Empowering effective biomarker-driven precision oncology: A call to action.

Precision oncology has a significant role to play in delivering optimal patient care. Biomarkers are critical enablers for precision oncology across the continuum of cancer diagnosis, in defining patient prognosis, and in predicting the response to treatments and their potential toxicities, as well as delineating the risk of hereditary cancer syndromes. Biomarkers also potentiate cancer drug development, accelerating patient access to safe and effective therapies. However, despite an accurate and timely diagnosis being critical to patient survival, advances in genomic testing are not being fully exploited in daily clinical practice, leading to missed opportunities to deliver the most effective treatments for patients. Biomarker testing availability and implementation often lag behind approvals of respective biomarker-informed therapies, limiting prompt patient access to these life-saving drugs. Multiple factors currently impede the routine adoption of biomarker testing including, but not limited to, cost, lack of test reimbursement, limited access, regulatory hurdles, lack of knowledge, insufficient cooperation on assay development, and the urgent need to harmonize and validate testing assays, all leading to inefficient diagnostic pathways. Clinical guidelines increasingly include genomic profiling, and recent evidence suggests that precision oncology can be delivered in a cost-effective way for financially-challenged health systems. Therefore, precision genomic testing for cancer biomarkers must be embedded into the clinical practice of oncology care delivery going forward. We articulate a series of recommendations and a call to action to underpin the mainstreaming of a biomarker-informed precision oncology approach to enhance patient outcomes and deliver cost effective 21st century cancer care.

Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.

Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1+ stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers.

Skin in the game: The cost consequences of skin cancer diagnosis, treatment and care in Northern Ireland.

BACKGROUND: Skin cancer is a prevalent cancer in the UK. Its rising incidence and mortality rates are expected to result in substantial financial implications, particularly on diagnostic and treatment services for skin cancer management in Northern Ireland (NI). Such anticipated disease increases underscore the need for prevention and control measures that should help guide policymaking and planning efforts. METHODS: We conducted a cost of illness study to assess the economic impact of skin cancer in NI from the healthcare system's perspective, using a bottom-up method, employing NHS reference costs (UK£) for skin cancer diagnosis and treatment patient pathways in 2021/22. Sensitivity analyses varied diagnostic volumes by applying multipliers for benign cases, assuming a diagnostic conversion rate of 6.8%, and examined an alternative chemotherapy regimen compliance rate of 75%. Additionally, proportional cost increases were projected based on future estimated increases of 9% and 28% to malignant melanoma (MM) cases for diagnostic, treatment, and follow-up volumes. RESULTS: Significant numbers of non-melanoma skin cancers (NMSC) and MM cases were recorded, 4289 NMSCs and 439 MM cases. The total cost for managing NMSC was £ 3,365,350. Total costs for MM skin cancer were £ 13,740,681, including £ 8,753,494 for procurement, administration, and chemotherapy drug use. Overall healthcare spending on skin cancer care totalled £ 21,167,651. Sensitivity analysis suggested diagnostic cost may increase significantly to £ 12,374,478 based on referral volume assumptions. If base case rates rise by 9 or 28% estimated total costs of treating skin cancer will increase to £ 22.3 million and £ 24.9 million, respectively. CONCLUSIONS: Skin cancer management costs in NI totalled ∼£ 21.1 million to £ 32.1 million, depending on diagnostic referral assumptions. Costs have risen ∼10-fold over the past decade for MM due largely to chemotherapy costs. A predicted 28% increase in MM cases by 2040 would lead to ∼£ 3.8 million of additional expenditures, providing a significant challenge for cancer health systems.

Implementing the European code of cancer practice in rural settings.

Existing evidence often indicates higher cancer incidence and mortality rates, later diagnosis, lower screening uptake and poorer long-term survival for people living in rural compared to more urbanised areas. Despite wide inequities and variation in cancer care and outcomes across Europe, much of the scientific literature explicitly exploring the impact of rurality on cancer continues to come from Australia and North America. The European Code of Cancer Practice or "The Code" is a citizen and patient-centred statement of the most salient requirements for good clinical cancer practice and has been extensively co-produced by cancer patients, cancer professionals and patient advocates. It contains 10 key overarching Rights that a cancer patient should expect from their healthcare system, regardless of where they live and has been strongly endorsed by professional and patient cancer organisations as well as the European Commission. In this article, we use these 10 fundamental Rights as a framework to argue that (i) the issues and needs identified in The Code are generally more profound for rural people with cancer; (ii) addressing these issues is also more challenging in rural contexts; (iii) interventions and support must explicitly account for the unique needs of rural residents living with and affected by cancer and (iv) new innovative approaches are urgently required to successfully overcome the challenges faced by rural people with cancer and their caregivers. Despite equitable healthcare being a key European policy focus, the needs of rural people living with cancer have largely been neglected.

The future of cancer care in the UK-time for a radical and sustainable National Cancer Plan.

Cancer affects one in two people in the UK and the incidence is set to increase. The UK National Health Service is facing major workforce deficits and cancer services have struggled to recover after the COVID-19 pandemic, with waiting times for cancer care becoming the worst on record. There are severe and widening disparities across the country and survival rates remain unacceptably poor for many cancers. This is at a time when cancer care has become increasingly complex, specialised, and expensive. The current crisis has deep historic roots, and to be reversed, the scale of the challenge must be acknowledged and a fundamental reset is required. The loss of a dedicated National Cancer Control Plan in England and Wales, poor operationalisation of plans elsewhere in the UK, and the closure of the National Cancer Research Institute have all added to a sense of strategic misdirection. The UK finds itself at a crossroads, where the political decisions of governments, the cancer community, and research funders will determine whether we can, together, achieve equitable, affordable, and high-quality cancer care for patients that is commensurate with our wealth, and position our outcomes among the best in the world. In this Policy Review, we describe the challenges and opportunities that are needed to develop radical, yet sustainable plans, which are comprehensive, evidence-based, integrated, patient-outcome focused, and deliver value for money.

surviveR: a flexible shiny application for patient survival analysis.

Kaplan-Meier (KM) survival analyses based on complex patient categorization due to the burgeoning volumes of genomic, molecular and phenotypic data, are an increasingly important aspect of the biomedical researcher's toolkit. Commercial statistics and graphing packages for such analyses are functionally limited, whereas open-source tools have a high barrier-to-entry in terms of understanding of methodologies and computational expertise. We developed surviveR to address this unmet need for a survival analysis tool that can enable users with limited computational expertise to conduct routine but complex analyses. surviveR is a cloud-based Shiny application, that addresses our identified unmet need for an easy-to-use web-based tool that can plot and analyse survival based datasets. Integrated customization options allows a user with limited computational expertise to easily filter patients to enable custom cohort generation, automatically calculate log-rank test and Cox hazard ratios. Continuous datasets can be integrated, such as RNA or protein expression measurements which can be then used as categories for survival plotting. We further demonstrate the utility through exemplifying its application to a clinically relevant colorectal cancer patient dataset. surviveR is a cloud-based web application available at https://generatr.qub.ac.uk/app/surviveR , that can be used by non-experts users to perform complex custom survival analysis.

Gender inequity in cancer research leadership in Europe: Time to act.

AIM: Cancer is one of Europe's key research missions, with gender equity a major policy pillar. To benchmark how well European countries perform for gender balance in cancer research, high quality intelligence is required. METHODS: For cancer research papers in Europe (EUR31; the 28 EU Member States plus Iceland, Norway and Switzerland) from two specific years (2009 and 2019), we evaluated the numbers of female authors overall and then the female last-author presence, as a proxy of female cancer research leadership. RESULTS: Overall, female authorship increased from 42% to 49%. In 2009, females represented 50% or more of cancer research authors in only five EUR31 countries. By 2019, that number had risen to 17. In Eastern European (EE) countries, females were more likely to be in the majority. The presence of female cancer research authors in the last (senior) author position increased from 24% to 34%. Five of the top six countries for female authorship in 2019 were from EE, whereas disappointingly four central European countries (Austria (AT), Czechia (CZ), Germany (DE) and Switzerland (CH)) were below the 25th percentile. A number of European powerhouses of cancer research (UK, DE, CH) underperformed in terms of female cancer research leadership. However, when cancer researchers from these countries worked abroad (e.g. Scandinavia, USA) the percentage of females was similar to that of their host countries. A factor potentially influencing female cancer research participation was availability and relative cost of child-care, which is more favourable in Scandinavia and EE than in central/western Europe. CONCLUSION: Our data show that Horizon Europe's Cancer Mission must ensure gender equity in its future research programmes and support the enhancement of female cancer research leadership opportunities.

Health diplomacy in action: The cancer legacy of the Good Friday Agreement.

2023 marks the 25th anniversary of the Good Friday Agreement, which led peace in Northern Ireland. As well as its impact on peace and reconciliation, the Good Friday Agreement has also had a lasting positive impact on cancer research and cancer care across the island of Ireland. Pursuant to the Good Friday Agreement, a Memorandum of Understanding (MOU) was signed between the respective Departments of Health in Ireland, Northern Ireland and the US National Cancer Institute (NCI), giving rise to the Ireland - Northern Ireland - National Cancer Institute Cancer Consortium, an unparalleled tripartite agreement designed to nurture and develop linkages between cancer researchers, physicians and allied healthcare professionals across Ireland, Northern Ireland and the US, delivering world class research and better care for cancer patients on the island of Ireland and driving research and innovation in the US.

The impact of the COVID-19 pandemic on community prescription of opioid and antineuropathic analgesics for cancer patients in Wales, UK.

PURPOSE: Public health measures instituted at the onset of the COVID-19 pandemic in the UK in 2020 had profound effects on the cancer patient pathway. We hypothesise that this may have affected analgesic prescriptions for cancer patients in primary care. METHODS: A whole-nation retrospective, observational study of opioid and antineuropathic analgesics prescribed in primary care for two cohorts of cancer patients in Wales, using linked anonymised data to evaluate the impact of the pandemic and variation between different demographic backgrounds. RESULTS: We found a significant increase in strong opioid prescriptions during the pandemic for patients within their first 12 months of diagnosis with a common cancer (incidence rate ratio (IRR) 1.15, 95% CI: 1.12-1.18, p < 0.001 for strong opioids) and significant increases in strong opioid and antineuropathic prescriptions for patients in the last 3 months prior to a cancer-related death (IRR = 1.06, 95% CI: 1.04-1.07, p < 0.001 for strong opioids; IRR = 1.11, 95% CI: 1.08-1.14, p < 0.001 for antineuropathics). A spike in opioid prescriptions for patients diagnosed in Q2 2020 and those who died in Q2 2020 was observed and interpreted as stockpiling. More analgesics were prescribed in more deprived quintiles. This differential was less pronounced in patients towards the end of life, which we attribute to closer professional supervision. CONCLUSIONS: We demonstrate significant changes to community analgesic prescriptions for cancer patients related to the UK pandemic and illustrate prescription patterns linked to patients' demographic background.

Delivering the precision oncology paradigm: reduced R&D costs and greater return on investment through a companion diagnostic informed precision oncology medicines approach.

BACKGROUND: Precision oncology medicines represent a paradigm shift compared to non-precision oncology medicines in cancer therapy, in some situations delivering more clinical benefit, and potentially lowering healthcare costs. We determined whether employing a companion diagnostic (CDx) approach during oncology medicines development delivers effective therapies that are within the cost constraints of current health systems. R&D costs of developing a medicine are subject to debate, with average estimates ranging from $765 million (m) to $4.6 billion (b). Our aim was to determine whether precision oncology medicines are cheaper to bring from R&D to market; a secondary goal was to determine whether precision oncology medicines have a greater return on investment (ROI). METHOD: Data on oncology medicines approved between 1997 and 2020 by the US Food and Drug Administration (FDA) were analysed from the Securities and Exchange Commission (SEC) filings. Data were compiled from 10-K, 10-Q, and 20-F financial performance filings on medicines' development costs through their R&D lifetime. Clinical trial data were split into clinical trial phases 1-3 and probability of success (POS) of trials was calculated, along with preclinical costs. Cost-of-capital (CoC) approach was applied and, if appropriate, a tax rebate was subtracted from the total. RESULTS: Data on 42 precision and 29 non-precision oncology medicines from 56 companies listed by the National Cancer Institute which had complete data available were analysed. Estimated mean cost to deliver a new oncology medicine was $4.4b (95% CI, $3.6-5.2b). Costs to bring a precision oncology medicine to market were $1.1b less ($3.5b; 95% CI, $2.7-4.5b) compared to non-precision oncology medicines ($4.6b; 95% CI, $3.5-6.1b). The key driver of costs was POS of clinical trials, accounting for a difference of $591.3 m. Additional data analysis illustrated that there was a 27% increase in return on investment (ROI) of precision oncology medicines over non-precision oncology medicines. CONCLUSION: Our results provide an accurate estimate of the R&D spend required to bring an oncology medicine to market. Deployment of a CDx at the earliest stage substantially lowers the cost associated with oncology medicines development, potentially making them available to more patients, while staying within the cost constraints of cancer health systems.

Circulating tumour DNA kinetics in recurrent/metastatic head and neck squamous cell cancer patients.

PURPOSE: Immune checkpoint blockade (ICB) has become a standard of care in the treatment of recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC). However, only a subset of patients benefit from treatment. Quantification of plasma circulating tumour DNA (ctDNA) levels and on-treatment kinetics may permit real-time assessment of disease burden under selective pressures of treatment. PATIENTS AND METHODS: R/M HNSCC patients treated with systemic therapy, platinum-based chemotherapy (CT) or ICB, underwent serial liquid biopsy sampling. Biomarkers tested included ctDNA measured by CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) and markers of host inflammation measured by neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). RESULTS: Among 53 eligible patients, 16 (30%) received CT, 30 (57%) ICB [anti-PD1/L1] monotherapy and 7 (13%) combination immunotherapy (IO). Median progression-free survival (PFS) and overall survival (OS) were 2.8 months (95% CI, 1.3-4.3) and 8.2 months (95% CI, 5.6-10.8), respectively. Seven (13%) patients experienced a partial response and 21 (40%) derived clinical benefit. At baseline, median ctDNA variant allele frequency (VAF) was 4.3%. Baseline ctDNA abundance was not associated with OS (p = 0.56) nor PFS (p = 0.54). However, a change in ctDNA VAF after one cycle of treatment (ΔVAF (T1-2)) was predictive of both PFS (p< 0.01) and OS (p< 0.01). Additionally, decrease in ΔVAF identified patients with longer OS despite early radiological progression, 8.2 vs 4.6 months, hazard ratio 0.44 (95% CI, 0.19-0.87) p = 0.03. After incorporating NLR and PLR into multivariable Cox models, ctDNA ∆VAF retained an association with OS. CONCLUSIONS: Early dynamic changes in ctDNA abundance, after one cycle of treatment, compared to baseline predicted both OS and PFS in R/M HNSCC patients on systemic therapy.

Whole-population trends in pathology-confirmed cancer incidence in Northern Ireland, Scotland and Wales during the SARS-CoV-2 pandemic: A retrospective observational study.

INTRODUCTION: The COVID-19 epidemic interrupted normal cancer diagnosis procedures. Population-based cancer registries report incidence at least 18 months after it happens. Our goal was to make more timely estimates by using pathologically confirmed cancers (PDC) as a proxy for incidence. We compared the 2020 and 2021 PDC with the 2019 pre-pandemic baseline in Scotland, Wales, and Northern Ireland (NI). METHODS: Numbers of female breast (ICD-10 C50), lung (C33-34), colorectal (C18-20), gynaecological (C51-58), prostate (C61), head and neck (C00-C14, C30-32), upper gastro-intestinal (C15-16), urological (C64-68), malignant melanoma (C43), and non-melanoma skin (NMSC) (C44) cancers were counted. Multiple pairwise comparisons generated incidence rate ratios (IRR). RESULTS: Data were accessible within 5 months of the pathological diagnosis date. Between 2019 and 2020, the number of pathologically confirmed malignancies (excluding NMSC) decreased by 7315 (14.1 %). Scotland experienced early monthly declines of up to 64 % (colorectal cancers, April 2020 versus April 2019). Wales experienced the greatest overall change in 2020, but Northern Ireland experienced the quickest recovery. The pandemic's effects varied by cancer type, with no significant change in lung cancer diagnoses in Wales in 2020 (IRR 0.97 (95 % CI 0.90-1.05)), followed by an increase in 2021 (IRR 1.11 (1.03-1.20). CONCLUSION: PDC are useful in reporting cancer incidence quicker than cancer registrations. Temporal and geographical differences between participating countries mirrored differences in responses to the COVID-19 pandemic, indicating face validity and the potential for quick cancer diagnosis assessment. To verify their sensitivity and specificity against the gold standard of cancer registrations, however, additional research is required.

Engaging European society at the forefront of cancer research and care: How discussions at the 5th Gago Conference on European Science policy led to the Heidelberg Manifesto

European cancer research stakeholders met in October 2022 in Heidelberg, Germany, at the 5th Gago conference on European Cancer Policy, to discuss the current cancer research and cancer care policy landscape in Europe. Meeting participants highlighted gaps in the existing European programmes focusing on cancer research, including Europe's Beating Cancer Plan (EBCP), the Mission on Cancer (MoC), Understanding Cancer (UNCAN.eu), and the joint action CRANE, and put forward the next priorities, in the form of the Heidelberg Manifesto for cancer research. This meeting report presents all discussions that shed light on how infrastructures can be effectively shaped for translational, prevention, clinical and outcomes cancer research, with a focus on implementation and sustainability and while engaging patients and the public. In addition, we summarize recommendations on how to introduce frameworks for the digitalization of European cancer research. Finally, we discuss what structures, commitment, and resources are needed to establish a collaborative cancer research environment in Europe to achieve the scale required for innovation.

Cost consequences of unscheduled emergency admissions in cancer patients in the last year of life.

OBJECTIVES: Cancer is a leading cause of death. This paper examines the utilisation of unscheduled emergency end-of-life healthcare and estimates expenditure in this domain. We explore care patterns and quantify the likely benefits from service reconfigurations which may influence rates of hospital admission and deaths. METHODS: Using prevalence-based retrospective data from the Northern Ireland General Registrar's Office linked by cancer diagnosis to Patient Administration episode data for unscheduled emergency care (1st January 2014 to 31st December 2015), we estimate unscheduled-emergency-care costs in the last year of life. We model potential resources released by reductions in length-of-stay for cancer patients. Linear regression examined patient characteristics affecting length of stay. RESULTS: A total of 3134 cancer patients used 60,746 days of unscheduled emergency care (average 19.5 days). Of these, 48.9% had ≥1 admission during their last 28 days of life. Total estimated cost was £28,684,261, averaging £9200 per person. Lung cancer patients had the highest proportion of admissions (23.2%, mean length of stay = 17.9 days, mean cost=£7224). The highest service use and total cost was in those diagnosed at stage IV (38.4%), who required 22,099 days of care, costing £9,629,014. Palliative care support, identified in 25.5% of patients, contributed £1,322,328. A 3-day reduction in the mean length of stay with a 10% reduction in admissions, could reduce costs by £7.37 million. Regression analyses explained 41% of length-of-stay variability. CONCLUSIONS: The cost burden from unscheduled care use in the last year of life of cancer patients is significant. Opportunities to prioritise service reconfiguration for high-costing users emphasized lung and colorectal cancers as offering the greatest potential to influence outcomes.