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Anthracycline chemotherapeutic agents are widely used in the treatment of hematological and solid tumors, working principally through DNA intercalation and topoisomerase II inhibition. However, they are also well known to have cardiotoxic sequelae, commonly denoted as a reduction in ejection fraction. Drug-associated cardiotoxicity remains a significant limiting factor in the use of anthracyclines.In this review, we explore the potential mechanisms of anthracycline-associated cardiotoxicity, identifying high-risk cohorts and approaches to cardiovascular monitoring. The mechanisms through which cardiotoxicity occurs are complex and diverse, ultimately leading to increased oxidative stress, mitochondrial dysfunction, and subsequent cellular apoptosis. Many of the cardiotoxic effects of anthracyclines exhibit a dose-dependent cumulative relationship and are more apparent in patients with previously existing cardiovascular risk factors. Long-term cardiovascular monitoring and optimization of risk factors, prior to commencing treatment as well as beyond the time of treatment, is therefore essential.We discuss some of the pharmacological strategies proposed to mitigate anthracycline-associated cardiotoxicity as well as prevention strategies to reduce the burden of coexisting cardiovascular risk factors. We highlight methods of early detection of patient cohorts who are at increased risk of developing anthracycline-associated cardiotoxicity and identify potential avenues for further research.

Over the past 20 years, the management of gastrointestinal stromal tumors has acted as an important model in the advancement of molecularly targeted therapies for solid tumors. The success of imatinib has established it as a lasting therapy in the management of early-stage and advanced disease in the first-line setting. Imatinib resistance inevitably develops, resulting in the need for further lines of therapy. Ripretinib is an orally administered switch-control tyrosine kinase inhibitor, specifically developed to target both primary and secondary KIT and PDGFRα resistance mutations. Herein, the authors discuss the molecular rationale, the preclinical evidence and the clinical use of ripretinib in the treatment of gastrointestinal stromal tumors in the advanced stages of disease.

Background Older patients are underrepresented in the clinical trials that determine the standards of care for oncological treatment. We conducted a review to identify whether there have been age-restrictive inclusion criteria in clinical trials over the last twenty five years, focusing on patients with metastatic gastroesophageal cancer. Methods A search strategy was developed encompassing Embase, PubMed and The Cochrane Library databases. Completed phase III randomised controlled trials evaluating systemic anti-cancer therapies in metastatic gastroesophageal malignancies from 1st January 1995 to 18th November 2020 were identified. These were screened for eligibility using reference management software (Covidence; Veritas Health Innovation Ltd). Data including age inclusion/exclusion criteria and median age of participants were recorded. The percentage of patients ≥ 65 enrolled was collected where available. The change over time in the proportion of studies using an upper age exclusion was estimated using a linear probability model. Results Three hundred sixty-three phase III studies were identified and screened, with 66 trials remaining for final analysis. The majority of trials were Asian (48%; n = 32) and predominantly evaluated gastric malignancies, (86%; n = 56). The median age of participants was 62 (range 18–94). Thirty-two percent (n = 21) of studies specified an upper age limit for inclusion and over half of these were Asian studies. The median age of exclusion was 75 (range 65–80). All studies prior to 2003 used an upper age exclusion (n = 12); whereas only 9 that started in 2003 or later did (17%). Among later studies, there was a very modest downward yearly-trend in the proportion of studies using an upper age exclusion (-0.02 per year; 95%CI -0.05 to 0.01; p = 0.31). Fifty-two percent (n = 34) of studies specified the proportion of their study population who were ≥ 65 years. Older patients represented only 36% of the trial populations in these studies (range 7–60%). Conclusions Recent years have seen improvements in clinical trial protocols, with many no longer specifying restrictive age criteria. Reasons for poor representation of older patients are complex and ongoing efforts are needed to broaden eligibility criteria and prioritise the inclusion of older adults in clinical trials.

796 Background: Comprehensive geriatric assessment (CGA) is recommended to inform treatment decisions in older patients with cancer. Patients ≥ 70 years are referred to the Geriatric Oncology and Liaison (GOAL) clinic in University Hospital Waterford, for a pre-treatment CGA, which includes assessment of mobility, cognitive, nutritional, functional, and psychological status, along with comprehensive geriatric pharmacological assessment. Informed treatment recommendations are made using CGA outcomes and risk assessed using the Cancer and Aging Research Group toxicity calculator. Limited information exists on treatment decisions based on age subgroups within the geriatric oncology population. Methods: Data from patients with gastrointestinal (GI) malignancies attending the GOAL clinic over a 3-year period to September 2022 were included. Patients ≥ 70 years with a G-8 (screening tool) score ≤14, and all patients aged ≥ 80 underwent CGA. An age-based subgroup analysis (< 80 vs ≥ 80) of systemic anti-cancer therapy (SACT) decisions was performed using the Chi-square test. Results: In total, 206 patients with GI malignancies were assessed, comprising 67 (33%) patients with gastroesophageal cancer, 40 (19%) with pancreaticobiliary and 92 (45%) with colorectal cancer. 40% of patients were ≥ 80 years (n = 83). The majority of patients had stage III/IV disease (82%, n = 168). Across all groups, 58% (n = 120) of patients were treated with SACT, comprising 70% of those < 80 (n = 86) and 41% (n= 34) of those ≥ 80. Across all stages (I-IV), patients ≥ 80 years were less likely to be treated with SACT compared to patients < 80 years (p < 0.01). There was no significant difference between age groups when comparing treatment intent (curative vs palliative) (p = 0.15). There was no significant difference between age groups for baseline dose reductions vs full dose (p = 0.18). Patients ≥ 80 years were less likely to receive polychemotherapy regimens in comparison with the < 80 subgroup (p < 0.01). Conclusions: Older patients with GI malignancies are a heterogeneous population. In the setting of a CGA, patients ≥ 80 years are less likely to receive SACT across any stage group, and are more likely to receive monochemotherapy regimens. The use of CGA ensures a considered and personalised approach to identify older adults most likely to benefit from active treatment and those where best supportive care alone is more appropriate.

We report a case of metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) sensitizing mutation – deletion exon 19 – treated with first line chemotherapy using Carboplatin and Pemetrexed. The treatment was then changed to first generation tyrosine kinase inhibitor (TKI), Gefinitib following the detection of EGFR sensitizing mutation. Upon disease progression on Gefitinib, the need for tissue biopsy for resistant point mutation that substitutes methionine for threonine at amino acid position 790 (T790M) was met with diagnostic challenge due to difficulty in sampling tissue from the site of progressive disease. We opted, instead, to perform the non-invasive method using exhaled breath condensate (EBC) and plasma circulating tumour DNA (ctDNA); both of these tests detected the presence of T790M mutation. Third generation TKI, Osimertinib, was commenced based on these non-invasive diagnostic methods, and the patient showed partial response followed by ongoing stable disease after 28 months which exceeded the median progression-free survival (PFS) demonstrated in the AURA3 trial. We believe that a non-invasive method using novel EBC or plasma ctDNA can be used not only as an adjunct test but as an alternative to tissue biopsy where there are diagnostic challenges with invasive procedures.

335 Background: Clinical trials are considered the cornerstone of improving outcomes for cancer patients. The understanding of an individual patient of the trial on which they are enrolled can vary significantly, with some studies demonstrating poor patient understanding of their involvement in trials. This exploratory study aimed to improve patient understanding of clinical trials and patient experience of the informed consent process by implementing measures to present complex trial information in alternative formats. Methods: The project was undertaken in a sarcoma trials unit in a specialist cancer treatment centre. Baseline knowledge was assessed using an adapted version of the Quality of Informed Consent (QuIC) questionnaire. A decision-aid was created following focus group discussions with stakeholders, focussing on key trial questions for patients, such as consent, the research description, risks, benefits, and alternatives to the trial. A patient education video was produced by the research team, explaining general aspects of clinical trials in patient-friendly language. The decision-aids and videos were distributed during the informed consent process of trial recruitment over a 12-week period. The patient group was assessed with post-intervention questionnaires. Statistical analysis was descriptive due to the small numbers. Results: Thirty sarcoma patients participated in the project, including baseline assessment of 15 patients previously enrolled on study, and 15 patients considering participation in a trial who underwent the intervention. 100% (n = 15) of the interventional group found the video and decision-aid useful. 60% (n = 18) of patients had a university level education, indicating a well-educated population. A pre- and post-intervention comparison demonstrated an improved understanding of 10 key elements of clinical trial information as shown in Table. Conclusions: Our exploratory study has shown that patient education tools including decision-aids and patient videos can be successfully implemented to help improve patient understanding of clinical trial information and may be of benefit in other trials units. Further larger studies are required to confirm these findings.[Table: see text]

BackgroundNatural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK cells become dysfunctional during cancer. Overcoming NK cell exhaustion would be an important step to allow them to function optimally in a range of NK cell therapies, including those that depend on autologos circulating NK cells. We have previously demonstrated that NK cells undergo a normal metabolic reprogramming in response to cytokine activation and that this is required for optimal function. The objective of this work was to investigate if cellular metabolism of circulating NK cells is dysregulated in patients with metastatic breast cancer and if so, to gain insights into potential mechanisms underpinning this. Such discoveries would provide important insights into how to unleash the full activity of NK cells for maximum immunotherapy output.MethodsSingle-cell analysis, metabolic flux and confocal analysis of NK cells from patients with metastatic breast cancer and healthy controlsResultsIn addition to reduced interferon-γ production and cytotoxicity, peripheral blood NK cells from patients had clear metabolic deficits including reduced glycolysis and oxidative phosphorylation. There were also distinct morphologically alterations in the mitochondria with increased mitochondrial fragmentation observed. Transforminggrowth factor-β (TGFβ) was identified as a key driver of this phenotype as blocking its activity reversed many metabolic and functional readouts. Expression of glycoprotein-A repetitions predominant (GARP) and latency associated peptide (LAP), which are involved with a novel TGFβ processing pathway, was increased on NK cells from some patients. Blocking the GARP–TGFβ axis recapitulated the effects of TGFβ neutralization, highlighting GARP as a novel NK cell immunotherapy target for the first time.ConclusionsTGFβ contributes to metabolic dysfunction of circulating NK cells in patients with metastatic breast cancer. Blocking TGFβ and/or GARP can restore NK cell metabolism and function and is an important target for improving NK cell-based immunotherapies.

Background: The COVID-19 pandemic has dramatically changed how healthcare services are provided. In order to comply with public health recommendations, the multidisciplinary team (MDT) network of the South East Cancer Centre at University Hospital Waterford made a transition to a virtual meeting format. The centre coordinates a network of eight individual cancer MDTs with three satellite hospitals. Following adaptation to virtual format, remote participants now join by videoconference, telephone call, or by phone application. Methods: A 30-part questionnaire was developed in electronic format and distributed to consultants who comprise the senior membership of the cancer MDTs. The objectives were to investigate experience of the virtual meetings post-implementation, and assess preference regarding the future of the meetings. Results: Among 36 respondents, surgeons accounted for 38.9%, medical oncologists (22.2%), pathologists (13.9%), radiologists (11.1%), haematologists (5.6%) and radiation oncology, palliative care and physicians for 2.8% each. The most common means of joining the meeting included videoconference (61.1%), physical attendance at MDT room (19.4%), telephone (11.4%) and by phone application (8.3%). 67% experienced difficulties using the technology including issues connecting (67%) and screen-sharing (50%). 78% reported that the virtual format did not affect their attendance at MDT, with 11% reporting increased attendance. 56% thought the case discussion at the virtual MDT was not as in-depth as the conventional MDTs, but a majority (81%) believe that decisions made are not impacted by the virtual format. 71% believe it has negatively impacted on education. Most respondents (40%) preferred the traditional face-to-face format, with 37% preferring a combination of virtual and face-to-face. The majority of consultants determine that virtual MDTs should continue past social distancing guidelines. Conclusions: The results of this study suggest that virtual MDT meetings can be implemented into routine MDT practice. Although challenges are encountered, transition to a virtual format enables continuation of MDT meetings in uncertain times and may become a lasting legacy of COVID-19. Legal entity responsible for the study: C.M. Goggin. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

e24017 Background: Cancer is a disease of aging, however older patients are underrepresented in the clinical trials that determine the standards of care for oncological treatment. We conducted a review to identify whether there have been age-restrictive inclusion criteria in clinical trials over the last twenty five years. We focused on patients with metastatic gastroesophageal cancer. Methods: A search strategy was developed encompassing Embase, Pubmed and The Cochrane Library databases. All completed Phase III randomised controlled trials evaluating systemic anti-cancer therapies in metastatic gastroesophageal malignancies for the period 01.01.95 to 18.11.20 were identified. Reference management software (Covidence; Veritas Health Innovation Ltd) was used to screen for inclusion/exclusion. The following details were extracted from trial protocols: country of study, date of publication, patient number, age inclusion and exclusion criteria. The median age of participants and the percentage of older patients enrolled in each study was collected. A linear probability model was used to estimate the change over time in the proportion of studies using an upper age exclusion. Results: 363 phase III studies were identified. 152 studies were eligible for full text review, 86 were excluded, leaving 66 trials for final analysis. 86% (n = 56) included Gastric, 9% (n = 6) Oesophageal and 5% (n = 3) Oesophagogastric malignancies. Asian studies represented 48% (n = 32) of trials, 29% (n = 19) were worldwide and 23% (n = 15) were European. The median age of trial participants was 62, (range 18-94). No clear trend in the ages of study participants over the time period was identified. 32% (n = 21) of studies specified an upper age limit for inclusion and 57% of these were Asian studies. The median age of exclusion was 75 years (range 65-80). All studies starting before 2003 used an upper age exclusion (n = 12); whereas only 9 of the 52 that started in 2003 or later did (17%). Among these later studies, there was a very modest downward yearly-trend in the proportion of studies using an upper age exclusion (-0.02 per year; 95%CI -0.05 to 0.01; p = 0.31). 52% (n = 34) of studies specified the proportion of their study population who were over 65 years. Older patients represented only 36% of the trial populations in these studies (range 7-60%). Our search of currently enrolling trials on clinicaltrials.gov yielded 11 active studies, none of which specified an upper age limit. Conclusions: Recent years have seen improvements in clinical trial protocols, with many no longer specifying restrictive age criteria. Reasons for poor representation of older patients are complex and ongoing efforts are needed to broaden eligibility criteria and prioritise the inclusion of older adults in clinical trials.

e21196Background: Immunotherapy (IO) has improved outcomes of advanced NSCLC patients in randomized clinical trials. Data on outcomes for these agents outside of a clinical trial setting in Ireland...

e18910Background: FDA approval for bevacizumab (BEV) in progressive glioblastoma (GBM) was based on two phase II studies, both of which used a 10mg/kg every 2 weeks regimen. However, other studies ...

e15689Background: Prospective clinical trials comparing FOLFOX to CAPOX are limited in the adjuvant setting and the only published trial was stopped early for poor accrual (Pectasides et al, 2015)....