Cancer Research UK Research Articles

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: R-CHOP remains the standard of care in DLBCL yet for up to 40% of patients (pts.) it fails either through refractory lymphoma or relapse after achieving an initial remission. In the phase Ib/II ACCEPT study (NCT03571308), acalabrutinib (A), a second generation Bruton Tyrosine Kinase inhibitor with enhanced kinase selectivity and a potential for better tolerability, was assessed in combination with R-CHOP in patients with de novo DLBCL. There were no dose-limiting toxicities and the maximum tolerated dose was not reached, At the recommended phase II dose of A 100 mg bd, R-CHOP+A demonstrated a 95% 24 month progression-free survival (PFS). In older patients there was no difference in safety and no compromise of delivery of full course R-CHOP. Efficacy was preserved across cell-of-origin and genomic sub-groups. The REMoDL-A study now builds upon these findings to examine efficacy of R-CHOP+A against R-CHOP. Methods: REMoDL-A is a stratified open-label, multicentre, randomised phase II study. Eligible patients have untreated histologically confirmed DLBCL requiring full course R-CHOP. All patients receive 1 cycle of R-CHOP chemotherapy. FFPE diagnostic pathology blocks have molecular profiling and are assigned subtype Germinal Centre B-cell, Activated B-Cell, Molecular High Grade, Unclassifiable, or failed RNA extraction (GEP Fail). Patients whose biopsies are successfully sub-typed are randomised 2:1 between R-CHOP+A (Arm B) or R-CHOP for a further 5 cycles (Arm A). The randomisation is stratified by molecular subtype, International Prognostic index and age. The primary endpoint for the study is progression free survival (PFS) in the modified intention to treat (ITT) population (non-Fail ITT population). Secondary endpoints include PFS related to the cell of origin and genomic subtypes, duration of response, overall survival, event free survival, toxicity and quality of life. Exploratory analyses will investigate how dynamic molecular (including CTDNA) and PET based biomarkers predict risk and can be incorporated into a dynamic risk prediction model. An early interim analysis is planned to explore safety in the ≥65 years population. The trial is powered to detect a hazard ratio of 0.668 with 90% power with 1-sided significance level of 20%. The number of patients to be randomised is 453 (302:151 per arm). To date 155 patients have been recruited. Of the FFPE diagnostic pathology blocks that have undergone molecular profiling, failed RNA extraction (GEP fail) has occurred in only 4 patients. This is a UK National Cancer Research Institute multicentre trial coordinated by Southampton Clinical Trials Unit. Molecular profiling is performed in HMDS, Leeds. Trial registration: ISRCTN14251143/ NCT04546620 The trial has been supported by an investigator initiated grant and drug access from AstraZeneca (ESR-19-20180) and has endorsement from Cancer Research UK (CRUKE/19/017). Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies, ongoing trials Conflicts of interests pertinent to the abstract G. P. Collins Honoraria: Roche, AstraZeneca C. Fox Consultant or advisory role Abbvie, AstraZeneca, Atarabio, BMS, GenMab, Gilead/Kite, Incyte, Lilly, Morphosys, Ono, Roche, Takeda Research funding: Beigene Educational grants: Roche, BMS G. Griffiths Honoraria: AstraZeneca P. Johnson Honoraria: Takeda, InCyte, Genmab, Epizyme A. J. Davies Consultant or advisory role Celgene, Roche, Kite, Takeda, Incyte Honoraria: Celgene, Roche, Kite, Takeda Research funding: Celgene, Roche, Kite, Takeda, Janssen, GSK Educational grants: Celgene, Roche

Lymph node location and retention properties of DC‐SIGN engagement with the Immunoglobulin Oligomannoses of Follicular Lymphoma

Introduction: The oligomannose-type glycans occupying the surface immunoglobulin antigen-binding site (sIg-Mann) are a tumor-founding post-translational requirement of classic follicular lymphoma (FL). These are universally acquired and a clonal necessity during the entire natural history of FL from the early stages throughout transformation into EZB-DLBCL (Chiodin G, Blood 2021, Odabashian M, Blood 2020). The low-affinity interaction of sIg-Mann with its specific ligand DC-SIGN distinguishes from conventional high-affinity antigen:Ig protein interactions for promoting prolonged low-level growth and prosurvival signals via PI3K/AKT and not endocytosis (Linley A, Blood 2015). However, the location and function of DC-SIGN remains to be further elucidated. Here, we investigated the hypothesis that the specific DC-SIGN:Ig-Mann interaction functions to promote retention of FL cells in tissue niches maintaining selective survival advantage. Methods: Immunofluorescence imaging was used to determine DC-SIGN histological location in primary FL lymph nodes. In WSU-FSCCL cells, DC-SIGN effects on sIg redistribution were measured by dSTORM; adhesion to VCAM-1 in presence/absence of inhibitors was measured by flow cytometry. Results: Immunofluorescence of lymph nodes from FL patients revealed that DC-SIGN was expressed on interfollicular CD163+ macrophages and, remarkably, on CD23+ follicular dendritic cells (FDC), claiming an influence on FL cell retention and survival. dSTORM revealed that DC-SIGN induced less dense and more diffuse surface Ig clusters compared to anti-Ig, reflecting an immature sIg redistribution unable to promote endocytosis and death. However, DC-SIGN efficiently induced adhesion of sIg-Mann+ve lymphoma cells to VCAM-1, known to be expressed on both lymph node macrophages and FDC, and inhibited migration towards SDF-1 in vitro. Blocking of DC-SIGN carbohydrate-recognition domain completely abrogated DC-SIGN-induced adhesion. Although intracellular signals were significantly lower, DC-SIGN induced levels of adhesion similar to those induced by anti-Ig. Adhesion to VCAM-1 was observed at concentrations from 20 µg/ml down to 20 ng/ml, even when AKT and ERK phosphorylation was not detectable. Either proximal inhibition of the PI3K/AKT pathway, or distal inhibition of ARP2/3, formin, and Cdc42 for lamellipodium formation at the surface membrane, suppressed adhesion. Conclusions: These results reveal an important mechanism of the DC-SIGN:sIg-Mann interaction that fine-tunes signals for membrane adaptation towards tumor cell adhesion, without promotion of cell death. This possibly facilitates FL cell retention in the lymph node protected tumor niche where selective growth and survival signals are maintained. Interrupting this interaction will be a novel way towards tumour-specific targeted therapy in FL patients. The research was funded by: This research was funded by Blood Cancer UK (grant 18009), Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, program C2750/A23669, and BTERP project C36811/A29101). D.T. was funded by the Eyles Cancer Immunology PhD scholarship, G.C. was funded by the Eyles Cancer Immunology Fellowship and the Southampton Cancer Immunology Centre Pump-priming award 2021). Keywords: Indolent non-Hodgkin lymphoma, Microenvironment, Targeting the Tumor Microenvironment Conflicts of interests pertinent to the abstract. F. Forconi Employment or leadership position: University of Siena Consultant or advisory role: Beigene Honoraria: Abbvie, Janssen-cilag, Beigene, Astra-Zeneca Research funding: Cancer Research UK Educational grants: Beigene, Abbvie Other remuneration: BC Platform

Global funding for cancer research between 2016 and 2020: a content analysis of public and philanthropic investments.

Cancer is a leading cause of disease burden globally, with more than 19·3 million cases and 10 million deaths recorded in 2020. Research is crucial to understanding the determinants of cancer and the effects of interventions, and to improving outcomes. We aimed to analyse global patterns of public and philanthropic investment in cancer research. In this content analysis, we searched the UberResearch Dimensions database and Cancer Research UK data for human cancer research funding awards from public and philanthropic funders between Jan 1, 2016, and Dec 31, 2020. Included award types were project and programme grants, fellowships, pump priming, and pilot projects. Awards focused on operational delivery of cancer care were excluded. Awards were categorised by cancer type, cross-cutting research theme, and research phase. Funding amount was compared with global burden of specific cancers, measured by disability-adjusted life-years, years lived with disability, and mortality using data from the Global Burden of Disease study. We identified 66 388 awards with total investment of about US$24·5 billion in 2016-20. Investment decreased year-on-year, with the largest drop observed between 2019 and 2020. Pre-clinical research received 73·5% of the funding across the 5 years ($18 billion), phase 1-4 clinical trials received 7·4% ($1·8 billion), public health research received 9·4% ($2·3 billion), and cross-disciplinary research received 5·0% ($1·2 billion). General cancer research received the largest investment ($7·1 billion, 29·2% of the total funding). The most highly funded cancer types were breast cancer ($2·7 billion [11·2%]), haematological cancer ($2·3 billion [9·4%]), and brain cancer ($1·3 billion [5·5%]). Analysis by cross-cutting theme revealed that 41·2% of investment ($9·6 billion) went to cancer biology research, 19·6% ($4·6 billion) to drug treatment research, and 12·1% ($2·8 billion) to immuno-oncology. 1·4% of the total funding ($0·3 billion) was spent on surgery research, 2·8% ($0·7 billion) was spent on radiotherapy research, and 0·5% ($0·1 billion) was spent on global health studies. Cancer research funding must be aligned with the global burden of cancer with more equitable funding for cancer research in low-income and middle-income countries (which account for 80% of cancer burden), both to support research relevant to these settings, and build research capacity within these countries. There is an urgent need to prioritise investment in surgery and radiotherapy research given their primacy in the treatment of many solid tumours. None.

Breast cancer awareness among women in the Syrian Coast: a cross-sectional study.

An online cross-sectional survey was conducted among Syrian females during the COVID-19 pandemic. The questionnaire used in the study was derived from the Cancer Research UK questionnaire and modified to fit the perspective of the study. Statistical Package for Social Sciences (SPSS) was used for data analysis. The independent samples t-test and the one-way analysis of variance (ANOVA) were applied to determine whether there is statistical evidence or any statistically significant differences between the variables. A total of 1305 females participated in the study. The majority aged between 18 and 25, (28.8%) of the participants obtained their information related to breast cancer from internet, (36.7%) of were smokers and (82.8%) had a family member with breast cancer. These results suggested a significant correlation between smoking, family history of cancer, marital status, and breast cancer awareness. This study showed which factors are significantly related to women's awareness of breast cancer risk factors. These results can contribute in the implementation of awareness programs and campaigns, thus raising the level of awareness among women.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Patients with B-cell lymphoma have poorer antibody responses to COVID-19 vaccines compared to patients with other malignancies. However, the immune responses are heterogeneous and its association with clinical outcomes are poorly understood. Here, we study the association between antibody and cellular responses with the outcomes from COVID-19 infection from the PROSECO study. Methods: THE UK PROSECO study is a prospective observational cohort study evaluating COVID-19 vaccine response in people with lymphoma. Peripheral blood antibody titres (anti-spike (S) IgG by Mesoscale Discovery), antibody avidity (surface plasmon resonance) and IFNγ T-cell responses (ELISpot) against spike protein after two to four COVID-19 vaccines, and clinical outcomes data were collected. Results: 524 patients (92 Hodgkin lymphoma, 180 aggressive B non-Hodgkin lymphoma (B-NHL), 234 indolent B-NHL and 18 peripheral T-cell lymphoma) were included: 334 (84·3%), 315 (79·5%) and 266 (67·1%) participants were eligible for post-two, three and four vaccine dose analysis, respectively. Breakthrough infections (BTI) occurred in 20 (5.9%), 40 (12.7%) and 36 (13.5%) participants after two, three and four vaccine doses. Of 96 participants with BTI, 12 (12.5%) needed hospitalisation. No deaths were observed due to COVID-19 infection. No differences were observed in T-cell responses between BTI and non-BTI groups, but 4/9 (44.5%) hospitalised BTI cases had undetectable cellular and antibody responses. There was no association between antibody titres and infection episodes after two vaccine doses, but antibody titres were associated with lower BTI risk after three or four vaccine doses on multivariable analysis. Intriguingly, the antibody threshold associated with infection risk was lower after four than three vaccine doses (41 vs. 820 BAU/mL). We also observed stronger antibody binding avidity to SARS-CoV-2 spike receptor-binding domain (RBD) proteins from Wuhan and Omicron BQ.1 variants, with increasing vaccine doses, i.e., fourth versus third dose: 10-fold increase (p: <0.01); fourth versus second dose:100-fold-increase than the second dose (p: <0.0001) (see Figure). The research was funded by: the Blood Cancer UK Vaccine Research Collaborative, which is led by Blood Cancer UK in partnership with Myeloma UK, Anthony Nolan and the British Society for Haematology; a Cancer Research UK Advanced Clinician Scientist Fellowship to SH Lim; Cancer Research UK/National Institute for Health Research (NIHR) Southampton Experimental Cancer Medicine Center; NIHR Southampton Clinical Research Facility (Southampton Research Biorepository) and NIHR Southampton Biomedical Research Center; NIHR Great Ormond Street Biomedical Research Center and the NIHR Oxford Biomedical Research Center and CRUK Experimental Cancer Medicines Center. Keywords: Lymphoid Cancers, Other: Covid-19, Therapeutics and Clinical Trials in Lymphoma, vaccination Conflicts of interests pertinent to the abstract. M. Ahearne Research funding: Pfizer C. P. Fox Consultant or advisory role: Astra Zeneca G. P. Collins Consultant or advisory role: Astra Zeneca and Pfizer Research funding: Pfizer A. J. Davies Honoraria: Astra Zeneca and Janssen Research funding: Astra Zeneca and Janssen S. H. Lim Honoraria: Astra Zeneca

External validation of Systematic COronary Risk Evaluation 2 - Older Persons (SCORE2-OP) in the EPIC-Norfolk prospective population study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): EPIC Norfolk was supported by the Medical Research Council UK (programme grants numbers MRC G0401527, MRC G0701863, MRC G1000143) and Cancer Research UK (programme grant number CRUK 8257). Introduction The Systematic COronary Risk Evaluation 2 – Older Persons (SCORE2-OP) algorithm is developed to assess 10-year risk of fatal and non-fatal cardiovascular disease (CVD) in apparently healthy individuals aged ≥70 years. We evaluated the performance of SCORE2-OP in the European Prospective Investigation of Cancer Norfolk (EPIC-Norfolk) prospective population cohort. Purpose To validate the SCORE2-OP model in men and women aged 70-80 years without prior myocardial infarction or stroke. Methods We included individuals aged 70-80 without prior myocardial infarction or stroke. We compared SCORE2-OP (low-risk algorithm) calculated 10-year risk with 10-year observed event rates in the EPIC-Norfolk cohort. SCORE2-OP was calculated using baseline EPIC-Norfolk data (1993-1997). Cardiovascular events were defined as a composite outcome of (i) death due to ischemic heart disease, cardiac failure, cerebrovascular disease or peripheral-artery disease, (ii) non-fatal myocardial infarction or (iii) non-fatal stroke. Observed rates were adjusted for competing fatal events. We evaluated discriminative power using C-statistic and calibration by plotting predicted versus observed event rates and calculating the observed/predicted ratios. Results SCORE2-OP was evaluated in 3,712 individuals (54% women) with a median (IQR) age of 73 (72-75) years. Ten-year SCORE2-OP was 10.3% (95% confidence interval (CI) 10.2-10.4) versus observed CVD of 16.8% (95% CI 15.6-18.0), yielding a ratio of 1.6 (95% CI 1.5-1.7). Observed events consisted of 9.4% (95% CI 8.4-10.3) fatal CVD events, 10.6% (95% CI 9.6-11.5) non-fatal myocardial infarctions, 10.5% (95% CI 9.5-11.5) non-fatal strokes, adjusted for 68.9% (95% CI 67.4-70.4) competing mortality events. C-statistic was 0.60 (95% CI 0.58-0.63), with a calibration plot demonstrating underestimation of risk across sex and risk groups.(Figure). Conclusion SCORE2-OP underestimates risk in individuals aged 70-80 years, and demonstrates suboptimal discriminative ability. However some underestimation of risk is to be expected given the EPIC-Norfolk baseline between 1993-1997, a low SCORE2-OP calculated risk should not be used as a standalone argument to withhold preventive efforts in older individuals.

Performance of the Systematic COronary Risk Evaluation 2 (SCORE2) in the EPIC-Norfolk prospective population study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): EPIC-Norfolk is supported by programme grants from the Medical Research Council UK (MRC G0401527, MRC G0701863, MRC G1000143) and Cancer Research UK (CRUK 8257). Introduction The latest European guidelines recommend the use of the Systematic COronary Risk Evaluation 2 (SCORE2) to assess 10-year risk of fatal and non-fatal cardiovascular disease (CVD) in individuals aged 40-70 years. Therefore, validation of the SCORE2 algorithm in a large population is needed. Purpose To assess the predictive performance of SCORE2 in individuals without prior myocardial infarction, stroke or diabetes mellitus. Methods Individuals aged 40-70 without prior myocardial infarction, stroke or diabetes mellitus were included from the European Prospective Investigation of Cancer Norfolk (EPIC-Norfolk) prospective population cohort. We assessed discriminative power using the C-statistic; calibration was assessed by plotting calculated SCORE2 (low-risk algorithm) 10-year risks against observed CVD event rates. We defined the composite cardiovascular outcome as death due to ischemic heart disease, cardiac failure, cerebrovascular disease or peripheral-artery disease, or non-fatal myocardial infarction or non-fatal stroke. Observed probabilities were adjusted for competing mortality events. Results We included 20,318 individuals (56% women) with a median (IQR) age of 56 (50-63) years, with baseline measures between 1993-1997. Mean predicted 10-year risk was 3.7% (95% confidence interval (CI) 3.7-3.8) versus adjusted observed 4.2% (95% CI 3.9-4.5) 10-year CVD incidence, yielding a ratio of 1.1 (95% CI 1.1-1.2).(Figure) Observed events consisted of 1.5% (95% CI 1.3-1.7) fatal CVD events, 1.8% (95% CI 1.6-2.0) non-fatal myocardial infarctions, 1.5% (95% CI 1.3-1.6) non-fatal strokes and 23.4% (95% CI 22.1-23.2) competing mortality events. Overall C-statistic was 0.75 (95% CI 0.73-0.77). Conclusion SCORE2 demonstrates reasonable discriminative ability and accurate risk estimations in low-risk individuals in a large, prospective population cohort. However, as actual CVD incidence is expected to be lower given the baseline between 1993-1997, these findings do not indicate that SCORE2 is suitable for current use for risk assessment in individuals from the United Kingdom.

Evaluation of the reach and impact of a UK campaign highlighting obesity as a cause of cancer among the general public and Members of Parliament

Objectives‘Overweight and obesity’ is the second biggest preventable cause of cancer after smoking. In 2018, Cancer Research UK launched an awareness raising campaign about the link between overweight and obesity and cancer risk. This study aimed to evaluate the reach and impact of the campaign. Study designThis study was a repeated cross-sectional online survey. MethodsThe campaign consisted of six elements including the main message that ‘Obesity is a cause of cancer’. UK adults and Members of Parliament (MPs) were surveyed before the campaign (W1; n = 2124 and n = 151), 1 month (W2; n = 2050 and n = 151) and 3 months after the campaign (W3; n = 2059 and MPs not surveyed). Outcome measures were campaign reach, awareness of overweight and obesity as risk factors for cancer, attitudes towards individuals who are overweight or obese, support for policies to reduce obesity and reactions to the campaign. ResultsOverall, 76.2% of MPs and just under half of the public (47.5% in W2 and 36.8% in W3) reported having seen the campaign. Unprompted awareness of obesity as a risk factor increased among the public from 17.1% at W1 to 43.3% in W2 (odds ratio 3.71, 95% confidence interval 3.18–4.33) and 30.3% in W3 (odds ratio 2.11, 95% confidence interval 1.80–2.47). A similar pattern was seen for prompted awareness and among MPs. There were no consistent changes in attitudes towards overweight individuals or support for policies to reduce obesity. ConclusionsThis evaluation suggests that the campaign achieved the primary objective of increasing awareness of the link between obesity and cancer without increasing negative attitudes towards individuals who are overweight or obese.

Analysis of communication styles underpinning clinical decision-making in cancer multidisciplinary team meetings.

In cancer care, multidisciplinary team (MDT) meetings are the gold standard. While they are trying to maximize productivity on the back of the steadily increasing workload, growing cancer incidence, financial constraints, and staff shortages, concerns have been raised with regards to the quality of team output, as reported by Cancer Research UK in 2017: "Sometimes we discuss up to 70 patients. This is after a whole day of clinics, and we do not finish until after 19.00. Would you want to be number 70?". This study aimed to explore systematically some of the dynamics of group interaction and teamwork in MDT meetings. This was a prospective observational study conducted across three MDTs/university hospitals in the United Kingdom. We video-recorded 30 weekly meetings where 822 patient cases were reviewed. A cross-section of the recordings was transcribed using the Jefferson notation system and analyzed using frequency counts (quantitative) and some principles of conversation analysis (qualitative). We found that, across teams, surgeons were the most frequent initiators and responders of interactional sequences, speaking on average 47% of the time during case discussions. Cancer nurse specialists and coordinators were the least frequent initiators, with the former speaking 4% of the time and the latter speaking 1% of the time. We also found that the meetings had high levels of interactivity, with an initiator-responder ratio of 1:1.63, meaning that for every sequence of interactions initiated, the initiator received more than a single response. Lastly, we found that verbal dysfluencies (laughter, interruptions, and incomplete sentences) were more common in the second half of meetings, where a 45% increase in their frequency was observed. Our findings highlight the importance of teamwork in planning MDT meetings, particularly with regard to Cancer Research UK in 2017 cognitive load/fatigue and decision-making, the hierarchy of clinical expertise, and the increased integration of patients' psychosocial information into MDT discussion and their perspectives. Utilizing a micro-level methodology, we highlight identifiable patterns of interaction among participants in MDT meetings and how these can be used to inform the optimization of teamwork.

Disparities in care and outcomes for primary liver cancer in England during 2008-2018: a cohort study of 8.52 million primary care population using the QResearch database.

Liver cancer has one of the fastest rising incidence and mortality rates among all cancers in the UK, but it receives little attention. This study aims to understand the disparities in epidemiology and clinical pathways of primary liver cancer and identify the gaps for early detection and diagnosis of liver cancer in England. This study used a dynamic English primary care cohort of 8.52 million individuals aged ≥25 years in the QResearch database during 2008-2018, followed up to June 2021. The crude and age-standardised incidence rates, and the observed survival duration were calculated by sex and three liver cancer subtypes, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA), and other specified/unspecified primary liver cancer. Regression models were used to investigate factors associated with an incident diagnosis of liver cancer, emergency presentation, late stage at diagnosis, receiving treatments, and survival duration after diagnosis by subtype. 7331 patients were diagnosed with primary liver cancer during follow-up. The age-standardised incidence rates increased over the study period, particularly for HCC in men (increased by 60%). Age, sex, socioeconomic deprivation, ethnicity, and geographical regions were all significantly associated with liver cancer incidence in the English primary care population. People aged ≥80 years were more likely to be diagnosed through emergency presentation and in late stages, less likely to receive treatments and had poorer survival than those aged <60 years. Men had a higher risk of being diagnosed with liver cancer than women, with a hazard ratio (HR) of 3.9 (95% confidence interval 3.6-4.2) for HCC, 1.2 (1.1-1.3) for CCA, and 1.7 (1.5-2.0) for other specified/unspecified liver cancer. Compared with white British, Asians and Black Africans were more likely to be diagnosed with HCC. Patients with higher socioeconomic deprivation were more likely to be diagnosed through the emergency route. Survival rates were poor overall. Patients diagnosed with HCC had better survival rates (14.5% at 10-year survival, 13.1%-16.0%) compared to CCA (4.4%, 3.4%-5.6%) and other specified/unspecified liver cancer (12.5%, 10.1%-15.2%). For 62.7% of patients with missing/unknown stage in liver cancer, their survival outcomes were between those diagnosed in Stages III and IV. This study provides an overview of the current epidemiology and the disparities in clinical pathways of primary liver cancer in England between 2008 and 2018. A complex public health approach is needed to tackle the rapid increase in incidence and the poor survival of liver cancer. Further studies are urgently needed to address the gaps in early detection and diagnosis of liver cancer in England. The Early Detection of Hepatocellular Liver Cancer (DeLIVER) project is funded by Cancer Research UK (Early Detection Programme Award, grant reference: C30358/A29725).

Evaluation of methodologies for indirect comparison of eplontersen and vutrisiran for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy (P12-4.005)

<h3>Objective:</h3> To investigate comparative efficacy and safety of eplontersen and vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). <h3>Background:</h3> ATTRv-PN is a rare, autosomal dominant disease caused by mutations in the gene encoding transthyretin (TTR) protein, resulting in accumulation of ATTR amyloid in multiple tissues including the peripheral nervous system. TTR silencers developed and in development to treat ATTRv-PN include vutrisiran (recently approved by the FDA and EMA), and eplontersen, which met its co-primary endpoints and demonstrated an overall favourable safety profile in a planned Week 35 interim analysis of the phase III NEURO-TTRansform trial (NCT04136184). The eplontersen and vutrisiran trials both used an external placebo arm from earlier trials. No head-to-head studies have been conducted for eplontersen and vutrisiran to date. Therefore, the feasibility and implications of indirect treatment comparisons (ITCs) should be evaluated. ATTRv-PN exhibits substantial clinical heterogeneity, which challenges traditional ITC methods. Additional challenges relate to the trial designs, including the use of external placebo comparators. Different ITC approaches will be evaluated to assess the impact of these factors on the ability to compare efficacy and safety of eplontersen and vutrisiran. <h3>Design/Methods:</h3> In addition to a naïve comparison, population-adjusted methods that attempt to account for heterogeneity and differences in trial designs were evaluated, including matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC). Whilst MAIC may fail to match characteristics demonstrating substantial heterogeneity, this is not an issue for STC. However, unlike MAIC, STC can falter when dealing with non-linear outcomes. Efficacy will be assessed based on the Modified Neuropathy Impairment +7 and Norfolk Quality of Life-Diabetic Neuropathy scores, and safety will also be assessed. <h3>Results:</h3> Results will become available ahead of AAN2023. <h3>Conclusions:</h3> This ITC feasibility assessment supports interpretation of comparative efficacy and safety analyses, which is important for decision-making by clinicians, payers and researchers. <b>Disclosure:</b> Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alnylam. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis. Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Karam has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neuroderm. Julian D. Gillmore has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alnylam Pharmaceuticals. Julian D. Gillmore has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Intellia. Julian D. Gillmore has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AstraZenica. Julian D. Gillmore has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BridgeBio. Julian D. Gillmore has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Mrs. Chen has received personal compensation for serving as an employee of AstraZeneca. Mrs. Chen has stock in AstraZeneca. Miss Jenkins has nothing to disclose. Dr. Hale has received research support from Cancer Research UK. Dr. Taylor has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NIH France. Dr. Chen has received personal compensation for serving as an employee of AstraZeneca. Dr. Chen has stock in AstraZeneca. Nicholas Viney has received personal compensation for serving as an employee of Ionis Pharmaceuticals Inc.. Nicholas Viney has stock in Ionis Pharmaceuticals. Nicholas Viney has received intellectual property interests from a discovery or technology relating to health care. Dr. Schneider has received personal compensation for serving as an employee of ionis pharmaceuticals.

Effect of rituximab on immune status in children with mature B-cell non-Hodgkin lymphoma: a prespecified secondary analysis of the Inter-B-NHL Ritux 2010 trial

Survival of children and adolescents with high-risk, mature B-cell non-Hodgkin lymphoma is improved by the addition of rituximab to chemotherapy. The effect of rituximab on immune reconstitution after therapy has not been well described. Herein, we evaluate the immune effects of the addition of rituximab to intensive chemotherapy, a prespecified secondary aim of the Inter-B-NHL Ritux 2010 trial. The Inter-B-NHL Ritux 2010 trial was an international, open-label, randomised, phase 3 trial in children (age 6 months to 18 years) with high-risk, mature B-cell non-Hodgkin lymphoma, comparing chemotherapy alone or chemotherapy with rituximab. Measures of immune status were completed at baseline, 1 month from the end of treatment, and 1 year from the start of therapy, and yearly thereafter until normalised. For this secondary analysis, we report on the proportions of patients with low lymphocyte counts and immunoglobulin concentrations at these timepoints with total lymphocyte count, B-cell count, and IgG concentration as the main endpoints. Other endpoints of interest included exposure to immunoglobulin replacement therapy and vaccine serologies. The population assessed for immune endpoints was the eligible per-protocol population with at least one immune parameter at one timepoint. Comparisons of immune status were made between the randomised treatment groups. Safety in the post-therapy period was assessed in the population eligible for the immunity study who were followed up at least 3 months after the end of treatment and without cancer-related events. The Inter-B-NHL Ritux 2010 study was registered with ClinicalTrials.gov, NCT01516580; status completed, with analyses of secondary aims ongoing. From Dec 19, 2011, to June 13, 2017, 421 patients (344 [82%] boys and 77 [18%] girls; mean age was 8·8 years [SD 4·1]) were enrolled and had immune data at baseline during follow-up, or both. The study population included randomly assigned patients (n=289) and a non-randomised cohort enrolled after the planned interim analysis (n=132). At baseline, 99 (34%) of 290 patients with available data (excluding patients with bone marrow disease with peripheral blast cells) had lymphopenia, and 178 (48%) of 368 had hypogammaglobulinemia. 1 month from the end of therapy, patients who received chemotherapy with rituximab were more likely than those who received chemotherapy alone to have lymphopenia (86 [81%] of 106 vs 53 (60%) of 89, odds ratio [OR] 2·92 [95% CI 1·53-5·57], p=0·0011), B-cell lymphopenia (72 [96%] of 75 vs 36 [64%] of 56, OR 13·33 [3·71-47·84], p<0·0001), and hypogammaglobulinemia (67 [71%] of 95 vs 37 [47%] of 79, OR 2·72 [1·45-5·07], p=0·0017). Differences remained at 1 year for hypogammaglobulinemia only (52 [55%] of 94 vs 16 [25%] of 63, OR 3·64 [1·81-7·31], p=0·0003). Patients in the chemotherapy with rituximab group were more likely than those in the chemotherapy group to receive immunoglobulin replacement (26 [16%] 164 vs nine [7%] of 158, hazard ratio [HR] 2·63 [95% CI 1·23-5·62], p=0·010), mainly due to low immunoglobulin concentration. In the combined treatment groups, including non-randomly assigned patients, the proportion of patients who had loss of protective serologies to a vaccine preventable infection varied from four (9%) of 47 for polio to 21 (42%) of 50 for Streptococcus pneumoniae (pneumococcus). One patient (chemotherapy with rituximab group) had a life-threatening infectious event of polymicrobial bacterial sepsis reported 2 months after the final chemotherapy administration. Children with high-risk mature B-cell non-Hodgkin lymphoma receiving chemotherapy with rituximab were at risk of prolonged hypogammaglobulinemia, although severe infections were rare. Strategies for immunoglobulin replacement and revaccination are needed. Clinical Research Hospital Program of the French Ministry of Health, Cancer Research UK, National Institute for Health Research Clinical Research Network in England, Children's Cancer Foundation Hong Kong, US National Cancer Institute, F Hoffmann-La Roche.

2022 Winners: Kathleen Scheffler, Federica Giannini and Tom Lemonnier

2022 Winners: Kathleen Scheffler, Federica Giannini and Tom Lemonnier

Abstract 4681: Human Cancer Models Initiative (HCMI): A community resource of next-generation cancer models and associated data

Abstract The Human Cancer Models Initiative (HCMI) is an international consortium founded by National Cancer Institute (NCI), Cancer Research UK, Wellcome Sanger Institute, and the foundation Hubrecht Organoid Technology. The initiative has generated patient derived Next-generation Cancer Models (NGCMs) from diverse tumor types and subtypes including rare adult and pediatric cancers as a community resource. HCMI addresses deficiencies in traditional cell lines models by collecting patients’ clinical data, as well as the genomes and transcriptomes of the parent tumor, case-matched normal tissue, and the derived next-generation cancer model. NCI’s Center for Cancer Genomics (CCG) sponsors four Cancer Model Development Centers (CMDCs) who are managed by Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc. CCG also supports the downstream model development pipeline. The CMDCs are tasked with generating HCMI NGCMs. The model-associated clinical data are submitted to the Clinical Data Center. The models, their associated tumor, and normal samples are processed at the Biospecimen Processing Center (BPC). The nucleic acids isolated at BPC are sent to the Genomic Characterization Centers for molecular characterization. All biospecimen, clinical, and molecular characterization data are quality controlled and submitted to NCI’s Genomic Data Commons (GDC) for the research community. The HCMI models and culture protocols are made available to the research community through a single third-party distributor. The HCMI Searchable Catalog (https://hcmi-searchable-catalog.nci.nih.gov/) is an online resource that allows users to query and identify available models using various data elements including clinical and molecular characterization data, including WGS, WXS, RNA-seq, and methylation array. To date, over 250 HCMI models are available to query on the Searchable Catalog and are available to the research community through the NCI designated model distributor, ATCC. These models have been derived from several cancer types including glioblastoma, colorectal, pediatric, gastroesophageal, pancreatic, and more. Biospecimen, clinical, and molecular characterization data are available for over 100 models at NCI’s GDC, with additional cases released as the data completes the HCMI pipeline. Data, tools, and resources generated by CCG initiatives are made publicly available via the CCG website and GDC. The CCG website also provides available data types, data usage policies and guides to access data (https://www.cancer.gov/about-nci/organization/ccg). Citation Format: Eva Tonsing-Carter, Rachana Agarwal, Cindy W. Kyi, Julyann Perez-Mayoral, Conrado T. Soria, Jean Claude Zenklusen. Human Cancer Models Initiative (HCMI): A community resource of next-generation cancer models and associated data. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4681.

Genetic and Microenvironment Features Do Not Distinguish Follicular Lymphoma Patients Requiring Immediate or Deferred Treatment.

Genetic and Microenvironment Features Do Not Distinguish Follicular Lymphoma Patients Requiring Immediate or Deferred Treatment.

Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials

Anthracycline-taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline-taxane regimens. We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including MEDLINE, Embase, the Cochrane Library, and meeting abstracts to identify trials assessing anthracycline and taxane chemotherapy. Adjuvant or neoadjuvant trials were eligible if they began before Jan 1, 2012. Primary outcomes were breast cancer recurrence and cause-specific mortality. Log-rank analyses yielded first-event rate ratios (RRs) and CIs. 28 trials of taxane regimens with or without anthracycline were identified, of which 23 were deemed eligible, and 15 provided data on 18 103 women. Across all 15 trials that provided individual data, recurrence rates were 14% lower on average (RR 0·86, 95% CI 0·79-0·93; p=0·0004) with taxane regimens including anthracycline than those without. Non-breast cancer deaths were not increased but there was one additional acute myeloid leukaemia case per 700 women treated. The clearest reductions in recurrence were found when anthracycline was added concurrently to docetaxel plus cyclophosphamide versus the same dose of docetaxel plus cyclophosphamide (10-year recurrence risk 12·3% vs 21·0%; risk difference 8·7%, 95% CI 4·5-12·9; RR 0·58, 0·47-0·73; p<0·0001). 10-year breast cancer mortality in this group was reduced by 4·2% (0·4-8·1; p=0·0034). No significant reduction in recurrence risk was found for sequential schedules of taxane plus anthracycline when compared with docetaxel plus cyclophosphamide (RR 0·94, 0·83-1·06; p=0·30). For the analysis of anthracycline regimens with versus without taxane, 35 trials (n=52 976) provided individual patient data. Larger recurrence reductions were seen from adding taxane to anthracycline regimens when the cumulative dose of anthracycline was the same in each group (RR 0·87, 0·82-0·93; p<0·0001; n=11 167) than in trials with two-fold higher cumulative doses of non-taxane (mostly anthracycline) in the control group than in the taxane group (RR 0·96, 0·90-1·03; p=0·27; n=14 620). Direct comparisons between anthracycline and taxane regimens showed that a higher cumulative dose and more dose-intense schedules were more efficacious. The proportional reductions in recurrence for taxane plus anthracycline were similar in oestrogen receptor-positive and oestrogen receptor-negative disease, and did not differ by age, nodal status, or tumour size or grade. Anthracycline plus taxane regimens are most efficacious at reducing breast cancer recurrence and death. Regimens with higher cumulative doses of anthracycline plus taxane provide the greatest benefits, challenging the current trend in clinical practice and guidelines towards non-anthracycline chemotherapy, particularly shorter regimens, such as four cycles of docetaxel-cyclophosphamide. By bringing together data from almost all relevant trials, this meta-analysis provides a reliable evidence base to inform individual treatment decisions, clinical guidelines, and the design of future clinical trials. Cancer Research UK, UK Medical Research Council.

Improving the effectiveness of multidisciplinary team meetings on skin cancer: Analysis of the National Cancer Research UK survey responses

IntroductionSkin cancer is the most common form of cancer in the UK, comprising at least 25% of all new cancer diagnoses. Many patients require referral to the local or specialist skin cancer multidisciplinary team (MDT) for ongoing management. However, national data have shown that Specialist Skin Cancer MDTs are costly and do not currently meet NICE standards for composition and quoracy. Innovative solutions to these problems are therefore warranted. MethodsWe performed a secondary comparative analysis of 3563 quantitative responses to two Cancer Research UK commissioned surveys along with subanalysis of 282 skin cancer MDT respondents. ResultsGood uniformity was observed amongst skin respondents in the belief that risk stratification and prioritization of complex cases were the most important factors compared to other cancer MDT members. The most important priorities for areas requiring change to MDT working deemed by the skin MDT were 1) imaging and pathology results ready for the meeting, 2) time to discuss patients in detail, 3) clear meeting owner in charge, and 4) clear agenda, in advance of the meeting. There was agreement (median Likert score 4) amongst skin MDT respondents that patients should be placed on protocolized treatment pathways. ConclusionThe responses of skin MDT respondents analyzed in the current study support changes to meeting attendance, preparation, and protocolized streaming. In line with other studies, we support tumor-specific guidance for streamlining MDT discussions. We also encourage stakeholders to adopt an evidence-based approach to test, develop, and reassess changes in this herculean task.

Researchers Invited to Tackle New "Grand Challenges".

Cancer Grand Challenges, an initiative of the NCI and Cancer Research UK, invites international teams to apply for up to $25 million each to tackle nine tough questions in cancer research. Past winners are already making strides in different areas, including understanding the causes of unusual cancer-associated mutations and developing novel therapies for childhood cancers.

A survey of quality-of-life tools used in the routine care of patients with multiple myeloma.

New treatment options have significantly improved the life expectancy of myeloma patients such that their cause of death is increasingly likely to be from something other than myeloma. Furthermore, the adverse effects of short- or long-term treatments as well as the disease are impacting on quality of life (QoL) for longer periods of time. Understanding people's QoL and what is important to them, is part of providing holistic care. Although QoL data has been collected for many years in myeloma studies, they have not been used to inform patient outcomes. There is growing evidence that supports the assessment of 'fitness' and consideration of QoL as part of routine myeloma care. A national survey was carried out to discover which QoL tools are currently being used in the routine care of myeloma patients, by whom and at which time point. An online survey using SurveyMonkey was adopted for flexibility and accessibility. The link to the survey was circulated via Bloodwise, Myeloma UK and Cancer Research UK contact lists. Paper questionnaires were circulated at the UK Myeloma Forum. Data about practices in 26 centres were collected. This included sites across England and Wales. Three out of 26 centres collect QoL data as part of standard care. QoL tools used include EORTC QLQ-My20/24, MyPOS, FACT-BMT and Quality of Life Index. Questionnaires were completed by patients before, during or after a clinic appointment. Clinical nurse specialists calculate the scores and create a care plan. Despite growing evidence to support an holistic approach to management of myeloma patients, there is a lack of evidence to confirm that health-related QoL is being addressed in standard care. This is an area that needs further research.

Project Optimus, an FDA initiative: Considerations for cancer drug development internationally, from an academic perspective.

Modern cancer therapeutics are increasingly targeted, bringing the promise of new and improved activity, alongside better tolerability. However, while many are indeed resulting in dramatic improvements in disease control and patient survival, short- and long-term tolerability has not always accompanied it. The choice of dose and schedule is often in the upper range of the therapeutic window, driven by the maximum tolerated dose (MTD) model of previous cytotoxic agents. There is increasing recognition that this needs to change, by taking a more holistic approach to determine the optimal dose for desired biological effects and tolerability early in clinical development. In the US, the FDA's Oncology Centre of Excellence is addressing this via the Project Optimus initiative: aiming to reform dose optimisation studies so that they can demonstrate the most appropriate dose selection. Early clinical development will need to demonstrate the dose-exposure, -pharmacodynamic, -toxicity and -activity relationships, including randomised evaluations for dose selection. Regulatory agencies outside the US are similarly exploring this. Along with Australia, Brazil, Canada, Israel, Singapore and Switzerland, the UK participates in Project Orbis, a collaborative program with the FDA to accelerate patient access to new cancer medicines through coordinated regulatory review. Close alignment with Project Optimus will be important internationally and will require changes across industry, including for academic units and small biotech. We discuss our perspective on the implications, and opportunities, for early phase oncology trials as a uniquely charity-funded drug development facility, the Centre for Drug Development within the Cancer Research UK charity.