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Diagnostics Oncology, Training and education, Histology, Precision medicine, Biochemistry and molecular biology, Companion diagnostics

Putting Pathology at the Heart

The path to implementing a new companion diagnostic test is often a long and difficult one: lack of familiarity with a test, inadequate knowledge and training, and inability to acquire funding, can all foil tests before they even make it to the hospital lab. I co-founded the Poundbury Cancer Institute (PCI) with the sole aim of alleviating many of these issues, and accelerating the adoption of companion diagnostics and other important lab tests.

What led me here?

My interest in cancer biology traces back to medical school, and during my postgraduate histopathology training I started getting involved in research. My career later led me to become senior lecturer at the Hedley Atkins Breast Unit in London, where I was also consultant pathologist at Guy’s Hospital, and director of the Breast Tissue Bank. When I left London to work at Dorset County Hospital (DCH) in Dorchester, I used my experience to set up a lab, which focused on innovation to provide a modern, and high quality diagnostic service.

During my time at DCH, I initiated a collaboration with the UK NEQAS (National External Quality Assessment Service) that resulted in a pilot project to translate landmark findings – already well-supported by peer-reviewed research – into clinical practice. The importance of some of these findings, for instance the assessment of microsatellite instability in colorectal cancer (CRC), have been known for at least two decades. Others, such as determining BRAF mutation status in melanoma to predict response to targeted therapies, are more recent findings. We teamed up with the multinational diagnostics company, Roche, and worked on a number of areas – including the establishment of routine prognostic and predictive tests for CRC (see  “Colorectal Cancer Collaboration: A Case Study” on page 2), prostate cancer and melanoma diagnosis, and the routine use of multiplex staining. We succeeded in establishing new molecular pathology services that can be delivered even by the histology departments of small district general hospitals, such as a practical molecular classification for CRC patients that necessitated the creation of an effective workflow through the lab, to meet the demands of a clinical service. Our success meant that we received numerous requests for more projects, but we simply weren’t set up to take on board the additional volume of work, and more importantly, we weren’t equipped to deliver the necessary training of lab staff and pathologists. I decided, along with my colleagues, to establish a laboratory and teaching center better suited for the challenges ahead – PCI.

Winning the trust of the NHS

Funding was never a major issue for us; PCI was set up using a mixture of private investments, commercial funding and charitable donations. But creating the Institute didn’t come without its problems. Paradoxically, gaining acceptability from the UK National Health Service (NHS) has been difficult. We found that, as an external, private institution, there is an assumption that we want to centralize testing and take work away from public labs. On the contrary, we want to support them and facilitate local introduction of the tests that we develop. We now have a network of NHS labs that want to collaborate with us, and we hope to expand this further. But despite this, I believe our main challenge is to ensure that our scope and functions are understood by the very hospitals and staff our work is intended to benefit.

Building our relationship with the NHS is essential, in particular because PCI has been developed to facilitate teaching and translational research. To do this, we are creating a small clinical service, including molecular diagnostics, to be made available to local patients. A digital microscopy classroom will be built and used to train pathologists, and biomedical and clinical scientists in the interpretation and quantification of cutting-edge diagnostics. Updates for oncologists and surgeons will also be available, to make sure that they are aware of new developments, and can interpret the results that we provide. We intend to inform patients, too – by providing information and holding lectures on advances in the detection and treatment of their diseases.

Reevaluating the pathologist’s role

Although the Institute will cater to both clinicians and patients, laboratory medicine will have a central role in our work. My colleagues and co-founders Teresa Thomas and Saleem Taibjee and I are all pathologists, and PCI has a strong focus on tissue diagnostics. However, in the past 20 years we have seen a progressive shift away from histopathology towards molecular biology and genetics, with much effort going into developing systems based on the so-called “grind and find” approach. Pathologists, once the linchpin of much of the progress in cancer research, have been confined to a diagnostic role.

But things are changing – renewed interest in the localization of molecular changes within the tissue microarchitecture has caused this role to be revalued. Histological slides contain a tremendous amount of information, and we need to develop and refine techniques to interpret this material and turn it into benefits for our patients. For example, recently developed checkpoint inhibitor drugs require quantification of PD-1 and PDL-1 staining in tumor cells and lymphocytes at the tumor-host interface, and this is only possible using on-slide tests. Sadly, I believe that lack of investment in UK histopathology has resulted in fewer pathologists available to support these innovations – and this needs to change.

It’s important, however, for us to think beyond pathology, though: successful diagnosis and treatment relies on a multidisciplinary approach. We need the expertise and advice of our surgeons, physicians and oncologists in order to identify diagnostic areas that could benefit most from further development; the formulation of molecular classifications and the identification of appropriate risk groups needs the support of all disciplines.

Lack of investment in UK histopathology has resulted in fewer pathologists available to support these innovations – and this needs to change.

Assuring quality

Another important collaboration within PCI is our work to support CADQAS (Cancer Diagnostic Quality Assurance Services), an independent, not-for-profit, community interest company. Since most new diagnostic tests influence critical decisions in patient treatment, it has become increasingly important that these tests are performed to the highest quality standards, because they often influence critical decisions in patient treatment. External QA plays a crucial role in this. CADQAS works with key opinion leaders in the UK and beyond to support the introduction of slide-based companion diagnostics and to help all UK NEQAS participating labs make improvements to their current practice. Additionally, CADQAS engages with industry at an early stage, so that these programs can be developed ahead of the launch of the corresponding targeted therapies. Providing support for CADQAS is a key objective that is recognized within PCI.

Industry expertise

This brings us to the other key player in our collaborative model – industry, and in particular, Roche. I believe their involvement brings many benefits to our work. In the past, the academic community had an important role in the development of tests, but industry has increasingly emerged as the major provider, especially in companion diagnostics. Working with Roche allows us to benefit from their considerable experience in performing and interpreting new tests, and in successfully transferring these technologies to clinical practice. Additionally, bioscience companies often have access to technology not yet on the open market, and they can make this available to their collaborators in order to accelerate development.

These benefits don’t come without challenges: the NHS is typically wary of industry, and fears opportunism rather than symbiosis. On the other hand, the private sector needs to ensure these partnerships are fruitful for patient care, and these interactions should not be viewed merely as a means for increasing revenue.

These benefits don’t come without challenges: the NHS is typically wary of industry, and fears opportunism rather than symbiosis.

Dispelling suspicions

The NHS might be suspicious of industry intentions, but they stand to benefit from these collaborations. Adoption of new technologies by the NHS can be slow, and the obstacles many. In general, the situation is much better in countries with insurance-based healthcare systems, such as the US or Germany. For example, when the FDA approves a new treatment, the approval and reimbursement associated with the necessary companion diagnostic are arranged simultaneously. In the UK and numerous other European health systems, there is a less structured provision for reimbursement. Some pharmaceutical companies provide free companion diagnostics for an initial period of time, and this encourages early adoption, but these tests are often handled by central labs, and little effort is made to ensure local hospitals can perform them. So once the free period ends, labs are left without the support or funding they need to implement the test themselves.

CADQAS aims to aid NHS labs with these issues. An important remit of the Institute is to support local labs in performing tests, interpreting results and using the data to plan treatment. We will also work to assess the health economics of diagnostics, and provide managers with data that helps them identify funding. Often, we find that new tests not only improve the quality of service but also reduce costs for the hospital – this kind of data is invaluable to managers.

Our relationships with other labs, both in the private and public sector, will allow us to disseminate training and technologies as quickly as possible. In the initial phase of test development, we plan to provide a remote service to our local clinicians, making sure treatments can be used as soon as they become accessible. This has the added benefit of allowing us to optimize workflows, improve efficiency, and troubleshoot tests. We can also examine interpretation, and identify the best format to communicate results to clinicians and patients; for a new test to become established, it is crucial that clinicians understand its context and how it can instruct treatment. Aided with all this practical knowledge, we can then support local labs in introducing these tests to their routine.

Increasing accuracy and improving outcomes

Although support and training will form an important part of the work at PCI, research will be a focus, too. We plan to develop tissue-sparing multiplex staining wherever feasible, to ensure sufficient tissue is preserved for use with companion diagnostics. The pharmaceutical industry is already combining targeted therapies to increase their effectiveness and prevent the emergence of resistant disease. Already, chemotherapy and radiotherapy have replaced surgery as the primary treatment of choice in some forms of low rectal cancer, and it’s possible that surgery will increasingly be replaced as the first-line treatment. Potentially, this will mean more detailed molecular assessment of each individual patient is needed ahead of initiating any treatment, and we need to ensure that pathologists are able to deliver this data. With increasingly accurate tests for predicting the biological potential of each cancer, we can offer patients better cancer management, and more personalized treatments – helping us to further the Institute’s key operating principle: to help the NHS improve outcomes for cancer patients.

Corrado D’Arrigo is a consultant histopathologist at Dorset County Hospital, UK, and the co-founder of Poundbury Cancer Institute.

Colorectal Cancer Collaboration: A Case Study

Back in 2012, before teaming up for PCI, Corrado D’Arrigo, UK NEQAS and Roche Diagnostics collaborated on a colorectal cancer (CRC) program, the success of which kick-started talks of a more long-term partnership, which has now been realized in Poundbury.

What inspired the first collaboration? The clear need to improve CRC testing. Traditionally, prognostic testing was restricted to staging; not the most precise of models. And while a number of well-supported tests have now been developed for molecular profiling of the condition, these tests are often only available in large institutions, or as part of research programs and clinical trials. In cases where local hospitals do have access, samples usually need to be sent away, which can result in long turnaround times.

The aim of the alliance was to introduce new, efficient and accurate tests to small NHS hospitals. It involved setting up an integrated workflow to ensure all individual tests could be performed together on a sample (as opposed to the common practice of batching several different samples that require the same test), without disrupting the work of an already busy diagnostic service. A classification system was also devised, to communicate the information gained from testing to clinicians.

The work of the partnership team resulted in the creation of a panel of predictive and prognostic tests (see Table 1) that aids oncologists in separating the various disease entities that fall under the umbrella of CRC, helping them to choose the most appropriate treatment. Some of the tests are now seeing more widespread use – for example, the 2014 RCPath revision of the minimum dataset for reporting CRC now includes microsatellite instability (1).

Colorectal Cancer Panel – What Tests and Why?

Table 1. The CRC panel and its rationale. Developed by a collaboration between staff at Dorset County Hospital, Roche Diagnostics and UK NEQAS. MSI, microsatellite instable; MSS, microsatellite stable; 5-FU, 5-Fluorouracil; PDL-1, Programmed death-ligand
MSI Mutation Analysis for EGFR, KRAS, BRAF, NRAS and PI3K Loss of PTEN HER-2 Amplification Loss of CDX-2, Loss of CK20 and Expressionof CK7
• Numerous studies have shown that MSI tumors have a better prognosis, do not benefit from 5-FU based adjuvant chemotherapy, and respond well to combination therapy such as anti-VEGF and oxaliplatin (2, 3). • There are a number of new treatments such as cetuximab, panitumumab, regarofenib, and more which rely on these tests to predict responses (5). • There is evidence that loss of PTEN may predict a lack of benefit from anti-EGFR therapy in metastatic CRC (7); its prognostic role in CRC is currently debated. • The Heracles trial has resulted in renewed interest in HER-2 amplification. • Prognostic factors associated with aggressive clinical behavior.
• Recent data has also suggested that MSI patients may benefit from the checkpoint inhibitor anti-PDL-1, while MSS patients do not respond to this class of drug (4). • BRAF in combination with MSI also separates familial from sporadic disease (6). • Some observed discordances may result from inconsistent analysis and interpretation. • The study trialed lapatinib and trastuzumab in patients with HER-2 amplified, KRAS wild type metastatic CRC, with tumors that no longer responded to chemotherapy and anti-EGFR therapy, with positive initial results (8). • CRC patients with simultaneous loss of CDX2 and CK20 expression in tumor tissue constitute a highly aggressive subgroup of MSI CRC patients (9).
    • PTEN loss has been added to the panel to work towards standardization.    


Industry Insights

Christopher Hudson is Director of Tissue Diagnostics UK and Ireland at Roche, the multinational life sciences company that supports the Poundbury Cancer Institute through funding and research collaboration.

Quantifying Quality

Keith Miller is Director and co-founder of CADQAS (Cancer Diagnostic Quality Assurance Services), a not-for-profit community interest company hosted by Poundbury Cancer Institute (PCI), which works to provide information and training to laboratory staff, and to ensure the quality of cancer diagnostics.

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About the Author
Corrado D’Arrigo

Corrado D’Arrigo is a consultant histopathologist at Dorset County Hospital, UK, and the co-founder of Poundbury Cancer Institute.

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