ISMO Bursary Awards 2022

Irish Society of Medical Oncology, Bursary Awards, virtual, 28 January 2022 

High caliber, wide-ranging cancer research was presented at the annual ISMO meeting 

The 2022 Irish Society of Medical Oncology (ISMO) Bursary Awards took place on Friday, 28 January. Once again, the meeting was held virtually as a result of the Covid-19 pandemic and was streamed live from the Fintan Gunne Theatre, Catherine McCauley Centre, the Mater Misericordiae University Hospital (MMUH), Dublin. 

The keynote presentation was delivered by Dr Gopa Iyer, Memorial Sloan Kettering Cancer Centre, New York. Dr Iyer is a Medical Oncologist who specialises in research and treatment of patients with genitourinary malignancies, including bladder, prostate, kidney, and testis cancers. He also has a special interest in understanding the genetic basis for bladder cancer and is a member of Memorial Sloan Kettering’s Bladder Cancer Oncogenome Project, a multidisciplinary effort to discover the key genetic abnormalities that drive this disease. 

The Bursary candidate presentations were of a high caliber and focused on a wide array of subjects. This article provides an outline of the winning presentations. 

The title of the presentation delivered by Dr Catherine Murphy, University College Dublin, was ‘Standardising emerging terminology for immune-related adverse events (irAE) using the modified delphi method: A Society for immunotherapy in cancer (SITC) consensus statement’. 

The spectrum of adverse events from immune checkpoint inhibitors (ICI) is distinct from cytotoxic chemotherapies. Consensus definitions for irAE subtypes have not been elucidated. According to the study authors, standardised irAE terminology would benefit patients, clinicians, researchers, and industry partners in theimmunotherapy field, by providing a universal language for new irAEs, greater standardisation in the application of clinical guidelines, and a benchmark for prospective irAE studies. 

Using the modified delphi technique, the authors conducted two sequential rounds of anonymous web-based questionnaires with an expert panel from SITC. The group consisted of representatives from the following major stakeholder groups: Academic oncologists, academic medicine subspecialists, industry, regulatory, and nursing. The first-round questionnaire consisted of a series of statements that the respondents were asked to rate on a nine-point Likert scale. Consensus was considered reached when a statement is appropriate if the median score is greater or equal to seven. A virtual consensus meeting was held to encourage discourse on areas of where consensus was not reached. Responses to the first-round were collated and used to create a second-round questionnaire, after which a second virtual consensus meeting was held to finalise consensus definitions. 

The results of the surveys and consensus meetings were collated into consensus statements. For example, to be defined as recurrent, irAEs occurring after discontinuation of immunotherapy must spontaneously recur within two years of the last dose of immunotherapy. 

“The group deliberated whether to include a time-frame to define recurrence, given that irAEs may occur at any time after stopping therapy. The trade-off between sensitivity and specificity with a time-limit to define recurrence was debated. It was emphasised that the definition should encourage clinicians to follow patients long-term,” according to the authors. 

A series of other consensus definitions were agreed. These results will be collated to develop a white paper outlining the findings published in the Journal for ImmunoTherapy of Cancer (JITC) as part of new clinical guidelines. 

Dr Christopher Cronin, Cork University Hospital (CUH), delivered a presentation based on cases studies involving BRAF-inhibitor therapy in BRAF V600E-mutated gliomas. Primary central nervous system (CNS) malignancies comprise 1-to-2 per cent of all new cancer diagnoses in Ireland. Maximal safe surgical resection may be combined with adjuvant radiotherapy and chemotherapy based on tumour grade, molecular characteristics, and patient factors. Conventional systemic treatment options for recurrent disease have offered only modest clinical benefit, particularly for high grade gliomas. BRAF V600E oncogene mutations have been reported in multiple glioma grades and subtypes. The utility of BRAF-targeted therapy, alone or in combination with a MEK-inhibitor has been reported in multiple solid tumours where a BRAF mutation has been identified. Emerging evidence supports this therapeutic strategy in BRAF-mutated gliomas. 

The case study series involved four patients from two neurosurgical centres in Ireland with BRAF V600E-mutated gliomas. Patients include a 19-year-old male with anaplastic ganglioma (WHO Grade III), a 21-year-old male with Rosai-Dorfman Syndrome-associated granular cell tumour (WHO Grade I), a 28-year-old female with ganglioglioma (WHO Grade I), and a 30-year-old female with glioblastoma multiforme (WHO Grade IV). Three patients received chemoradiation with temozolomide prior to BRAF-targeted therapy. Duration of disease control with chemoradiation ranged from five-to-11 months. BRAF-inhibitor was combined with a MEK-inhibitor for two of the four patients. Duration of disease control with BRAF-targeted therapy ranged from six-to-60 months. Treatment-limiting toxicity was noted in one patient. 

“Durability of disease control with BRAF therapy was generally superior to that achieved with STUPP protocol chemoradiation; one patient has experienced ongoing disease control for five years with BRAF-targeted therapy,” according to the authors. 

Further data is warranted to enhance holistic care of patients with cancer to include the psychological, social and emotional, in addition to identifying the need for additional resources in these areas in the Irish healthcare system

“The increasing utilisation of next-generation tumour sequencing in clinical practice is likely to result in the identification of more potentially actionable driver mutations in tumour types where high-level evidence supporting a targeted therapy may be limited. Whilst data from phase 2 basket trials support the use of targeted therapy in BRAF-mutated glioma, the optimal sequencing of treatment in this population, and whether single agent BRAF-inhibitor or combination BRAF/MEK-inhibitor therapy should be utilised remains unclear. Moreover, this series raises broader challenges regarding off-label drug prescribing in oncology practice and the relative paucity of phase 3 data in rarer tumour types.” 

Quality-of-life 

‘Quality-of-life (QoL) in women with early and advanced breast cancer and the impact of resilience, coping, social supports and treatment related symptoms: An interim analysis’ was the title of the study discussed by Dr David O’Reilly, CUH. According to the authors, patients receiving endocrine therapy in the adjuvant setting for early breast cancer can suffer from significant treatment related toxicity which anecdotally, at least, has an impact on their QoL. There is limited real-world evidence investigating QoL of women with late-stage hormone receptor positive (HR+) breast cancer. The authors sought to explore the QoL and treatment related symptoms in patients with early and late-stage HR + breast cancer. 

Two validated QoL measures were chosen for this study, namely the FACT-ES and the EORTC QLQ-30. A sample size of 568 (Ratio of 3:1, Adjuvant (n= 426), Metastatic (n=142)) was calculated to detect a seven-point difference in the QoL of patients in each group (power of 80 per cent, α = 0.05). Patients completed written informed consent and were asked to complete the relevant questionnaires and sociodemographic questions at one-time point only. In addition to the above QoL measurements, the authors explored factors which may be contributing to patients’ QoL via other validated questionnaires including resilience (Brief Resilience scale), coping (Brief-COPE) and social supports (modified social support survey). Data presented here includes patients recruited across four sites; namely CUH, MMUH, South Infirmary Victoria University Hospital, and University Hospital Kerry. 

There were no significant differences in QoL (as measured by FACT-ES) identified in this interim analysis. 

“However, consistent with our hypothesis, there was a suggestion that patients receiving endocrine therapy in the A setting have more endocrine related symptoms and this does impact their QoL,” according to the authors. 

“This interim analysis suggests that patients with metastatic disease may have impaired physical and role functioning. Limitations of our work include the heterogeneity of our study population and the one-time point only data collection. Following completion of accrual, a regression model will be utilised to identify the most significant determinants of QoL, based on the data collected.” 

QoL was also the focus of the presentation by Dr Fiona Brady, University College Cork. The aims and objectives of the research project were to assess QoL using validated questionnaires (FACT and EORTC/Global health scale) in patients after treatment for lung, colon, breast, and cervical cancer at CUH. 

Perceived stigma levels were analysed in the same cohort using a validated Lung Cancer Stigma Inventory (LCSI) questionnaire. 

Of the 124 respondents, there were no difference in QoL with respect to gender and cancer type using the Fact-L scale (p=0.857 and p=0.480 respectively) or EORTC/global health scale (p=0.126 and p=0.482, respectively). There were notable differences in the social/family and emotional wellbeing subgroup analyses in breast and colon cancer patients. No statistically significant difference was noted comparing LCSI stigma scores between gender (p=0.671), but a statistically significant difference was observed regarding LCSI stigma score and cancer type (p=0.033). This difference was observed in pairwise comparison of colon and lung cancer (p=0.018). When cancer types were grouped into cancers with expected associated stigmatisation, additional statistical significance was noted (breast + colon vs cervix + lung). 

“Stigma scores were significantly higher in patients with lung cancer over colon cancer,” according to the authors. 

“Additionally, combining lung cancer with cervical cancer had further statistical significance over colon and breast patients combined. There is a scarcity of published information regarding QoL and stigma in cancer survivorship patients. Further data is warranted to enhance holistic care of patients with cancer to include the psychological, social, and emotional, in addition to identifying the need for additional resources in these areas in the Irish healthcare system.” 

Combination therapies 

‘Tremelimumab (day one only) and durvalumab in combination with transarterial chemoemobilisation (TACE) in patients with hepatocellular carcinoma (HCC)’ was the title of the study discussed by Dr Jemma Buchalter, MMUH. 

Patients with HCC (Childs Pugh A/B7, Barcelona clinic liver cancer stage B/C; ECOG 0/1; sorafenib-naive or experienced) were enrolled in a pilot study of tremelimumab at two dose levels (DL1: 75mg IV q4-weekly x 4 and DL2: 300mg IV D1 only) in combination with durvalumab (1500mg IV q-28d) and TACE (D36 +/- 96 hours) until progression of disease (per irRECIST) or off-study criteria. Peripheral immune monitoring was performed and tumour biopsies were obtained at time of TACE. 

Based on the results, the authors concluded: “Tremelimumab (day one only) and durvalumab in combination with TACE is safe and feasible in patients with HCC.” 

Dr Karine Ronan, St Vincent’s University Hospital, Dublin, presented on a study titled ‘Trastuzumab-deruxtecan in HER2 positive metastatic breast cancer and HER2 positive breast cancer with brain metastases, experience and efficacy data from an Irish cancer centre’. 

Over-expression of HER2 is present in approximately 15-to-20 per cent of metastatic breast cancers (mBC), conferring an aggressive tumour behaviour, but also an opportunity for targeted therapies that continue to improve survival. The antibody-drug conjugate, Trastuzumab-deruxtecan(T-DXd), is currently available via an expanded access programme to patients in Ireland with HER2+ mBC. T-DXd has proven impressive in clinical trials. 

A retrospective review of patients who received T-DXd at St Vincent’s University Hospital and St Vincent’s Private Hospital was carried out. Demographic, histopathological, radiological and clinical outcome data were obtained from electronic and paper medical records. Response was assessed by review of most recent staging CT for visceral disease, or MRI for intracranial disease. 

Between May 2021 and January 2022, 25 patients received T-DXd at the recommended starting dose of 5.4mg/kg. The median age was 59 years. The median number of prior treatments received in the metastatic setting was five. An objective response was observed in nine of 21 patients at the time of data analysis( ORR=43 per cent, CBR=57 per cent). Median time to response was three months. Ten patients had BCBMs prior to commencing T-DXd. Two patients (20 per cent) had undergone WBRT and eight patients (80 per cent) had stereotactic radiosurgery prior to T-DXd. At the time of analysis, an intracranial response was observed in four-of-nine patients (ORR-IC=44 per cent; CBR-IC=44 per cent), with a median time to response of 2.5 months. Six-of-21 patients (29 per cent) had progressive disease (PD), four (67 per cent) of these with CNS disease. Three patients have discontinued treatment due to PD, three others were referred to neurosurgery. The most common ≥grade 3 adverse events were fatigue (n=5, 20 per cent), nausea (n=1, 4 per cent), diarrhoea (n=1, 4 per cent), interstitial lung disease (ILD) (n=1, 4 per cent), anaemia (n=1, 4 per cent) and neutropenia(n=1, 4 per cent). Two patients discontinued treatment due to ILD and colitis. Ten patients (40 per cent) underwent dose reduction, after a median of six cycles. 

“T-DXd is an effective therapy for HER2+ mBC with a manageable and tolerable safety profile,” according to the authors. 

“Although our sample size is small, results for both visceral and intracranial disease are comparable to those reported in international clinical trials, providing real world evidence supporting these outcomes.” 

Dr Michael Conroy, Beaumont Hospital, Dublin, discussed the study titled ‘Combining a HDAC6 inhibitor (ACY1215) with KRAS inhibitor (Adagrasib) in KRAS/ LKB1 non-small cell lung cancer (NSCLC) patients’. 

KRAS mutations are the most common driver mutations in NSCLC. Thirty per cent of KRAS-mutated NSCLC will also have a LKB1 (STK11) mutation. KRAS/LKB1 co-mutated NSCLC represents a unique subset of lung cancer with reduced survival and primary resistance to immunotherapy. The authors’ preclinical research demonstrated that KRAS/LKB1 co-mutated NSCLC are more sensitive to histone deacetylase 6 (HDAC6) inhibition. Therefore, the authors proposed a phase 1b trial combining a HDAC6 inhibitor (HDAC6i) and KRAS inhibitor (KRASi) in the management of KRAS/LKB1 co-mutated NSCLC. 

Primary endpoints were safety (according to CTCAE v5.0) and maximal tolerated dose. Secondary endpoints included pharmacokinetics, overall response rate, duration of response, progression-free survival, and overall survival (according to the Kaplan-Meier method). 

Other research 

Chemotherapy toxicity in older patients with cancer attending the geriatric oncology and liaison (GOAL) clinic in University Hospital Waterford (UHW) was the subject of the talk given by Dr Munzir Hamid, UHW. 

The comprehensive geriatric assessment (CGA) is recommended to guide treatment choices in older adults with cancer. Patients aged ≥70 newly-diagnosed with cancer attend the GOAL clinic in UHW and undergo multidimensional assessments at baseline, with interventions to manage any deficits identified. The authors’ reported outcomes for patients attending the GOAL clinic, to assess rates of treatment dose modifications, delays and unscheduled hospitalisation as surrogates for therapy toxicity. 

“Despite intensive assessment, clinical optimisation and personalised treatment decisions, older adults with cancer remain at high risk of chemotherapy toxicity,” according to the study’s conclusion. 

“These data highlight the need to adequately resource a geriatric-oncology service and build capacity to closely monitor older patients on active therapy.” 

Is diverticular disease a risk factor for colitis from immune checkpoint inhibitors was a question asked in a study discussed by Dr Orla Fitzpatrick, Beaumont Hospital. 

ICIs have transformed the landscape of cancer treatment, but are associated with a range irAEs. ICI-colitis is a common and potentially severe irAE from ICIs, particularly CTLA-4-based combinations, and the gut microbiome may be implicated in its development. While there are no known host risk factors associated with the development of ICI-colitis, the authors’ hypothesised that other gastrointestinal conditions, such as diverticular disease, may alter the gut microbiome and thus may be associated with the development of colitis. 

A retrospective review of electronic medical and prescribing records for patients treated with ICIs between 2011 and 2021 was conducted. 

“In a large retrospective dataset of ICI-treated patients, we identify that one-third of patients have a history of diverticular disease, 4 per cent will develop high grade colitis,” according to the authors. 

“We identify that history of diverticular disease is significantly associated with high-grade colitis, and confirm prior knowledge that combination ICIs are associated with high grade colitis. These data will be explored in larger datasets and validated in an independent cohort.” 

Dr Pranshul Chauhan, Beacon Hospital, presented on a study titled ‘Circulating tumour cells (CTCs) and total cell free DNA (cfDNA) levels as predictive biomarkers of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer and oesophageal cancer’. Locally advanced rectal cancer (LARC) patients who do not achieve a complete pathological response (pCR) after neoadjuvant chemoradiotherapy (NACRT) have higher relapse and death rates. Higher CTC numbers at the time of diagnosis are predictive of poorer outcome in colorectal cancer, but there are limited studies in rectal cancer specifically, and there are no studies looking at changes in CTCs or cfDNA over the course of NACRT treatment as a predictor of pCR. A similar principle can be applied to oesophageal cancer patients undergoing NACRT. 

This study validated CTCs and total cfDNA during treatment as predictors of pCR after NACRT in LARC patients and oesophageal cancer patients. The authors’ also aimed to observe the growth potential of CTCs in a subset of patients. 

Retrospective analysis was carried out on 70 LARC patients. Prospective analysis is being carried in LARC and oesophageal patients with 25 patients accrued to each group. An interim analysis shows overall, there is a rise in the number of CTCs at week three during the treatment in LARC patients. 

“Ultimately, the development of a pCR predictor in LARC will allow stratification of non-responding patients to other treatments,” according to the authors. 

‘Synergistic effects of alpelisib (PI3K inhibitor) and ribociclib (CDK 4/6 inhibitor) in preclinical colorectal cancer (CRC) models,’ was the title of the study discussed by Dr Razia Aslam, RCSI. 

Multiple activating genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen-activated protein kinase (MAPK) pathways have been implicated in the development of resistance to anti-cancer therapies. Ribociclib has limited activity as a single agent in CRC. However, combining ribociclib with targeted therapies of the MAPK and PI3K pathways may be a promising treatment strategy in CRC. The authors explored the in vitro efficacy of drug combinations (ribociclib and alpelisib (R+A)) in four CRC cell lines with different mutational status; CACO-2 (PIK3CA/KRAS wildtype), LS-1034 (KRAS mutated), SNU-C4 (PIK3CA mutated), and DLD-1 (PIK3CA/KRAS mutated). 

“A synergistic response to treatment with the combination of R+A is seen in all cell lines,” the authors stated. 

“We are currently investigating this combination in CRC animal models.” 

Dr Ruba Hamed, University Hospital Limerick, presented on a study titled ‘Rectal cancer in the elderly: Characteristics, management, and outcomes from a single centre retrospective cohort review’. Retrospective data of patients treated for rectal cancer between 2010 and 2019 was collected through electronic records. Patients were split into cohorts above and below the age of 70 (at time of diagnosis). Patient demographics, radiological and histopathological disease characteristics, adopted management strategies, and resulting outcomes were recorded. 

“Elderly patients (>70 years) were less likely to be treated with curative-intent radiation therapy and surgery and were less likely to receive chemotherapy in the concurrent and adjuvant setting compared to younger patients (<70),” according to the authors. 

“Younger patients were more likely to demonstrate more aggressive disease features and develop disease recurrence than elderly patients. This is despite elderly patients receiving less aggressive therapy than younger patients. As such, there may be a role for therapy in treatment de-escalation in elderly patients with locally advanced, early-stage rectal cancer (pending further research and trials).”