Molecular Testing: An overview for commissioners and key oncology stakeholders August 2013

Transcription

1 Molecular Testing: An overview for commissioners and key oncology stakeholders August 2013 North of England Cancer Network Pharmaceutical Industry Partnership (PIP) Group

2 Molecular testing: an overview for commissioners and key oncology stakeholders Steve Williamson, 1 Stephen Connell, 2 Louise Wilson 3 1 Consultant Cancer Pharmacist, NHS North East and Cumbria. 2 Senior Haemato-oncology & Oncology Account Manager, Pfizer. 3 Key Account Manager, Astra Zeneca Ltd This report has been developed by the North of England Cancer Network Pharmaceutical Industry Partnership (PIP) group under a joint working agreement. The aims of this report are to provide commissioners and administrators, as well as clinicians and other stakeholders, with background information on molecular testing, to support decisions on the commissioning and implementation of current and future molecular testing services. Introduction We are entering an era of personalised cancer management, i.e. the use of targeted anticancer agents aimed at specific biological mechanisms or pathways identified in the individual patient s tumour. An effective process for commissioning molecular testing specific to individual treatments is an essential component of this personalised approach. Accurate and timely detection of biomarkers can show whether a given tumour has the specific biological target required for a particular agent, and hence whether or not the patient is likely to respond to a particular treatment. An effective process for the commissioning of molecular testing for biomarkers will provide clinicians with the information they need to direct the use of targeted agents (current agents and those still in development) to those patients most likely to respond. Importantly, molecular testing will also identify patients unlikely to respond to the targeted agent, thereby supporting clinicians in the decision not to use the treatment. In this way, investment in molecular testing has the potential to save healthcare resources including the costs associated with drug acquisition, drug delivery and supportive care and to avoid treatment toxicity in individuals unlikely to derive clinical benefit. The new NHS structure, in place since April 2013, has changed the commissioning process, with much responsibility devolved to local Clinical Commissioning Groups and Area Teams. While it has been made clear that cancer treatments approved for NHS use will be commissioned at national level, via Area Team Specialised Commissioning there remains a great deal of uncertainty and variation surrounding the commissioning of molecular testing for new cancer medicines. Prior to April 2013, there was already wide variation between areas in the access to molecular testing services. NHS specialised commissioners have supported genetic and molecular testing relating to diagnosis and screening of rare familial cancers as part of commissioning NHS genetics services. However, molecular biomarker testing for new cancer medicines requires a different pathway, and does not fit into the existing model for commissioning tests for NHS genetics services. Given the commitment of the NHS to equity of access to cancer care, 1 there is now a pressing need, driven by an increasing volume of tests, to ensure the availability of accurate, timely molecular testing services across all of England. NECDAG PIP Page 2 of 17. Date of preparation: August 2013

3 Executive summary Personalised medicine, using drugs that target pathways responsible for the growth and progression of tumours, is a key goal of recent and ongoing cancer research. Central to its use is molecular testing of tumour samples, to identify the presence (or absence) of the specific molecular target associated with a given drug, thereby providing information on whether the treatment is likely to be effective (or ineffective) in the individual patient. Personalised medicine offers several clinical, financial and organisational benefits, notably: Greater confidence in the efficacy of a chosen treatment Smaller number of patients need to be treated ( number needed to treat, NNT) to obtain a response Avoidance of ineffective treatments, and hence also avoidance of associated supportive care, side effects and NHS costs Time not wasted on ineffective treatments, so that appropriate alternative care can be considered in a timely way Possible opportunity for improved cost effectiveness of drug therapy, and increased chance of reimbursement for chosen treatment Clearer patient pathways, with routes defined by test results Potential for treatment delivery close to patients homes (many targeted agents are oral) Potential to test new agents only in patients whose tumours have the molecular basis for a response, thereby reducing the trial population size required to achieve statistical significance and speeding up drug development Most NHS trusts use one or more local laboratories plus services outside of the region to provide molecular testing, and many existing laboratory services may require investment and resources to meet the new demand. A move towards more centralised testing is predicted. New approaches to molecular testing are being developed, e.g. use of circulating DNA to identify treatment targets in patients too unwell to undergo biopsy. The demand for molecular testing is increasing both in volume and in the range of molecular targets that can be identified, and will continue to increase as new targeted agents are developed and licensed, but there is inequity across the UK (i.e. a postcode lottery ) in access to testing services and in their quality. There is growing concern that some new tests might not be funded in a timely fashion in some areas, leading to delays in access to new cancer treatments. There is an important and urgent need for commissioners to ensure an infrastructure for molecular testing that is adequate for current and predicted needs, and with capacity to provide testing required for future molecular treatments. However, there are several areas of uncertainty: Lack of knowledge of test providers, and the range and quality of their service Lack of clarity on how local/regional molecular testing will be commissioned Need for clear quality assurance arrangements Uncertainty over Cancer Drugs Fund (CDF) funding for tests required for CDF-funded treatments Issue of maintaining the quality of in-house NHS testing, which is exempt from regulation Impact of new approaches to molecular testing, e.g. a panel, whereby a sample is screened for several potential molecular targets in a single procedure NECDAG PIP Page 3 of 17. Date of preparation: August 2013

4 In tumours such as lung cancer tissue can be an issue, but there is little guidance on tissue sampling. There are some inherent disadvantages to conventional histopathological testing, e.g. biopsy sampling may miss essential areas of tissue, samples are normally small thereby limiting the number of tests that can be conducted, and patients may become too unwell to undergo further biopsy. An alternative is cytology sampling, which is less invasive than biopsy. However, cytology and pathology services are often in different locations, and local physicians may be unaware of local options for cytological testing. Timely turnaround of test results is essential. Late results can lead to delays in patient care, poor patient outcomes and failure to meet national targets for cancer management. Delays may be caused by use of remote testing services with reliance on standard postal services for delivery of tissue samples, lack of clarity over the quality of molecular testing services, errors (e.g. mislabelling), inadequate quantity of tissue (particularly where biopsy material is divided for dispatch to different testing facilities), and the development of unforeseen histology requirements. Quality standards for molecular testing are essential to ensure safe, effective and appropriate use of targeted therapies. Routine quality control assessment (e.g. 3 4 times/year) can help to identify problems. Notable resources are the UK National External Quality Assessment Scheme (NEQAS) and the European Society of Pathology. NECDAG PIP Page 4 of 17. Date of preparation: August 2013

5 Personalised medicine in cancer therapy One of the key goals of current cancer research is the identification of agents that target pathways responsible for the growth and progression of tumours. This has led to increasing use of novel anticancer agents, such as antibodies that block receptors integral to a specific tumour cell process. Agents of this type are referred to as biological or molecular, to distinguish them from the cytotoxic chemotherapy agents that were, until recently, the primary focus of research into cancer treatment. Central to the use of molecular therapy is the rational combination of molecular target and agent a molecular treatment will work in an individual patient only if the tumour s biochemistry includes the specific pathway targeted by the treatment. This relationship opens the door to personalised therapy, whereby a patient s management is guided by the molecular profile of their tumour; i.e. treatments are offered only if the relevant tumour pathway is confirmed by molecular testing. Examples of commonly used molecular agents and their targets are shown in Table 1 (see Appendix 1 for a fuller list). Table 1. Examples of molecular cancer treatments and their targets Molecular agent Tumour Target pathway Drug action Required for agent efficacy Cetuximab Colorectal cancer Epidermal growth factor (EGF) sends signal to KRAS protein, which switches on tumour growth Trastuzumab Breast cancer Genetic abnormality leads to overproduction of human epidermal growth factor receptor 2 (HER2), causing cancer to grow and spread Vemurafenib Malignant melanoma BRAF mutation at position V600 in patients with unresectable or metastatic melanoma Blocks EGF receptor (EGFR) Blocks receptors for HER2 Inhibits BRAF enzyme (part of the RAS/MAPK signalling pathway) Normal KRAS (Mutated KRAS does not require EGF activation) Overproduction of HER2 Mutated BRAF Because of its targeted design and intent, the molecular approach differs from that of conventional cytotoxic therapy, in which a given agent is shown to be effective in some but not all patients with a particular cancer type, but with no objective guidance on which individuals within the defined population will derive clinical benefit. Current and forthcoming technologies for directing the use of targeted molecular therapies are listed in Appendices 2 and 3. The personalised approach offers benefits not only for patients, but also for the NHS, for research, and for drug manufacturers (Figure 1). NECDAG PIP Page 5 of 17. Date of preparation: August 2013

6 Figure 1. Wide-ranging benefits of personalised medicine For the patient, because a specific agent is selected to target a known biological characteristic of their tumour, treatment expectations can be defined with greater confidence when that biological characteristic is present. For example, in the IPASS trial, EGFR mutation was a strong predictive biomarker for progression-free survival with gefitinib (hazard ratio 0.48, versus 3.85 without mutation). 2 Equally relevant, absence of a particular biological target means that the patient will avoid undergoing a treatment that will be ineffective in their tumour. The benefits of a negative test are multifactorial. The patient avoids not only the drug itself, but also the associated supportive medicines, and the disruption of treatment administration. The patient also avoids the risk of side effects ranging from inconvenient/uncomfortable to serious or even life-threatening and the measures needed to treat them. Side effects are, of course, a particular burden when the treatment brings no benefit in terms of clinical response. In addition, the patient s hopes will not be falsely raised, and they will be considered for an appropriate alternative care strategy in a timely way, without the delay associated with trying an ineffective treatment. For the NHS, the number of patients that need to be treated to obtain a response is lower with personalised treatment than with conventional cytotoxic therapy, meaning less money wasted on drugs that don't work. Furthermore, the withholding of molecular treatment where the treatment target is absent avoids not only the acquisition cost of the targeted agent, but also procurement and delivery costs, associated supportive treatments and the resources required to manage side effects. There are also benefits in terms of patient pathways, with routes defined by test results. In addition, because many targeted agents are oral, rather than intravenous, their use may lead to the development of new care models that allow treatment delivery close to patients homes, thereby increasing patient convenience and potentially easing some of the burden on chemotherapy day units. For research (both independent and commercial), there is potential to test new agents only in those patients whose tumours have the molecular basis for a response, thereby reducing the trial population size required to achieve statistical significance (number needed to treat), and speeding up drug development. For drug manufacturers, increased cost effectiveness means a greater chance that a product will be approved for reimbursement. NECDAG PIP Page 6 of 17. Date of preparation: August 2013

7 Molecular testing: the status quo Increasing demand Historically, there has been variation across the UK in access to molecular testing for biomarkers mirroring the variation in uptake of new cancer medicines. This variation is a reflection, in part, of a lack of government direction as new medicines and associated tests become available, and under-investment in both histological and molecular testing services. In addition, the uptake of molecular testing has been lower in the UK than in some other European countries. A survey by Cancer Research UK in found that molecular testing for cancer (solid and haematological/lymphatic tumours) was conducted in around 40 laboratories in England. Around 96,000 tests were conducted in the survey period (excluding immunohistochemistry [IHC], and HER2 testing other than via in situ hybridisation [ISH]), at a cost of around 16 million. 3 Not only is there a growing range (and awareness) of treatments requiring molecular testing, but patients may need repeated testing throughout the course of their disease, because of a risk of alteration in the molecular status of the tumour. As a result, the demand for molecular tests is increasing rapidly. For example, the volume of NHS activity at the Royal Marsden Hospital Molecular Diagnostic Laboratory increased from fewer than 1,000 tests in 2006, to more than 5,000 in Meanwhile, several new molecular agents for cancer are likely to be considered for the NHS over the coming year, with more than 150 currently in the research pipeline. There is, therefore, growing pressure to increase molecular testing resources, and for an effective strategy to manage the introduction of new tests as they become available. This issue is one that needs to be resolved. Funding Before the changes to the NHS commissioning structure were implemented in April 2013, molecular testing for cancer was funded in a variety of ways: By commissioners o Included in associated tariff treatment costs o Through agreement with a local provider (cost per test or block contract) o Through agreement with a specialist NHS or private provider (cost per test or block contract) o Otherwise absorbed by providers without specific funding made available Through pharmaceutical industries paying for all or part of the cost (not a sustainable long-term strategy) Through research funding Directly from the regional Cancer Drug Funds (CDFs) for specific CDF-funded drugs As of April 2013, anticancer drugs approved for NHS use are funded centrally by NHS England (NHSE) as part of specialist commissioning. In addition, several drugs that are licensed but as yet not approved for NHS use are available via the Cancer Drugs Fund (CDF). 4 Purchase of drugs via the CDF will be audited and is likely to be subject to far closer scrutiny than in previous years. While tests for CDF-funded agents can be included in the CDF funding arrangements, 4 this funding route is intended as a last resort if funding cannot be found, or is not already provided, elsewhere. There remains a lack of clarity on the funding for tests associated with treatments commissioned via NHSE. Now, as before April 2013, patients access to molecular testing varies from location to location, depending on the size and resourcing of local laboratories. A few selected trusts with a strong cancer research base, such as the Royal Marsden, tend to have well developed testing services, as part of their research infrastructure. However, the majority of trusts, even NECDAG PIP Page 7 of 17. Date of preparation: August 2013

8 those with a strong research base, tend to have a more fragmented approach, with use of one or more local laboratories plus reliance on services outside of the region. Many of the existing laboratory services may require investment and resources in order to meet the new demand. For example, genetic testing services have been developed largely to diagnose hereditary cancers and genetic diseases. As such they may lack the capacity and rapid turnaround time needed to support clinical decision making by the cancer multidisciplinary team (MDT) and to meet the demands of the cancer treatment time targets. Variation in capacity and turnaround time may contribute to a postcode lottery in patient access to tests and treatments. Of note, test results are often needed within the 62-day target from referral to first treatment. At the same time, there are several key changes on the horizon, including: An increase in demand for molecular testing as new molecular agents are developed and licensed A significant increase in the range of tests needed to support approved agents New approaches to molecular testing, e.g. use of circulating DNA to identify treatment targets in patients too unwell to undergo biopsy A predicted move towards more centralised commissioning of molecular testing With constraints on NHS spending, there is growing concern that some new tests might not be funded in a timely fashion in some areas, leading to delays in access to new cancer treatments. Treatment delays The decision whether or not to use a particular molecular treatment is dependent on the result of the associated molecular test, and this information is required in time for the relevant MDT meeting on the patient s care. Delays in the acquisition of the test result can lead to unacceptable delays in the patient pathway, failure to meet trust targets for cancer management, and poorer outcomes for the patient as a result of inappropriate treatment. The problem is exacerbated when patients require repeated testing throughout the course of their disease, because of a risk of alteration in the molecular status of the tumour. There are several reasons why test results might be delayed: Use of remote testing services, and reliance on standard postal services for delivery of tissue samples Lack of clarity over the quality* of molecular testing services, and hence the risk of a substandard service Use of laboratories that undertake a low volume of tests, and may have to await a batch of tissues before running a particular test Operational errors, e.g. inappropriate handling of tissue, mislabelling Inadequate quantity of tissue for the test(s) requested a particular issue where biopsy material is divided into smaller samples for dispatch to different pathology and molecular testing facilities Additional, unforeseen histology requirements *Note many of the genetic tests are newly developed tests and can be obtained from different platforms; there are, therefore, often no international quality assurance standards for the individual tests, rather the laboratories themselves participate in the United Kingdom National External Quality Assessment Service (NEQAS). Figure 2 shows how a suboptimal infrastructure for EGFR testing can delay the initiation of lung cancer treatment by 4 weeks. Case study 1 is an example of a programme to streamline EGFR testing in this setting. NECDAG PIP Page 8 of 17. Date of preparation: August 2013

9 Figure 2. Lung cancer treatment pathway, and the potential delays introduced by EGFR testing 5 NECDAG PIP Page 9 of 17. Date of preparation: August 2013

10 Test inertia Once processes and protocols have been established locally for a molecular test, and it is in regular use, it can be difficult to persuade stakeholders to consider updating to newer test platforms (see Case study 2). Test avoidance There are anecdotal reports that, faced with a choice of agents for a particular cancer, clinicians may sometimes opt for the treatment that does not require molecular testing. Although this approach avoids the delays and bureaucracy associated with testing procedures, it means that the full range of available treatments will not have been properly considered for the individual patient. Use of multiple test centres Current technology typically requires separate testing for individual molecular markers. In some areas, there are well established local facilities for some tests but not for others. This means that the tissue sample from the patient may need to be divided into small portions for separate delivery to the different testing locations. There are several disadvantages to this approach: Increased risk of transport delay Risk that the small portion of tissue received by any one laboratory will not adequately reflect the overall disease (e.g. tumour heterogeneity) Tissue block may be too small to divide between all the testing locations required Small increased risk of tissue loss/mishandling/mislabelling Reliance on histopathological sampling Currently, molecular testing is mainly conducted on histopathological tissue samples obtained during surgery or biopsy. There is an inherent risk that biopsy sampling may miss areas of tissue essential to accurate molecular categorisation of the tumour, or that the samples may fail to reflect tumour heterogeneity. Tissue obtained in this way is limited in quantity, and may need to be divided for testing at different locations. Furthermore, once the histopathological sample has been used up, or the disease has progressed to a stage where repeat molecular testing is recommended, the patient may be too unwell to undergo further biopsy. It is essential to ensure that use of tumour biopsy tissue is prioritised, i.e. treatment-related testing is first and foremost, while prognostic testing is applied only if there is sufficient tissue remaining. Cytology sampling provides an alternative approach. It is less invasive than biopsy, e.g. mediastinal lymph nodes can be sampled using endobronchial ultrasound-guided transbronchial fine-needle aspiration. Hence, cytology specimens may be accessible from patients who are no longer well enough to undergo conventional biopsy procedures. However, cytology and pathology services are often in different locations, adding complexity to the molecular testing pathway. In addition, local physicians may be unaware of local options for cytological testing. NECDAG PIP Page 10 of 17. Date of preparation: August 2013

11 Examples of problems Case study 1. Treatment delays A Trust was experiencing delays of around 1 month in the initiation of gefitinib for the treatment of lung cancer as a result of the time required to obtain information on EGFR status. Surgeons, oncologists and pathologists at the trust worked in partnership with AstraZeneca to streamline the testing process, often using simple solutions e.g.: Switching to first-class post for sending samples (previously second-class post was used) Improved timing of test runs to coordinate with MDT meetings Case study 2. Test inertia Roche rolled out HER2 testing resources throughout the NHS from 2005 to 2007 to support the identification of patients with breast cancer who would be eligible for treatment with trastuzumab. Trusts varied in their speed of adoption. Where the Roche programme is in place, there now tends to be slow uptake of updated practices in HER2 testing, because local laboratories have become dependent on the external funding and have not monitored the changing test practices. Questions of quality Quality standards for molecular testing are essential to ensure safe, effective and appropriate use of targeted therapies. Routine quality control assessment (e.g. 3 4 times/year) can help to identify problems. The UK National External Quality Assessment Scheme (NEQAS) is a nonstatutory organisation that provides quality assurance on diagnostic tests. Membership of the organisation is voluntary and may of itself be an indicator of a good-quality laboratory. The European Society of Pathology is another key resource, offering quality assurance on a range of molecular tests. One determinant of the quality of a particular test at a particular centre may be the quantity of samples processed. Low test numbers can lead to delays (e.g. tests may be stockpiled until there is a sufficient quantity to run the test efficiently) and limit the experience and expertise of the laboratory staff. For this reason, where only small numbers of specific key tests are required at local level, there may be a need to consider centralisation of diagnostic testing. Furthermore, the volume of tests should be seen as a key quality indicator, with government guidance indicating the minimum number of individual tests that should be performed before a test centre is deemed appropriate as a diagnostic resource. Mechanisation of testing provides higher throughput, but increases the costs. In many cases, tissue is the issue. Currently, there is little guidance on the techniques used in tissue sampling, and a likelihood of variability in the quality of the techniques used. Again, this variability can ultimately contribute to a postcode lottery in the treatment that patients receive. Key issues for commissioners The move towards greater application of personalised medicine is inevitable, and will account for an increasingly large component of cancer care in the years to come. Commissioners need to make sure they have the infrastructure for current tests, scope to expand access as demand for molecular treatments increases, and capacity to commission testing for future molecular treatments, some of which are on the near horizon. The role of the National Institute for Health and Care Excellence (NICE) in the diagnostic test commissioning process remains to be decided. NECDAG PIP Page 11 of 17. Date of preparation: August 2013

12 Meanwhile, however, the new national CDF may expand access to novel therapies and, therefore, both accelerate the demand for molecular testing and expand the range of tests that need to be available to local cancer teams. There are several challenges facing commissioners, notably: Knowledge of providers and the range of tests they provide Lack of clarity on how local/regional molecular testing will be commissioned Fragmentation and inequity in the current service, leading to variable time scales in testing (and hence delays in uptake of treatments and poorer outcomes for patients) Inconsistent quality of testing, and a need for clear quality assurance arrangements Agreements between laboratories and specific manufacturers of testing consumables, which may leave them unable to offer a test manufactured by other companies, thereby potentially hampering the introduction of new services Lack of funding from NICE for tests associated with treatments indicated in NICE guidance Financial pressure on the CDF, which may affect funding of tests required for CDFfunded treatments Potential to use tissue samples for prognostic as well as diagnostic testing Issue of maintaining the quality of in-house NHS testing, which is exempt from regulation Changes on the horizon including: o New approaches to molecular testing, e.g. a panel approach whereby a sample is screened for several potential molecular targets in a single procedure o o A likely move towards more centralised commissioning of molecular testing An increase in both the range of, and the demand for, molecular testing as new targeted agents are developed, licensed and recommended by health technology appraisal Commissioners may wish to consider the following key questions: What is available, where is it available, and what does it cost? Is there a cost per test threshold below which providers are expected to absorb the cost and above which a separate charge is appropriate? What aspects of the commissioning of molecular testing have worked well previously? What aspects have not worked well? Should local diagnostic services be provided by a smaller number of centralised laboratories? o Advantages include centralisation of expertise, relatively high throughput of less common tests and economies of scale o May be difficult to achieve in areas with small populations Is distinct charging for tests appropriate? o Costs associated with a test need to be identified separately from treatment to o determine cost effectiveness Distinct charging provides an incentive to improve efficiency and reduce the cost of testing, e.g. through centralisation Will a particular new test fit into an existing commissioned pathway, e.g. block contract with a regional laboratory? If so, how will existing contracts be affected? Is there a role for the pharmaceutical industry in the development of the diagnostic test commissioning structure? How can other stakeholders contribute to the commissioning process, e.g. Cancer Research UK, the Royal College of Pathologists and the Pharmaceutical Oncology Initiative? How will sequential testing be managed in the absence of guidance (national or from a royal college) to ensure optimisation of patient treatment and rational use of limited tissue volume? NECDAG PIP Page 12 of 17. Date of preparation: August 2013

13 Patient/public viewpoint The patient must be at the centre of the commissioning process. Patients want and need the best available treatment option, and hence it is important to provide rapid, accurate testing of the molecular status of their tumour. There have been instances of patients requesting private testing when such resources have been unavailable on the NHS. Patients (and the larger public) do not necessarily understand the intricacies of the NHS and the various services it provides. However, all users of the NHS in England have a right to expect equality of access to appropriate services, according to their need, and regardless of their region/locality. It is also important to ensure that when biopsy is undertaken, there is sufficient quantity of tissue, and appropriate storage, to cover current and future testing requirements, thus avoiding repeat biopsy except where clinically indicated (e.g. to test for an alteration in the molecular status of the tumour). Conclusion Cancer care has already emerged into the age of personalised medicine, and can expect to see a huge expansion in the number of molecular agents and associated molecular tests. This approach to cancer treatment stands to benefit the NHS and the progress of cancer research as well as individual patients. However, these benefits will not be fully realised without a well organised, high-quality infrastructure of molecular testing services. Those responsible for commissioning cancer services nationally and locally must work with providers to ensure that molecular testing services are fit for purpose, available to all patients, and responsive to ongoing advances in clinical and laboratory science. Acknowledgements This report was prepared by the authors, with the assistance of Janis Smy, Medical Writer, Succinct Healthcare Communications. Contributions, comments and advice were made by members of NECDAG PIP and Will Horsley Area Team Pharmacist, Cumbria, Northumbria and Tyne and Wear. This molecular testing document was developed in collaboration with AstraZeneca. The production of this report has been supported by a grant from Novartis Pharmaceuticals Ltd. Novartis has had no editorial input into the writing of this article. Novartis reviewed the report for scientific factual accuracy only. Pfizer has contributed to the writing and editing of this article. NECDAG PIP Page 13 of 17. Date of preparation: August 2013

14 References 1. NHS. Cancer Reform Strategy. London: DH, Fukuoka M, Wu YL, Thongprasert S et al. J Clin Oncol 2011; 29: Department of Health. Ensuring equitable access to complex molecular diagnostic testing for cancer patients. Draft v3.2 for consultation. Available at: (accessed July 2013). 4. NHS Commissioning Board. Standard operating procedures: the Cancer Drugs Fund Available at: (accessed July 2013). 5. Williamson S, Robinson J. European Biopharmaceutical Review 2012; April: NECDAG PIP Page 14 of 17. Date of preparation: August 2013

15 Appendix 1. Targeted agents requiring molecular testing Drug Target pathway Drug Mechanism Required for agent efficacy Anastrozole Bosutinib Cetuximab Crizotinib Dasatinib Erlotinib Everolimus Exemestane Fulvestrant Gefitinib Imatinib Letrozole Nilotinib Panitumumab Oestrogen production, mediated by aromatase Promotion of tumour growth and angiogenesis by tyrosine kinases ( Epidermal growth factor (EGF) sends signal to KRAS protein, which switches on tumour growth Promotion of tumour growth via ALK receptor TK Promotion of tumour growth and angiogenesis by TKs Promotion of tumour growth and angiogenesis by TKs Tumour growth and proliferation via the mammalian target of rapamycin complex 1 (mtorc1) pathway Oestrogen production, mediated by aromatase Promotion of tumour growth by oestrogen Promotion of tumour growth and angiogenesis by TKs Promotion of tumour growth and angiogenesis by TKs Oestrogen production, mediated by aromatase Promotion of tumour growth and angiogenesis by TKs EGF sends signal to KRAS protein, which switches on tumour growth Aromatase inhibition Tyrosine kinases (TK) inhibition Blocks EGF receptor (EGFR) Inhibition of ALK receptor TK TK inhibition Blocks TK activity of EGFR mtor inhibition Aromatase inhibition ER Blocks TK activity of EGFR TK inhibition, including bcr-abl Aromatase inhibition TK inhibition Blocks EGFR Normal oestrogen receptor (ER) status Philadelphia chromosome Normal KRAS ALK Philadelphia chromosome Mutation that activates EGFR Hormone receptors Normal ER status Normal ER status Mutation that activates EGFR Philadelphia chromosome (bcr-abl) Normal ER status Philadelphia chromosome Normal KRAS Pertuzumab Toremafine Tamoxifen Promotion of tumour growth by human epidermal growth factor receptor 2 (HER2) Promotion of tumour growth by oestrogen Promotion of tumour growth by oestrogen Blocks receptors for HER2 ER (ER Trastuzumab Promotion of tumour growth by HER2 Blocks receptors for HER2 Vandetanib Promotion of tumour growth by TKs Inhibition of VEGF EGF and RET Vemurafenib BRAF mutation at position V600 in patients with unresectable or metastatic melanoma Inhibits BRAF enzyme HER2 Normal ER status Normal ER status HER2 RET mutation Mutated BRAF NECDAG PIP Page 15 of 17. Date of preparation: August 2013

16 Appendix 2. Currently available testing technologies for molecular targets in cancer Test Testing methodology Advantages and disadvantages Example Testing Location Immunohistochemistry (IHC) Uses specific antibodies to bind to a target; the antibodies can then be visualised by tagging them with fluorescent markers or antibody/enzyme conjugates that produce a colour change Useful for detecting expression of the target of interest Quantitative analysis may be difficult Detection of HER2 expression Can be done in trusts In situ hybridisation (chromogenic/fluorescen ce/silver ISH) Uses colour generating, fluorescentlytagged or silvertagged probes to bind to and visualise a specific DNA or RNA sequence FISH is highly accurate, and allows quantitative analysis of DNA markers such as copy number Detection of ALK-EML4 fusion mutations Certain trust/genetics laboratories Cytogenetics Examination of the shape and structure of chromosomes to detect abnormalities Uses simple to collect blood sample, but the risk of missing a subtle abnormality is increased if other tissue types used Detection of Philadelphia chromosome -positive chronic myeloid leukaemia Certain trust/genetics laboratories Reverse transcriptase polymerase chain reaction (RT-PCR) Allows amplification of mrna for detection of abnormal gene products Requires a small amount of source material Can be used for HER2 and prostatespecific antigen (PSA) Specialist genetics laboratories DNA sequencing Uses a range of methods, such as Sanger sequencing, to determine the sequence of a section of DNA Allows identification of point mutations in tumour tissue samples Detection of EGFR mutations associated with response to gefitinib therapy Specialist genetics laboratories NECDAG PIP Page 16 of 17. Date of preparation: August 2013

17 Appendix 3. Testing technologies for molecular targets in cancer expected to be introduced in the near future Test Advantages Disadvantages Potential uses Next generation sequencing Circulating DNA Able to sequence far larger amounts of DNA; allows simultaneous testing of many genes at once and processing of samples from multiple patients Suitable for use when routinely testing tumours for a predetermined large panel of biomarkers Convenient; ready availability of blood samples Able to test tumours in patients too unwell for a biopsy High equipment cost High cost of consumables Less suitable for testing for single biomarkers in single tumours New technology still in development, needs verifying on larger numbers of patients KRAS and EGFR mutation testing Biomarker discovery Tracking breast and ovarian cancers, replacement for traditional tumour markers NECDAG PIP Page 17 of 17. Date of preparation: August 2013