Birth of the first oesophageal All-Ireland Cancer Network

What is the oesophageal All-Ireland Cancer Network (AllCaN)?

The incidence of oesophageal adenocarcinoma (OAC) has risen by 48 per cent over the past four decades, with a dismal five-year survival of approximately 15 per cent. Ireland and the UK have the highest reported incidence rates worldwide – yet no effective cancer prevention intervention strategies or diagnostic and therapeutic tools have reached the clinic.

In April 2023, the Breakthrough Cancer Research charity established the first oesophageal All-Ireland Cancer Network (AllCaN) symposium (www.allcan.ie).AllCaN will seek to address these unmet clinical needs for both Barrett’s oesophagus (BO) and OAC patients on the island of Ireland.

The AllCaN consortium, which is directed by Prof Jacintha O’Sullivan (Trinity College Dublin), Prof Helen Coleman (Queens University Belfast) and Prof Juliette Hussey (Trinity College Dublin), is focused on accelerating research and improving outcomes for BO and OAC patients across the island.

By uniting resources and fostering cooperation among these and other leading academic institutions, AllCaN aims to conduct innovative research by carrying out groundbreaking studies that push the boundaries of the current understanding and treatment of BO and OAC. AllCaN plans to do this through the management of resources by ensuring that all knowledge, tools, and technologies are shared across the network, optimising the use of available resources.

AllCaN will also encourage collaboration across the island of Ireland, connecting Northern Ireland with other universities and state-of-the-art hospitals in Ireland. Most importantly, AllCaN will prioritise and adopt a patient-centred care approach, by engaging and actively highlighting the importance of patient perspectives across all AllCaN research projects to ensure that the care provided is effective and empathetic.

Thanks to these objectives and various key academic, industrial, and charity partnerships, AllCaN hopes to establish a more cohesive and effective framework for BO and OAC research and care, and to make significant strides in improving patient outcomes and setting a standard for future collaborative cancer research initiatives.

Today, the AllCaN partnership includes six major academic institutions – Trinity College Dublin, Queen’s University
Belfast, University College Dublin, the Royal College of Surgeons in Ireland, University of Galway, and University College Cork; three industry partners – OncoAssure, Mirai Medical, and Deciphex; and three charity partners – Breakthrough Cancer Research, Oesophageal Cancer Fund, and CROSS, all working with
health agencies in Northern Ireland and the Republic of Ireland.

AllCaN, at its launch in April 2023, detailed all its research objectives across four main work packages – prevention, intervention, targeted diagnostics, and novel therapeutics.

Prevention

Prevention reduces the incidence of cancer by addressing risk factors and promoting healthy behaviours, thus decreasing the overall burden on healthcare systems. Population-based and multi-centre research across the island of Ireland shows that the risk of cancer progression in non-dysplastic BO patients is relatively low (~0.2%-0.3% per year) but this significantly rises in dysplastic patients. Therefore, major research gaps remain in determining how best to stratify patients with BO into low- or high-risk groups to avoid unnecessary burden on limited healthcare resources and to provide reassurance to these patients at lower risk, while improving surveillance strategies for higher-risk patients.

In terms of prevention of OAC and BO risk and progression, ‘known’ risk factors include obesity and tobacco smoking, and yet implementation of prevention strategies for patients at high-risk of OAC remain largely unexplored. Consumption of alcohol is not associated with OAC risk, however, other exposures, such as physical activity, nutrition, and medication use require further study.

In this work package, AllCaN researchers will monitor the number of patients being diagnosed with BO and OAC, and for the first time make North/South comparisons that combine Barrett’s registries in Northern Ireland and the Republic of Ireland, and cancer registries. AllCaN will also examine if there are any inequalities according to where people live, their age and sex, and whether different healthcare systems on the island influence patient outcomes.

Early intervention can significantly improve outcomes by detecting potential cancer mechanisms at a more treatable stage, potentially leading to higher survival rates and better quality of life. As the incidence of OAC increases steadily in Western countries in tandem with increasing overweight and obesity, there is a need to examine how risk and outcome may be modified and optimised through more personalised lifestyle interventions.

Obesity is not just excess adipose tissue. Certain dietary elements, including saturated fatty acids, are particularly harmful. Overconsumption of saturated fatty acids specifically increases visceral adipose tissue in men, which in turn could augment risk of BO transitioning to OAC. Saturated fats are pro-oncogenic and contribute to the transition from BO to OAC, thereby justifying more rigorous investigation of diet and exercise interventions contributing towards better quality of life.

Physical activity behaviours and the impact of a diagnosis and risk of progression on overall quality of life are poorly understood in people with BO. This AllCaN work package will also explore correlates of physical activity as well as mental health and overall quality of life in BO patients.

Diagnostics

Targeted diagnostics enable the precise identification of the specific oesophageal disease and stage, allowing for more accurate prognosis and personalised treatment plans.

Another key strength of the All-Ireland Barrett’s registry platform from the prevention work package is its ability to enable AllCaN researchers to access linked tissue samples to generate a unique All-Island Integrated Analysis Platform to facilitate the in-depth study of the molecular biology of BO and OAC. AllCaN anticipates that this research platform will be unparalleled worldwide, providing the largest resource of BO samples and clinical data to enable biomarker discovery to predict progression of BO to OAC.

While the majority of BO patients do not develop OAC, risk stratification measures to identify those at the highest risk of developing cancer are not available in clinical practice. Standard screening relies upon the identification of dysplasia to select patients for more intensive screening, ablation, or even surgical resection. The detection of dysplasia shows substantial inter-observer variability between pathologists and requires a large population to undergo invasive and costly endoscopic surveillance.

In short, current practice over-diagnoses low-risk non-progressive disease, while under-diagnosing high-risk life-threatening lesions. There is an immediate need to identify objective biomarkers to prioritise non-dysplastic Barrett’s oesophagus (NDBO) patients at greatest risk of progression to cancer. AllCaN hypothesises that an integrated analysis of gene expression and methylation data can be applied to develop biomarkers to predict which NDBO patients will progress to high grade dysplasia (HGD) or OAC. This will enable high-risk BO lesions to be eradicated endoscopically, while low-risk patients can have the frequency of endoscopic screening reduced or even discontinued.

By building upon the pioneering work that has been undertaken within the Northern Ireland Barrett’s Register, the Northern Ireland Biobank, and the Republic of Ireland Barrett’s Registry, Bioresource and Oesophageal Cancer Network (RIBBON), AllCaN will assemble an unparalleled tissue and data resource for biomarker discovery and validation.

Treatment

Novel therapeutics would offer new and potentially more effective treatment options, especially for OAC, which
can be resistant to conventional therapies. New therapies could also improve patient outcomes and expand treatment possibilities.

For this work package, AllCaN will determine if the use of immune checkpoint inhibitors in BO can affect disease progression. The role of the evolving tissue microenvironment and supportive stromal cells in driving immune checkpoint dysfunction as the disease progresses will also be examined. This will lead to the identification of new immunotherapeutic targets in premalignancy, a largely untapped area for immunotherapeutic development.

Cancer immunotherapy, in the form of immune checkpoint inhibition, has changed the face of cancer treatment, including GI cancers. While it uniquely offers the promise of a cure for a small cohort of patients, many patients only gain short-term or no benefit.

AllCaN researchers will also explore electroporation – electrical pulses applied to a cell to render its membrane porous. As the electroporation pulses vastly increase the porosity of the cell membrane, different drugs, including certain immunotherapies which require internalisation, can be used in combination to facilitate their targeted absorption. In fact, AllCaN is already seeing some positive results with this therapeutic approach.

Next, AllCaN researchers will examine the effect of electroporation on the inflammatory microenvironment in Barrett’s non-dysplastic and dysplastic ex vivo human tissues and the effect of this secretome on immune cell activation.

Future

Although AllCaN is very much in its infancy, it is anticipated that more work packages will also be developed over subsequent cycles as the AllCaN network grows.

By combining data and resources across the island of Ireland through these four work packages, AllCaN will uniquely identify appropriate prevention strategies, lifestyle interventions, and novel diagnostic platforms and therapeutics through enhanced understanding of BO-OAC progression.

More pertinently, the AllCaN programme has the capacity to positively impact people’s lives in the near future. Findings related to the prevention work package could immediately inform clinical guidelines and policies for BO management and enable oesophageal cancer screening and risk prediction in primary care.

The research infrastructure created through this work package could also pave the way for future studies through the Barrett’s All-Island Registry, such as geographic information system mapping of environmental exposures (such as radon) to BO and OAC incidence data.

Research findings from the intervention work package could offer the scientific basis for exercise prescription, dietary modifications, and symptom management in BO, which would be immediately beneficial to patients and carers, thereby instantly informing clinical guidelines for BO management. This in turn could hold potential for improved quality of life and better risk factor management through targeted, personalised lifestyle interventions for people living with BO.

New research findings through the targeted diagnostics work package could also help to improve the quality of life for high-risk and low-risk patients through targeted approaches to disease management, including treatment of lesions and the frequency of endoscopic screening.

Innovative discoveries through the novel therapeutics work package could have significant implications in the clinic, including whether electroporation treatment can be applied in outpatients to improve inflammation in BO patients. Moreover, AllCaN will seek to identify new immunotherapeutic targets in patients with BO and OAC, and obtain more knowledge on the effective use of immunotherapy in both pre-malignant and malignant diseases.

The first AllCaN Symposium will take place on 23 October 2024 in the Trinity Translational Medicine Institute. We anticipate that this and future AllCaN symposia will become increasingly pivotal in advancing the understanding, treatment, and prevention of BO and OAC across the island of Ireland. October’s gathering will bring together a diverse array of stakeholders, including charity partners, industrial partners, oncologists, researchers, healthcare professionals, policy makers, and patient advocates, fostering a collaborative environment that is essential for tackling the multifaceted challenges of BO and OAC.

https://allcan.ie/Visit www.allcan.ie for more information.