ISMO Bursary Awards 2024

This year’s ISMO meeting heard presentations on a variety of high-quality cancer studies that have taken place in Ireland

The 2024 Irish Society of Medical Oncology (ISMO) Bursary Awards meeting took place on Friday 19 January. The meeting was held in the Fintan Gunne Theatre, Catherine McAuley Centre, the Mater Misericordiae University Hospital, Dublin.

The Bursary winning presentations, outlined in this report, focused on a wide range of subjects.

The title of the presentation by Dr Kate Coakley, Beaumont Hospital, Dublin, was ‘An evaluation of disparities of care regarding nationality in breast cancer in Ireland’. The aim of the study was to identify if a disparity of care exists between Irish and non-Irish national breast cancer patients in a National Cancer Control Programme-designated cancer centre.

A retrospective chart review documenting diagnosis, treatment plan and time to treatment was performed. It included 100 non-Irish national patients who were matched with 100 Irish national patients based on age and sex. The patients included received a diagnosis of breast cancer between July 2017 and July 2023 in Cork University Hospital (CUH). A questionnaire was distributed to 34 non-Irish national breast cancer patients and their translators to assess the quality of received breast cancer care and translation services.

The mean time to first treatment was 33.2 days [95% CI: 29.84-36.58] for non-Irish national patients and 26.3 days [95% CI: 23.86-28.9] for the national cohort (p<0.01). This is unlikely to be clinically significant, according to the researchers. The rates of neoadjuvant chemotherapy were higher in the non-Irish national group (28 per cent) than the national group (15 per cent) (p<0.05). Irish patients had a statistically significant higher expression of the oestrogen (80 vs 68 per cent, p<0.05) and progesterone receptors (72 vs 56 per cent, p<0.05) compared to non-Irish nationals. In the response to the questionnaire, 57 per cent of patients rated their experience of care as excellent.

“Non-national breast cancer patients in Ireland rated their received care highly on average and their timelines for treatment were comparable to national Irish patients,” according to the conclusion.

“However, the more advanced and aggressive natures of their tumours relative to the matched national cohort patients highlights their vulnerability and the need for vigilance in our healthcare system regarding their care. Further studies assessing survivorship needs, breast awareness, and outcome assessments are warranted to assess and ensure emigrant responsive breast cancer services in Ireland.”

GBM

Dr Yazan Mustafa, University College Cork (UCC), won for the presentation ‘Single institutional analysis of glioblastoma multiforme outcomes based on year of diagnosis – A 17-year review’.

The aim of this study was to present the clinical and molecular attributes, systemic therapeutic interventions, and survival outcomes, among patients diagnosed with glioblastoma multiforme (GBM) at CUH during the period 2005-2016 compared to those diagnosed between 2017-2021. The study cohort included 309 patients, with 142 patients diagnosed between 2005-2016, and 167 between 2017-2021. Of these, 202 were males (65.4 per cent) and 107 were females (34.6 per cent). The median age at the time of diagnosis was 71 years, ranging from 23-to-93 years. The methylation status of the MGMT gene was tested extensively in patients diagnosed between 2017-2021, but rarely in the earlier time period. Seizures were identified as a prevalent presenting symptom in 14.8 per cent of cases during the first time period and 21.0 per cent during the subsequent time point.

Median overall survival (MOS) for the entire population was 15.2 months, with a MOS of 16 months for those diagnosed between 2005-2016 and 13.9 months for individuals diagnosed between 2017-2021. The one-year and two-year survival rates exhibited similarity between the two groups, with rates of 48.1 and 14.3 per cent, respectively, during the 2005-2016 period, and rates of 42.1 and 8.8 per cent, respectively, during the 2017-2021 period.

Survival outcomes did not improve between the two periods highlighting the importance of ongoing research to improve therapeutic approaches for these patients.

ECOG

‘The older patient and the ECOG’ was the title of the award-winning presentation by Dr Caroline O’Leary, University Hospital Waterford (UHW). The Eastern cooperative oncology group performance status scale (ECOG) is the most commonly used performance scale utilised to assess a patient’s physical status and suitability for systemic anti-cancer treatment (SACT). However, the ECOG criteria are a broad scale and in an older population often do not capture other data often relevant to determining suitability for systemic treatment such as body confirmation, co-morbidities, and cognitive factors. Conversely, patients with mobility issues, but otherwise good health can be inappropriately scored highly.

This study performed a retrospective data analysis of patients attending the specialist geriatric oncology assessment and plan clinic at UHW over a three-year period to December 2023. All patients ≥70 years referred to the oncology department were screened with the G-8 screening tool and those with scores ≤14, and all patients aged ≥80 underwent comprehensive geriatric assessment (CGA), including an ECOG and a cancer and ageing research group geriatric assessment tool (CARG) measure. Following assessment, the information gained is used to guide treatment planning or treatment adjustment going forwards. Analysis was performed on the subsequent data.

A total of 385 patients were CGA assessed over the time period, with information available on 341 patients for analysis. The majority of 54 per cent had an ECOG 1 with 30  per cent ECOG 2 and 10 per cent ECOG 3. Some 82 per cent were stage 3 and 4. After assessment, 59 per cent proceeded with systemic treatment while 41 per cent did not. Some 24 per cent of ECCOG 1 patients did not proceed with treatment due to the findings of their CGA despite technically fitting the criteria for treatment, while 42 per cent of ECOG 2 did not proceed. Some 30 per cent of ECOG 3 patients assessed proceeded with treatment with recommendations. Further subgroup analysis was performed.

“The complexities of older patients means that the ECOG is not always most suitable tool to assess suitability for systemic treatment, with some low ECOG patients not appropriate for treatment while some higher ECOG patients may potentially be suitable for treatment with appropriate adjustments, especially in the palliative setting,” according to the conclusion.

“Increased use of verified geriatric assessment tools may allow more patient-specific and appropriate anti-cancer treatment in this population going forwards.”

Ovarian cancer

Dr Ciara McNevin, St James’s Hospital, Dublin, delivered a presentation titled ‘Clinical and histopathologic analysis of young onset ovarian cancer: A tertiary referral centre experience over 18 years’.

Patients diagnosed with invasive ovarian cancer (OC) <50 years between March 2005 and September 2023 were identified through the gynaecologic biobank at St James’s Hospital, for which they had previously provided consent.

A total of 950 patients were consented to the biobank with malignant disease over this period; 140 (14.7 per cent) were identified as invasive OC <50 years. The mean ± SD age was 40.5 years ± 8.01 years, range 16-to-50 years. Most frequent histologies included serous (n=69, 49 per cent); mucinous (n=23, 16.43 per cent); endometrioid (n=15, 10.71 per cent); and clear cell (n=9, 6 per cent). Positive correlations of significance were noted between the subtype of ovarian cancer and parity (<0.001); pre-menopausal status (<0.001); height (<0.027); miscarriages (<0.009); and alcohol (<0.004).

“We confirm that young-onset OC is a distinct entity, occurring in 14.7 per cent of patients consented to the biobank in a tertiary referral centre over an 18-year period,” according to the conclusion.

“We demonstrate a broad distribution of ovarian cancer histologies in this age group and present parity, pre-menopausal status, height, miscarriages, and alcohol intake as potential risk factors of significance. Data regarding genetic information is currently being collated and may provide further insights.”

KMT2C and KMT2D

The title of the presentation by Dr Philip Bredin, Beaumont Hospital, Dublin, was ‘Identification of synthetic lethality targets in solid tumour cell lines with mutations in KMT2C or KMT2D’.

Mutations in the epigenetic modulators histone-lysine N-methyltransferase 2C and 2D (KMT2C and KMT2D) are the seventh and eighth most common driver gene mutations across all cancers. Despite this high frequency, therapeutic implications of deleterious KMT2C/D mutations are poorly understood and detailed pre-clinical work is still needed.

The aim of this study was to identify potential synthetic lethality drug targets in cell lines with damaging mutations in KMT2C and KMT2D.

RNA-seq confirmed reduction in expression of KMT2C in KMT2C siRNA-treated cells compared to controls. Gene set enrichment analysis showed reduced ER target gene expression as well as reduced DNA damage repair (DDR) gene expression. RT-qPCR showed a reduction in expression of DDR genes including BRCA1 (RQ=0.36); BRCA2 (RQ=0.37); RAD51 (RQ=0.36); RAD54L (RQ=0.28); and POLD3 (RQ=0.47).

Gene dependencies of note in KMT2C-mutated cancer cell lines included WRN (p=2.04 x 10-15) and KMT2D (p=2.86 x 10-6), as well as MDM4 (p=2.37 x 10-5). Gene dependencies of note in KMT2D-mutated cancer cell lines included WRN (p=1.8 x 10-42) and HDAC1 (p=3.91 x10-8).

Compounds targeting AKT accounted for half of the combined top 10 most significant drug sensitivities in KMT2C and KMT2D-mutated cell lines vs wildtypes. GSK2110183, an inhibitor of AKT-1/2/3, was the fourth and second most significant result for KMT2C (p=4.51 x 10-5) and KMT2D (p=1.46 x 10-7) respectively. Capivasertib was the top drug for increased sensitivity in KMT2D-mutated (p=6.59 x 10-6) cancer cell lines compared to wildtypes.

“KMT2C loss-of-function mutations in breast cancer may be implicated in resistance to endocrine therapy as well as response to PARP-inhibitors, outside of standard predictive biomarkers, and this requires further study,” according to the conclusion.

“The targetable gene dependencies included MDM4 in the setting of KMT2C mutations and HDAC1 in the setting of KMT2D mutations; however, HDAC-inhibitors have been tested clinically in breast cancer with limited success.

“In vitro validation of the AKT inhibitor activity against KMT2C/D mutant breast and colorectal cell lines and comparison to biomarker-matched wildtype cell lines is planned, including capivasertib, which was recently approved for breast cancer by the FDA [Food and Drug Administration, US].”

Immuno-oncology

Dr Christopher Cluxton, Beaumont Hospital, Dublin, delivered a presentation entitled ‘Proteomic signatures in predicting clinical outcomes and toxicity in patients treated with immunotherapy’.

In this study, the focus was on the role of serum-based proteomic testing in predicting the response and toxicity of immunotherapy. Serum proteomic signatures are identifiable patterns of protein expression that are associated with immune response in patients with cancer. The researchers performed proteomic and bioinformatic analysis of pre-treatment serum samples from patients with non-small cell lung cancer (NSCLC) subsequently treated with either immuno-oncology (IO) monotherapy or combination therapy to identify predictive biomarkers for either toxicity or response.

The researchers have performed an initial analysis of a pilot patient group of 121 patients with NSCLC; 56 patients treated with IO monotherapy and 65 with combination chemotherapy/IO. Patients with true immune-related adverse events (IrAEs) (based on the CTCAE v5.0) were then selected for proteomic analysis based on physician designation of toxicity, the grade of toxicity and treatment with corticosteroid. Pilot analysis identified 14 patients on single agent immunotherapy with confirmed IrAEs and 24 patients on combination therapy with confirmed IrAEs for further proteomic analysis.

Patient safety

Dr Clara Forrest, UCC, spoke about patients’ and doctors’ views and experiences of the patient safety trajectory of breast cancer care. A cross-sectional, quantitative 20-40 item questionnaire for patients and doctors was developed from previously published peer-reviewed papers. It was circulated to patients attending CUH Cancer Centre and breast cancer doctors in the Republic of Ireland between April and June 2022. Categorical variables were analysed using descriptive statistics. Pearson Chi-squared analyses and Fisher’s Exact test were used to examine associations between categorical variables. Z-test analysis was utilised for pairwise comparisons of proportions. Bonferroni method of adjustment of p-value was applied to correct for type one error.

A total of 184 patients and 116 doctors completed the first part of the survey. Of the doctors, 41.4 per cent felt patient safety deteriorated over the previous five years and 54.3 per cent felt patient safety measures were inadequate compared to 13.0 per cent and 27.7 per cent of patients respectively. Of the 30 patients who experienced medical errors/negligence claims, 60 per cent reported permanent or long-term physical and emotional effects. Some 42 of 48 doctors who experienced medical errors/negligence claims reported emotional health impacts. Almost half of doctors involved in negligence claims considered early retirement. A total of 44 patients and 154 doctors did not experience errors, but reported their patient safety concerns. Doctors were more concerned about communication and administrative errors, staffing and organisational factors compared to patients. Multiple barriers to reporting were highlighted for both groups including uncertainty surrounding the reporting process, lack of confidence in the difference it would make and the absence of an established culture of reporting.

Death and dying

The purpose of the award-winning study outlined by Dr Conor Moloney, CUH, was to ascertain the training and education received by doctors-in-training (DITs) in the hospital in dealing with death and explore the concept of spirituality in relation to their own experiences.

The researchers performed a qualitative survey of DITs using a 27 question electronic survey. Participants answered questions regarding the prior training or education they had received relating to death and dying, their confidence in recognising and managing dying, and their opinion on the adequacy of the training or support available currently. A modified version of the spiritual wellbeing scale questionnaire, a validated tool to provide an overall measure of perceived spiritual quality-of-life, was used to assess impact on spirituality.

To date, a total of 92 participants have responded to the survey. Some 51 were at intern level, 19 at senior house officer (SHO) level, and 22 at registrar or SpR level. Over 70 per cent disagreed (n=54) or strongly disagreed (n=12) that they have received adequate training in relation to death and dying. Over half did not feel confident discussing end-of-life care with patients or their families (n=60), and 70 per cent (n=65) felt that support/debriefing offered after the death of a patient was inadequate. The vast majority agreed (n=27) or strongly agreed (n=64) that end-of-life care was important to the delivery of acute care.

Some 71 per cent (n=66) reported that the death of a patient had had a personal impact on them. The median existential wellbeing score was 44 (range 24-59), indicating a moderate sense-of-life satisfaction. Of note, however, 47 per cent (n=43) agreed to some degree that they felt “unsettled about their future”.

“This survey highlights the importance of improving the training and supports available to DITs in dealing with death and dying,” according to the conclusion.

“This has the potential to benefit both DITs, through better wellbeing, and their patients, by improving confidence and competence providing end-of-life care.”

KMT2C loss-of-function mutations in breast cancer may be implicated in resistance to endocrine therapy as well as response to PARP-inhibitors, outside of standard predictive biomarkers, and this requires further study

Recruitment is ongoing in this survey, and the aim is to expand it to other hospitals in the South/South West group.

Documentation

‘A quality improvement plan for clinical trial documentation in outpatient clinics’ was the title of the presentation delivered by Dr Hannah Sammon, Beaumont Hospital, Dublin. A survey was designed to assess the knowledge of haematology and oncology consultants and NCHDs in Beaumont Hospital regarding the follow-up protocols for patients on trials and reporting of serious adverse events (SAEs).

Overall, 70 per cent of respondents felt that when a patient’s chart was available it was clear whether or not they were participating in a clinical trial. However, the majority of respondents agreed that when evaluating patients on call, their medical record was often not available in full (87 per cent of respondents). Furthermore, only 17 per cent of respondents agreed that whether a patient is participating in a clinical trial is clear from their electronic records.

In relation to the reporting of SAEs, there were differences demonstrated amongst clinicians of different medical grades. Only 30 per cent of SHOs surveyed understood there was a requirement to report SAEs, compared with 92 per cent of consultants and registrars combined. In addition, the results show that there is a great degree of uncertainty among registrars and consultants regarding specific aspects of patient follow-up for example the frequency of review required, the duration of follow-up required and which tests are needed at specific times.

Overall, 87 per cent of all respondents were in favour of the development of electronically available patient-specific follow-up forms for trials patients.

Based on feedback from the questionnaire a new clinical trial follow-up form was developed. This has been rolled out for one clinical trial to date. An audit of protocol trial compliance and NCHD knowledge is planned.

Pricing

The study discussed by Dr Ruth Kiernan, Beaumont Hospital, Dublin, sought to explore patient and staff knowledge of drug pricing and reimbursement, and their perceptions of strategies to reduce drug costs and wastage.

A six-page investigator-created, self-reported anonymous qualitative survey was distributed to oncology patients attending the day unit for SACT, and to oncologists, oncology trainees, pharmacists, and nurses (January-July 2023).

“This study demonstrates both patient and staff desire for a modest increase in current spending thresholds,” according to the conclusion.

“Irish patients are open to exploring split-fill prescribing, and this could provide an opportunity to significantly decrease drug wastage.”

Case reports

Dr Niamh Dorney, CUH, made a presentation concerning NUT midline carcinoma and a patient presenting with a cranial nerve palsy. NUT midline carcinomas are defined by mutations within the NUT gene causing chromosomal rearrangements. There are approximately 140 cases documented in the literature to date. Currently, there is no standard of treatment for NUT midline carcinomas and the literature shows varied approaches to treatment.

“There are various approaches documented involving surgery, radiotherapy, and chemotherapy, however, numbers for each study are small and no strong conclusions were made,” according to the conclusion.

“Further studies of these cases are needed to develop standard treatment regimens if possible.”

Another case report was described by Dr Emer Lynch, CUH. It related to a case of locally advanced unresectable thyroid cancer with mixed papillary and anaplastic thyroid cancer (ATC) histology, and ATC element demonstrating a BRAF V600E mutation.

Neoadjuvant BRAF and MEK inhibition with encorafenib and binimetinib was prescribed, with a rapid clinical response resulting in oesophageal rupture. A literature review was undertaken considering reported events of visceral organ rupture in solid organ malignancies in response to systemic therapy, including targeted therapy in ATC, in addition to reviewing the evidence for neoadjuvant therapy in ATC and considering alternative methods of enteral medication delivery where there is impairment of the routine per-oral delivery route. The case report described a life-threatening complication of a rapid and dramatic response to neoadjuvant targeted SACT with visceral perforation and the patient ultimately proceeding successfully to surgery.

“There exists promising non-randomised data describing the successful use of neoadjuvant BRAF and MEK inhibition in BRAF-mutated ATC, supported by the case study described,” according to the conclusion.

Meanwhile, the Tomás Lyons Advanced Fellowship at Memorial Sloan Kettering Cancer Centre 2025-2027 was awarded to Dr Orla Fitzpatrick from St James’s Cancer Institute, Dublin.