start processing large numbers of patient samples to test for specific mutations to see if they are suitable for the latest targeted therapy. There are also potential concerns regarding the regulation and governance of the use of the private sector; not least of which is who takes responsibility for assuring the analytical validity of molecular testing offered. In addition, how does a clinician or hospital cancer service choose which private provider to use and how can effective and seamless clinical test protocols and pathways be established?

Finally, adding to the complexity, there is also some debate in the literature regarding the stability of mutations and potential change in mutation status. This includes, for example, the natural progression of EGFR mutations in lung cancer patients. It has been suggested that there is a "need to investigate the possibility of EGFR-mutation alterations after adjuvant chemotherapy" – that is, that a patient’s mutation status may change over the course of their treatment, meaning repeated tests may be needed (2).

Implications for Commissioning Cancer Medicines in the UK

One of the challenges cancer medicine commissioning groups have had to face is the funding of genetic tests for new medicines. Where a commissioning group has approved a medicine from NHS funding, it has agreement from primary care commissioners that the test for the entire population is funded as part of the commissioning process. Given the relatively low cost of the average genetic mutation test, typically £150 to £300, versus the high cost of new cancer drugs, at £15,000 to £25,000 per patient, this is a viable approach for commissioners.

In 2011 the UK Government launched the Cancer Drug Fund (CDF), a threeyear fund, worth £200 million per year, designed to allow the NHS access to cancer medicines that were previously considered not to be cost-effective (and hence not funded) in the UK. In introducing the fund, the Government recognised the need to fund genetic tests, stating "the Fund may be used for molecular diagnostic testing which is necessary to help optimally target the use of drugs for patients who are most likely to benefit" (3).

Developing Genetic Testing

In the North East, the commissioning of cancer medicines is highly evolved. As part of this approach, the North of England Cancer Drug Approval Group (NECDAG) was formed to ensure that all cancer patients receive equitable access to a clinically defined appropriate range of cancer medicines.

To overcome issues surrounding testing, NECDAG works closely with NewGene, a pioneer in the application of next generation sequencing and genotyping technologies for personalised medicine.

Access to technologies such as high throughput platforms has enabled the development of new clinical assays for NECDAG and others as part of targeted and personalised medical treatment programmes. This involves working closely with major pharmaceutical companies on the use of flexible molecular pathology test platforms to develop new assays in response to the introduction of new genomic-based medicines

For NHS-based cancer drug commissioning groups, this high capacity analysis platform enables accurate diagnosis for personalised medicine treatments to be undertaken rapidly and very cost effectively – with consequent benefits in test turnaround times and overall costs.

Importantly, as well as developing the technical ability to provide these tests, specialist genetic testing companies also have significant experience in ensuring that its services and operational processes are fully integrated with the administrative and clinical systems of NHS and private hospitals and health organisations involved. For example, installing an intelligent pathology reporting system can electronically export clinical reports directly to referring clinicians. As well as reducing reporting times, this also reduces the administration burden for referrers.

KRAS Biomarkers

An illustration of the benefits of partnership is the commissioning of cetuximab (Erbitux) for colorectal cancer following the discovery of the KRAS biomarker.

Two key clinical trials, Crystal and Opus, first described the effect of KRAS mutation status on the effect of cetuximab (4,5). As a result we now know that only those patients (typically around 60 per cent) with wild type KRAS respond to cetuximab. The protein encoded by KRAS is part of the EGFR signalling pathway that is critical in the development and progression of cancer. Cetuximab blocks the pathway, preventing KRAS activation and consequent tumour growth. Activating mutations at four codons in KRAS (codons 12,13, 61 and 146) are recognised as predictors of resistance to treatment with cetuximab.

In this case, collaboration between the pharmaceutical manufacturer, drug approvals group and genetics testing laboratory provided a KRAS testing option that the local NHS could choose to commission.

EGFR Testing and Treatment of Lung Cancer

The next part of the development of local testing was in lung cancer. Lung cancer remains one of the biggest challenges in oncology. It is the fourth most common cancer in Europe and the most common cancer worldwide. In 2008, there were 288,118 new cases of lung cancer and 252,495 deaths from lung cancer in Europe, with 1.4 million deaths worldwide. With up to 75 per cent of patients not being diagnosed until they have metastatic or late-stage cancer, the five-year survival rate – around six per cent for small cell lung cancer and 15 per cent for non-small cell lung cancer – is depressingly poor (6,7).

Mutations and Over- Expression in Lung Cancer

It is estimated there are at least 10 different mutations in lung cancer genes that may ‘drive’ the progression of lung cancer; many of these have drugs under investigation to target them. Table 1 shows the frequency of driver mutations.

Data reported at the 2011 American Society of Clinical Oncology (ASCO) conference showed that, of the 830 patients with adenocarcinomas enrolled so far in a clinical trial coordinated by the Lung Cancer Mutation Consortium, 54 per cent had cancers with mutations and 95 per cent of the mutations seen were mutually exclusive – that is, patients had only one type of mutation (8). This research paves the way for testing patients for the most common mutations and then selecting the most appropriate targeted therapy. Even where mutations are not present in a lung cancer, there is often over expression of ‘normal’ proteins, such as EGFR-TK and VEGF, which also offer the opportunity to target treatments.

Lung Cancer Targeted Therapies – Erlotinib and Gefitinib

Epidermal growth factor receptortyrosine kinase (EGFR-TK), also known as human epidermal receptor-1 (Her1)-TK, is part of the control mechanism of cell growth. Its overproduction – not necessarily linked to a gene mutation – is common in non small-cell lung cancer, stimulating cell growth and proliferation. Erlotinib (Tarceva; Roche) is a small molecular inhibitor of EGFR, and was one of the first targeted treatments to be developed in lung cancer. It inhibits the over-expression of EGFR-TK, even if there is no mutation present. While the initial clinical trials of second- or third-line erlotinib showed a modest survival benefit, (median overall survival of 6.7 months versus 4.7 months for placebo), the tumours of patients enrolled in these studies were not tested for EGFR-positivity (such as expressing over a certain amount of EGFR) (9). Indeed, patients in the UK are still not routinely tested for EGFR over expression before second line erlotinib is prescribed.

The breakthrough in using EGFR inhibitors came with targeting patients with mutated EGFR. Gefitinib (Iressa; Astra Zeneca), another EGFRTK inhibitor, is targeted specifi cally at patients whose lung cancer has activating mutations of the EGFRTK gene. In 2010, the Iressa Pan Asian Study (IPASS) Phase 3 trial showed gefi tinib to be superior to chemotherapy (carboplatin plus paclitaxel) in individuals whose cancers had the EGFR-TK mutation (including an improved response rate of 74 per cent versus 31 per cent and improved and median progression-free survival (PFS) rate of 10.8 months versus 5.4 months) (10). Gefitinib was shown to be inferior in patients without the EGFRTK mutation. More recently, erlotinib has been investigated in patients whose cancers have activating EGFRTK mutations. Early results from the OPTIMAL Phase 3 study comparing first line erlotinib with chemotherapy (gemcitabine and carboplatin), show a response rate of about 84 per cent with erlotinib versus 37 per cent for chemotherapy (p < 0.00001). The median PFS with erlotinib was reported to be 13.1 months versus 4.6 months for chemotherapy (11). The EUTRAC study, a randomised controlled Phase 3 trial of erlotinib versus chemotherapy for the fi rst line treatment of EGFR mutations in a mainly caucasian population, showed the median PFS to be 9.7 months for erlotinb versus 5.2 months for doublet chemotherapy (12).

Gefitinib was approved by the National Institute of Clinical Effectiveness (NICE) in 2010. In order to successfully introduce gefi tinib into practice, EGFR testing had to be established for lung cancer patients. This posed a logistical problem for the NHS, as the majority of UK hospitals did not have the expertise, technology or experience to undertake mutation testing. The two challenges were developing the test and the pathway for undertaking the testing. Developing the test was perhaps the easier of the two, with the manufacturers of gefi tinib, AstraZeneca, ensuring that there were validated laboratories able to offer the test to the NHS.

Accessing a first definitive cancer treatment such as gefitinib in the UK is controlled by Government waiting time targets, and patients have to be able to receive treatment within 62 days of receiving a referral for a suspected cancer. Figures 1 and 2 show the potential impact of adding EGFR testing to the lung pathway and how in this example it increases the pathway time from 20 days (Figure 1) to 40 days (Figure 2). Providers of genetic tests must work with their purchasers to understand the pathway and streamline the process for requesting and processing tests.

In the north of England, to avoid the risk of delays to starting treatment, the cancer commissioning network worked with NewGene to develop local streamlined testing that is integrated into the patient pathway. An EGFR assay was developed on the Sequenom MALDI-TOF platform and covers all of the mutations related to gefi tinib and erlotinib sensitivity.


ALK Inhibition

Looking to the future in lung cancer, there are a number of new treatments that will require genetic testing when they come to market. For example, soon to be licensed for the treatment of non-small cell lung cancer in patients whose cancers harbour an ALK mutation is crizotinib. Crizotinib binds to the active portion of the ALK protein, inhibiting its activity.

Data from 82 patients, most of whom had already received some treatment for their lung cancer, showed a 57 per cent response rate, with one patient having a complete response (the disappearance of all clinical evidence of disease) and 46 patients showing a partial response to crizotinib treatment, with a six-month progression-free survival of 72 per cent (13). An exploratory analysis using historical controls has estimated that the twoyear survival rate for crizotinib-treated ALK mutation positive patients was 64 per cent, compared with 33 per cent for the control group. The difference in twoyear survival rate was even greater for patients who had already received two or more treatments (61 per cent versus nine per cent) (14). While this data has limitations, it provides some reassurance as to the benefit of crizotinib in the appropriate patient population. ALK testing will need to be added to the list of tests for lung cancer patients.



It seems clear that targeting specific mutations and over-expressed proteins in cancers is the future of patient treatment. However, without the technology and the political and clinical will to develop and use diagnostic tests to characterise each patient’s tumours, there is no guarantee that these treatments will be any more effective than traditional chemotherapy for most patients. As the development of personalised medicine treatments gathers momentum, the need for integrated genetic testing services has never been greater.


  1. Hanahan D and Weinberg RA, Hallmarks of cancer: the next generation, Cell 144: pp646-674, 2011
  2. Jung-Jyh Hung et al, EGFR mutations in non-small-cell lung cancer, The Lancet Oncology 11(5): pp412-413, 2010
  3. Department of Health, The Cancer Drugs Fund: Guidance to support operation of the Cancer Drugs Fund in 2011-12 24 March 2011, Gateway reference: 15,852
  4. Van Cutsem E et al, Cetuximab and chemotherapy as initial treatment for mestatic colorectal cancer, New England Journal of Medicine 360(14): pp1,408-1,417, 2009
  5. Opus Bokemeyer C et al, Fluorouracil, Leucovorin, and Oxaliplatin with and without Cetuximab in the first-line treatment of metastatic colorectal cancer, J Clin Oncol 27: pp663-671, 2009
  6. World health authority (WHO) Fact sheet N°297 Cancer February 2011 available at mediacentre/factsheets/fs297/en/ index.html
  7. Europe in 2008, Eur J Cancer 46(4): pp765-81, 2010
  8. Kris MG et al, Abstract CRA7506, ASCO 2011
  9. Shepherd FA et al, Erlotinib in previously treated non-small-cell lung cancer, N Engl J Med 353: pp123-32, 2005
  10. Mok TS, Wu Y-L, Thongprasert S et al, Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, N Engl J Med 361: pp947-957, 2009
  11. Zhou C, Efficacy results from the randomised phase 3 OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM) in Chinese advanced non-small-cell lung cancer (NSCLC) patients (pts) with EGFR activating mutations, Program and abstracts of the 35th European Society of Medical Oncology Congress; October 8-12, 2010; Milan, Italy, Abstract LBA13
  12. Rosell R et al, Oral abstract presented at ASCO 2011, 7503.
  13. Spigel DR et al, Randomised multicenter double-blind placebocontrolled Phase 2 study evaluating MetMAb, an antibody to met receptor, in combination with erlotinib, in patients with advanced non-small-cell lung cancer, J Int Med 254(2): pp184-192, 2003
  14. Sasaki T, Rodig SJ, Chirieac LR and Jänne PA, The biology and treatment of EML4-ALK non-small cell lung cancer, Eur J Cancer 46(10): pp1,773-1,780, 2010

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Steve Williamson is a Consultant Pharmacist working in a joint role with the North of England Cancer Network and Northumbria Healthcare Trust. Steve is lead clinician for the Trust chemotherapy services and a recognised expert on cancer medicines and cancer chemotherapy services. He has undertaken research and published on a variety of topics including capacity planning, oral chemotherapy, patient access schemes and complimentary and supportive care medicines. Steve recently was part of an international commission of experts looking at the cost of cancer medicines. In addition, his clinical commitment includes running an oral anticancer medicine clinic prescribing chemotherapy and supportive care and providing support to the lung cancer clinics. Working alongside medical consultants, he also has a clinical role on oncology wards, reviewing patients and verifying chemotherapy.

Jonathan Robinson is Business Development Manager at NewGene Ltd. He started his career in 1984 as a state registered Scientific Officer working across the full range of disciplines in NHS pathology laboratories. Following completion of a BSc in Biotechnology, he moved into manufacturing in the biopharmaceutical sector and in 2006 he became the Commercial Manager for a drug development company, before joining NewGene. The specialist company brings the benefits of high throughput gene sequencing technology to the NHS and wider health sector, providing cost-effective molecular diagnostic testing for a range of clinical applications and reducing waiting times for test results.

Steve Williamson
Jonathan Robinson
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