Bursary awards for best research by trainees in oncology

The 2025 Irish Society of Medical Oncology (ISMO) Bursary Awards were organised with Cancer Trials Ireland (CTI). This year, only the top 15-20 abstracts were selected for oral presentation at the CTI/ISMO National Training Day, with a further 20 invited to present a poster. The event was held on Friday 31 January 2025 in the Cheyne Lecture Theatre at RCSI, Dublin.

The winners of the oral presentations were: Dr Clara Forrest, Cork University Hospital; Dr Gavin Dowling, Beaumont Hospital, Dublin; Dr Ruth Hutch, St James’s Hospital, Dublin; and Dr Shauna Moore-Davis, University Hospital Galway.

ICIs

The title of the presentation by Dr Forrest was ‘Acquired lipodystrophy associated with pembrolizumab: A case report and review of the literature’. Triple-negative breast cancer (TNBC) accounts for 10-15 per cent of breast cancers, but is more aggressive than other subtypes with higher rates of recurrence and metastasis.

In recent years, immune checkpoint inhibitors (ICIs) have improved outcomes in patients with early-stage TNBC. The addition of pembrolizumab to neoadjuvant chemotherapy has significantly increased pathological complete response (pCR) rates and shown an overall survival (OS) benefit in the KEYNOTE-522 trial.

Lipodystrophy, characterised by the loss of peripheral subcutaneous adipose tissue and the accumulation of visceral fat, has been reported in association with ICIs, although it remains a relatively underrecognised condition. As the use of ICIs continues to grow, improving the recognition and management of adverse effects is essential. Incorporating ICIs into curative-intent regimens also raises important considerations regarding long-term immune-related toxicities and the risk of overtreatment.

In the case study, a patient presented with symptomatic right-sided, node-positive TNBC. Staging scans showed no distant metastatic disease. Germline BRCA testing was negative. She had no medical history and took the progesterone-only pill. The patient started neoadjuvant chemoimmunotherapy with carboplatin, paclitaxel, and three-weekly pembrolizumab in accordance with the KEYNOTE-522 trial protocol. She completed four cycles of paclitaxel and two cycles of carboplatin, which was discontinued due to a hypersensitivity reaction. She then transitioned to doxorubicin and cyclophosphamide (AC) while continuing pembrolizumab; however, AC was dose-reduced after the first cycle due to grade 2 nausea and fatigue.

A significant clinical response was evident following neoadjuvant chemoimmunotherapy, as no breast mass or axillary lymphadenopathy was palpable. The patient underwent a wide local excision and an axillary lymph node dissection. Histopathological examination revealed a pCR with no evidence of residual carcinoma. She subsequently received adjuvant radiotherapy while continuing pembrolizumab. The patient completed one year of pembrolizumab therapy, receiving 17 cycles in total.

Two months after completing adjuvant pembrolizumab, the patient developed new skin changes in both arms, characterised by puckering, indentation, and asymmetry of the subcutaneous tissues. These painless changes were more pronounced on the right side and were not associated with muscle weakness or pitting oedema. Over the following six weeks, the skin changes progressed and began to affect her thighs.

Diagnostics revealed alanine transaminase was elevated at 73 U/L, and abdominal ultrasound revealed diffuse fatty infiltration. Haemoglobin A1c, cholesterol, and triglycerides were also found to be elevated. An autoimmune panel was negative. A skin biopsy revealed subcutaneous fat containing foamy histiocytes and lymphocytes consistent with immune checkpoint inhibitor-induced lipodystrophy. The epidermis and dermis appeared unremarkable. The patient then commenced on a six-week tapering course of prednisolone, starting at 60mg (1mg/kg). At the time of submitting the study abstract, there had not been an improvement in these skin changes and second-line immunosuppressant therapy is currently being considered.

“This report describes a patient with node-positive TNBC treated with neoadjuvant chemoimmunotherapy and adjuvant pembrolizumab,” according to the conclusion.

“She achieved a pCR, but subsequently developed ICI-associated lipodystrophy, highlighting the complexities of ICI integration into the curative-intent treatment of TNBC. This case emphasises the need for more research to examine treatment de-escalation and to improve the recognition and management of long-term immune-related toxicities.”

Cyclin-dependent kinase 12

The title of Dr Dowling’s presentation was ‘Cyclin-dependent kinase (CDK) 12 as a potential therapeutic target in HER2-positive breast cancer’.

The CDK12 gene is located at chr17q12, near HER2, and its upregulation has been previously reported in approximately 80-90 per cent of HER2-positive breast cancers. Growing evidence suggests that CDK12 is more than a passive bystander of ERBB2 amplification – it may actively contribute to tumorigenesis and trastuzumab resistance by upregulating the IRS1‐ErbB‐PI3K and WNT signalling pathways. High expression levels of both CDK12 and HER2 have been associated with trastuzumab resistance, disease recurrence, and poor survival outcomes. The TCHL trial evaluated neoadjuvant treatment for HER2-positive breast cancer using either TCH (docetaxel, carboplatin, trastuzumab) or TCHL (TCH plus lapatinib). In this study, whole exome sequencing of pre-treatment tumour biopsies revealed a statistically significant higher total copy number (TCN) of CDK12 in patients with residual disease (n=13) compared to those who achieved pCR (n=9). Dinaciclib, a cyclin-dependent kinase inhibitor with strong activity against CDK1, 2, 5, 9, and 12, has demonstrated anti-tumour effects in trastuzumab-resistant HER2-positive breast cancer through CDK12 inhibition.

This study aimed to investigate the efficacy of a group of CDK12 inhibitors in a panel of HER2 positive breast cancer cell lines, including those with acquired resistance to trastuzumab, and determine whether combination treatment with dinaciclib and trastuzumab could overcome resistance.

A panel of HER2-positive breast cancer cell lines were selected, including those with acquired resistance to trastuzumab. SKBR3-Par, SKBR3-Res, BT474-Par, and BT474-Res were treated with a group of CDK12 inhibitors to establish IC50 values. These cell lines were then treated with combinations of 10g/ml of trastuzumab with various concentrations of dinaciclib. Proliferation was measured using an acid phosphatase assay. Western blots were performed to investigate the effect of dinaciclib treatment on protein expression (pAKT, CDK12, and HER2). Chick chorioallantoic membrane (CAM) assays were used to investigate the effect of dinaciclib treatment in vivo.

Data analysis was performed on whole exome sequencing data from the TCHL clinical trial. Although only a small cohort of patients (n=22), there was a statistically significant difference in the mean total copy numbers of CDK12 between those patients who achieved a pCR compared to those patients with residual disease (p=0.008, Mann Whitney U). Patients with a higher total copy number of CDK12 were more likely to have residual disease after neoadjuvant therapy. IC50 values for Dinaciclib, THZ531, THZ1, and SR4835 in a panel of HER2-positive breast cancer cell lines, including those with acquired resistance to trastuzumab, were established. Combination treatment with dinaciclib and trastuzumab showed that in the SKBR3 cell line, the trastuzumab-resistant SKBR3 cells were more sensitive to this treatment than their trastuzumab-sensitive counterparts. Western blot analysis demonstrated the effect of dinaciclib treatment on protein expression of pAKT, CDK12 and HER2. CAM experiments are currently ongoing. Whole genome sequencing and RNAseq data from the cell line panel is currently being analysed.

“CDK12 holds promise as a therapeutic target in HER2-positive breast cancer, with potential to act in conjunction with HER2-targeted therapies, and warrants further investigation,” according to the conclusion.

Anaplastic thyroid cancer

The subject of Dr Hutch’s presentation was the genomic landscape of anaplastic thyroid cancer. Anaplastic thyroid cancer is a rare and frequently lethal cancer, accounting for 2 per cent or less of thyroid cancer and characterised by an aggressive phenotype and poor prognosis. Recent advances in precision oncology have highlighted the importance of identifying actionable variants in rare cancers.  The research team aimed to characterise the genomic landscape of this rare tumor in an Irish population, and compare and contrast with a larger international genomic cohort. A total of 197,980 samples from 171,957 patients available from the AACR Project GENIE v.15.1 database were analysed for the prevalence of mutations, fusions and copy number alterations in anaplastic thyroid cancer. Retrospective cases of anaplastic thyroid cancer were then accessed retrospectively in St James’s Hospital, Dublin. Genomic analysis was performed to assess most frequent actionable alterations.

A total of 288 samples were identified in 280 patients across 15 cancer centres. Anaplastic thyroid cancer occurred at a frequency of <1 per cent of reported cancers (0.1 per cent). 146 were identified as male (51 per cent); 141 (49 per cent) identified as female. Median age was 67 (range 33-89). Most samples were taken from the primary site (62.2 per cent) versus metastatic site (31.6 per cent). Somatic mutations were noted in all 288 samples (100 per cent). Most frequently altered genes included TP53 (57.6 per cent), TERT (50.2 per cent), BRAF (40 per cent), PIK3CA (13.9 per cent), and NRAS (15.3 per cent). In the St James’s cohort, 27 patients were identified; genomic alterations were detected in 83 per cent of samples. Some three samples failed testing due to quality. 60 per cent of patients were male, median age was 72. Most common variants identified included BRAF (6; 25 per cent), PIK3CA (3; 12.5 per cent), NRAS (5; 21 per cent), and FGFR (3, 12.5 per cent).

“Anaplastic thyroid cancer is a rare tumour with a high frequency of somatic alterations,” according to the conclusion.

“Leveraging independent datasets, we characterise the genomic landscape of this rare tumour, confirming a similar pattern of actionable variants in both a global cohort of patients with anaplastic thyroid cancer and an Irish population. Our data highlight the urgent need to increase access to [next-generation sequencing] in Irish patients, to identify actionable variant in patients with rare cancers and ultimately improve patient outcomes.”

Visual aids

The presentation of Dr Moore-Davis concerned the use of visual aids to improve communication between oncologists and their patients.

The project was undertaken as medical language “can often be esoteric and confusing to patients, leading to communication errors, ineffectiveness, and patient dissatisfaction”.

“Clinicians often overestimate a patient’s health literacy or capacity for retention of information during consultations,” according to the study.

“Particularly emotive conversations can further negatively impact their ability to process and retain information.”

Currently, clinicians primarily rely on verbal or written language to communicate health information. However, patients’ ability to recall verbal information alone has been reported to be as low as 25 per cent, a figure that can potentially be doubled with the addition of visual cues. This study explored the impact of incorporating images as a supplement to verbal communication during oncology consultations.

Visual aids were introduced to the clinics from July 2024 for new breast cancer patients and systemic treatment change visits for all cancer types. Patients receiving systemic therapy at the Portiuncula University Hospital, Galway, day ward were approached between September and November 2024 to fill out voluntary patient satisfaction questionnaires. Descriptive statistical analysis was performed on the data using Microsoft Excel.

A total of 50 questionnaires were distributed with a 54 per cent response rate. 27 patients were enrolled: 18 female and nine male. Median age was 66 years (range 37-80). Most common cancer types were GI (59.2 per cent), breast (22.2 per cent), and lung (7.4 per cent). 81.5 per cent of patients attended clinic with a companion while 18.5 per cent attended alone. 29.6 per cent had consultations where visual aids were utilised.

Cancer stage awareness was reported as ‘early’, ‘metastatic’ or ‘unsure’ as 18.5 per cent, 29.6 per cent, and 51.9 per cent respectively.

Of the visual aid users (n=8), 88 per cent found it helpful in remembering information discussed. 87.5 per cent found it helpful in remembering their treatment schedule. 75 per cent found it helpful for explaining to family who were not present.

Of the visual aid non-users (n=19), 74 per cent believed they would be helpful as a memory aid. 100 per cent of those who attended alone (n=5) felt they would be helpful in explaining the information discussed to family not present.

72 per cent of the visual aid non-users found the information overwhelming or difficult to process, compared to 44 per cent of visual aid users.

62.5 per cent of visual aid users could cite their cancer stage and treatment goals in comparison to 42.2 per cent who did not use them. Patients with lower levels of education were more likely to be unsure of their cancer stage.

“Patient attitudes towards the visual aids were overwhelmingly positive,” according to the conclusion.

“Particular benefit was identified through their use as a memory aid and as a means of communicating to family. Education status had a notable effect on patient’s knowledge of their cancer stage and treatment goals and visual aids appeared to help bridge this gap. Visual aid users were also less likely to feel overwhelmed by the amount of information discussed during consultations. With the success of the visual aids among the newly diagnosed breast cancer patients, we will aim to expand it to other cancer types in the near future.”