A gathering to showcase the health of oncology research in Ireland

Paul Mulholland reports on the recent ISMO Fellowship and Bursary Awards meeting

The 2020 Irish Society of Medical Oncology (ISMO) Fellowship and Bursary Awards took place in the Catherine McAuley Centre, Mater Misericordiae University Hospital, Dublin, on Friday and Saturday 24 and 25 January. As usual, the meeting featured some of the very best oncology research currently being conducted in Ireland. The winners of the oral presentations were as follows: Dr Iseult Browne; Dr Shahid Iqbal; Dr Maeve Hennessy; Dr Sarah Lochrin; Dr David O’Reilly; Dr Niamh Peters; Dr Thamir Mahgoub; Dr Fionnuala Crowley; Dr Rachel Keogh; Dr Yasar Ahmed; Dr Mahala Tharmabala; Dr Catherine Weadick; and Dr Zac Coyne.

Pembrolizumab

The paper by Dr Browne, University Hospital Limerick (UHL), was titled: ‘Efficacy and safety of pembrolizumab in advanced cervical cancer — a real-world treatment study’. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor, blocking its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumour immune response.

The aim of this research was to assess the experience with pembrolizumab in patients with advanced cervical cancer in an Irish healthcare setting. Patients’ key clinical data was collected from hard copy and electronic medical records. All patients had recurrent or metastatic cervical cancer. Patients received pembrolizumab 200mg IV once every three weeks. To enable the research team to compare their results with the reported outcomes from Keynote-158, they analysed progression-free survival (PFS), overall survival (OS), and objective response rate (ORR), both in the total and PD-L1 positive populations.

Data collection was between April 2018 and December 2019. The results showed 45 per cent of patients experienced all-grade toxicity, with 10 per cent experiencing grade 3-4, and that 10 per cent discontinued pembrolizumab secondary to toxicity. At the time of the analysis, 70 per cent had discontinued treatment and 65 per cent of patients had died. Of the 35 per cent that were alive, 85 per cent were still on pembrolizumab (with 10 per cent of these patients continued post radiological progression). The median duration between last dose of pembrolizumab and death was four weeks.

“The observed clinical activity in our patient population is superior to the interim results from Keynote-158,” according to the results.

“We report a consistent safety profile with no new safety signals. It is important to note that there are limited therapeutic options in these symptomatic and often terminally-ill patients with advanced cervical cancer. Additionally, all of these alternate treatments create a significant toxicity profile, impacting hugely on the patients’ quality-of-life. Therefore, in our real-life experience, pembrolizumab provides an effective and much-improved toxicity profile alternative in this patient population. We believe, based on our findings, pembrolizumab should be considered as a standard option for those with advanced PDL1+ cervical cancer.”

Crowdfunding

The research conducted by Dr Iqbal, Cork University Hospital (CUH), focused on crowdfunding for cancer treatment. The research was titled, ‘Crowdfunding for anticancer therapies: An analysis of non-US GoFundMe pages’. The study set out to analyse what the current non-United States (US) GoFundMe cancer pages were requesting monetary donations in order to get a deeper understanding of this unregulated activity. For the research, 150 non-US GoFundMe webpages were reviewed between November 2019 to January 2020.

US web pages were excluded on account of the markedly different healthcare systems, with the majority requesting basic healthcare not covered by patient health insurance. Data collected included clinicopathological details such as age, gender, cancer type and stage of disease, in addition to the type of treatments being sought for funding, the total amount of funding sought and the quantity of donors.

Of the 150 pages reviewed, 83 requestors were adults and 64 per cent (n=96) were of female gender. The majority of the requestors had brain cancer, followed by breast cancer and ovarian cancer. The median amount of money requested was €48,205 (range €1,171-€588,759). Of the 150 pages, 89 were from the UK (59 per cent), 24 from Ireland (16 per cent), 12 from Australia (8 per cent) and 10 from Canada (7 per cent). A quarter of patients requested financial support for their anti-cancer care (n=38, 25per cent), with requests for immunotherapy the second-most common (n=31, 21 per cent) reason, followed by alternative therapies (n=28, 19 per cent) and funding for an approved drug not financed by the specific health system (n=17, 12 per cent). The largest sum of money requested was for immunotherapy (median €187,064). Of the 24 Irish webpages, the majority were requesting either alternative therapy (n=7, 29per cent) and immunotherapy (n=6, 25 per cent).

“Crowdfunding using webpages such as GoFundMe are platforms by which patients can request donors to fund their anti-cancer treatment,” according to the authors.

“Our analysis has identified that these platforms are predominantly used for requesting financial support, but worryingly, a large proportion are requesting immunotherapy for unlicensed indications and alternative therapies with no evidence base to support its use. Future efforts to improve patient education are required to better manage this route of cancer funding.”

Patient expectations

The paper by Dr Hennessy, Beaumont Hospital, Dublin, was titled ‘Patient knowledge and expectations of anti-cancer treatments in the advanced disease setting’. The aim of the research was to evaluate the expectations for cure and palliation from systemic therapies among patients with advanced, incurable cancer in Beaumont. Patients on active treatment attending the oncology day ward completed anonymised questionnaires over a four-week period. Personal demographics, decision-making for treatment and expectation of benefit and toxicity were assessed in the survey. Analysis was carried out on patients assessed to have advanced metastatic disease.

A total of 254 patients completed the questionnaire, of which 217 were assessed to have metastatic/incurable disease. Fifty-seven per cent were male, 56 per cent were aged between 30-to-64 years and 35 per cent had completed third-level education. According to the results, 42 per cent of patients stated that treatment was very likely or somewhat likely to cure their cancer. The responses showed 84 per cent felt treatment was either very likely or somewhat likely to help them live longer, while 68 per cent felt treatment was either very likely or somewhat likely to help them with problems related to their cancer. The study found that 33 per cent of patients felt their treatment was very likely to have side-effects or complications and 22 per cent of the surveyed patients stated that doctors made decisions without their input.

“Our findings demonstrate that many patients receiving treatment for incurable cancers do not understand that it is unlikely to be curative,” according to the study’s conclusion.

“This could compromise their ability to make informed treatment decisions.”

OATP1B3

The presented research by Dr Lochrin, National Cancer Institute Centre for Cancer Research, NIH, Bethesda, US, concerned Eovist-enhanced MRI for the detection of OATP1B3 expression in prostate cancer. OATP1B3 is a hepatic uptake transporter that facilitates the diffusion of multiple substrates, including testosterone. It is expressed in several cancer types, including prostate cancer. OATP1B3 is expressed de novo in prostate cancer as compared to surrounding normal prostate tissue and is expressed more frequently and to a greater degree in prostate cancer metastases. OATP1B3-mediated testosterone uptake is greater in cells expressing certain OATP1B3 germline variants, and these variants have also been associated with poor overall survival from diagnosis, poor progression-free survival on androgen deprivation therapy, and prostate cancer-specific mortality. For the study, patients underwent Eovist-enhanced MRI and tissue biopsy. Tissue was stained for OATP1B3 by immunohistochemistry to correlate with imaging findings, and blood samples were collected for genotyping germline OATP1B3 haplotype.

A total of 24 patients were enrolled, 12 with localised prostate cancer and 12 with metastatic castration-resistant prostate cancer (mCRPC), and four patients were excluded due to poor image quality or lack of adequate tissue on biopsy. MRI imaging was obtained without complication and no side-effects were seen. Uptake of >25 per cent compared to baseline was seen in eight local cases and five mCRPC cases. Immunohistochemistry staining of biopsy tissue is pending. Initial genotyping results show 14 patients with variant haplotype, three with wild-type, and three patients’ results are pending. No correlation between genotype and Eovist uptake was seen based on initial results.

Multi-modality management

Dr O’Reilly, Mater Hospital, Dublin, presented on multi-modality management of metastatic prostate cancer. The aim of the study was to define the treatment paradigm and outcomes for patients treated for metastatic prostate cancer between 2008 and 2016 in patients from the Mater public and private hospitals. A total of 194 patients were included in the final analysis from both hospitals. The majority of patients had a prostate biopsy (81 per cent versus 19 per cent) with 85 per cent of biopsies identifying either Gleason 7, 8 or 9 disease. Almost half of patients had de novo metastatic prostate cancer (46.2 per cent) and more than two-thirds of patients had a family history of cancer (72 per cent). Rates of skeletal events (SRE) were low, at 14.9 per cent. Clinical trial accrual was “excellent”, with 17.1 per cent of patients enrolled onto a clinical trial. At the time of data cut-off, median overall survival was 40.7 months (95 per cent CI of 33-47 months). Outcomes among patients enrolled into clinical trials were superior to those not (median OS of 55.33 months versus 33.11 months, p <0.05).

“Overall survival in this patient cohort is comparable with international data,” according to the study result.

“Clinical trial accrual is associated with a significant improvement in overall survival. Finally, SRE are low, which may be a consequence of early initiation of bisphosphonate therapy.”

SCLC

The title of the presentation by Dr Mahgoub, UHL, was ‘Characterisation of DLL3, PD-L1 and c-Myc expression in patients with small cell lung cancer (SCLC)’. Tissue samples from patients diagnosed with SCLC at UHL from January 2010 to December 2016 were identified, a total of 75 formalin fixed paraffin-embedded tissue blocks. All samples were anonymised. From these, cases of non-SCLC (NSCLC) and samples lacking adequate tissue for testing were excluded. A further 19 cases were excluded during the laboratory work due to the lack of adequate tumour cells remaining, extensive crush artifact and necrosis or tissue-lifting. Sections were cut at 4µm thickness onto Leica Bond slides. Five sections were cut from the tissue blocks: One  for H&E, three for antibodies and one spare slide. Ventana (Roche) DLL3 SP347, Ventana (Roche) PD-L1 SP263 antibody and Ventana (Roche) c-Myc Y69 primary antibodies were used. Slide staining was conducted following an optimised protocol. Sixty-four specimens were evaluable for DLL3 expression. The vast majority, 86 per cent (55/64), of cases were positive and 14 per cent (9/64) were negative. A total 17 per cent (11/64) had 1-to-49 per cent positive tumour cells, and 69 per cent (44/64) had ≥50 per cent positive tumour cells. In terms of staining intensity, 11 per cent (7/64) of cases were 1+ for DLL3, 31 per cent (20/64) of cases were 2+ for DLL3, and 44 per cent (28/64) of cases were 3+ for DLL3. Fifty-nine samples were assessable for PD-L1 expression. Almost all, 95 per cent (56/59), of the cases had <1 per cent positive tumour cells, and 5 per cent (3/59) of the cases had 1-to-5 per cent positive tumour cells. There were no cases with ≥5 per cent PD-L1 expression. With regards to c-Myc, 60 cases were evaluable. Of these, 13 per cent (8/60) of cases were positive and 87 per cent (52/60) of cases were negative for c-Myc.

“DLL3 expression levels were high in our cohort and this is in keeping with internationally-published studies. The expression levels for both PD-L1 and c-Myc were low in our cohort. Low levels of PD-L1 expression were observed in several SCLC studies. On the other hand, c-Myc expression was lower in our study than in published data,” according to Dr Mahgoub.

‘Serum identification of MYC-amplification in SCLC patients using droplet digital PCR’ was the title of the study by Dr Crowley, who is based in CUH. Comprehensive genomic analyses of SCLC have reported MYC-amplification as a frequent oncogenic event in up to 30 per cent of tumours and this correlates with an aggressive tumour phenotype and markedly reduced OS, she said.

Recruitment for this study is ongoing. Newly-diagnosed or relapsed SCLC patients underwent phlebotomy of 10-15mls of blood. Clinicopathological details including tumour response to chemotherapy and progression-free and overall survival were collected. Following centrifugation, plasma from patients samples was stored at -80 degrees. Circulating tumour DNA extraction and droplet digital PCR analysis took place at the Institute for Cancer Research, London. Each droplet was analysed for presence/absence of MYC. All positive/borderline results were repeated using single-assay mix.

Currently, 19 patients have been recruited to the study. Results for the first 14 patients were presented at the ISMO event. Half of these patients were male, with a median age of 65 years old. Twelve patients (85.7 per cent) were newly-diagnosed and two were limited-stage disease patients who relapsed. Five were current smokers (35.7 per cent), with the remainder ex-smokers with a mean pack-year history of 67. The majority (85.7 per cent) of patients were ECOG 0, 1 or 2. Two patients had MYC amplified on ddPCR analysis. One patient had a borderline amplified result. Both patients with MYC-amplified ctDNA presented with superior vena cava obstruction and were both T4N3 at time of diagnosis. Both are currently undergoing chemotherapy and no radiological assessment has been performed to date.

“SCLC is a cancer with a dismal prognosis and there is a dire need to improve patients’ care,” according to the presented conclusion.

“MYC amplification may not only offer prognostic information but in the near future, may be potentially targetable with a wide variety of compounds, in addition to direct MYC inhibitors currently under development. Real-time ddPCR of ctDNA in patient plasma is an effective, cost-efficient method for serum identification of MYC amplification. Future analysis in this study will correlate these findings with clinical and radiological outcomes, in addition to increasing the cohort size.”

Breath alcohol concentration

Dr Keogh, Beaumont Hospital, spoke about her study, ‘An exploration of the impact of ethanol diluent on breath alcohol concentration (BrAC) in patients receiving paclitaxel chemotherapy’.

This was a prospective, non-interventional cohort study examining the effect of paclitaxel chemotherapy on BrAC. A total of 50 patients were recruited to participate in the study over a nine-month period. Over two-thirds were female (36, 68 per cent). Diagnoses included breast cancer (54 per cent), oesophageal cancer (30 per cent), lung cancer (12 per cent), urothelial cancer (2 per cent), and primary of unknown diagnosis (2 per cent). Ten patients in the study had metastatic disease, with four cases of confirmed hepatic metastases.

All patients recruited to the study had a duration of paclitaxel infusion of 60 minutes. The correlation between ethanol concentration in exhaled breath after 15 minutes and total dose of ethanol administered was significant (R2=.450, p=0.001). The maximum concentration of ethanol in exhaled breath (0.11 mg/L) was equivalent to 50 per cent of the threshold for drink-driving, as specified under the Road Traffic Act in Ireland.

“In this study, no patient had a breath alcohol concentration exceeding the legal threshold for drink-driving in Ireland,” it was stated.

“However, despite this, it is still essential to advise patients to avoid driving home after receiving paclitaxel infusions. If driving is unavoidable, it is necessary to counsel patients on the importance of waiting a sufficient amount of time before driving.”

Immune checkpoint inhibitors

Dr Ahmed, University Hospital Waterford (UHW), spoke about antibiotics and resistance to immune checkpoint inhibitors (ICI). The aim of this study was to evaluate the association between antibiotic use and ICI efficacy in advanced NSCLC and advanced malignant melanoma (MM).

A retrospective analysis was conducted of unselected patients with advanced NSCLC and MM treated in UHW with ICI from June 2016-June 2019. The study included consecutive patients who received at least one dose of a PD-1 inhibitor (nivolumab or pembrolizumab).

The status of any oral or intravenous antibiotic (Abx) use during the periods one month before or one month after ICI initiation was evaluated. This cohort included 89 NSCLC and 52 MM patients and their median age at the start of immunotherapy was 68 years (range 36-to-88).

Median ICI treatment duration was 2.8 months (0.1-56.4) and median number of cycles was seven (1-to-33).

Overall, 35 patients (37.5 per cent) used Abx within one month before or after the first administration of PD-1 inhibitor.

After a median follow-up of 8.5 months (0.3-56.4), a significant improvement in PFS was observed in the untreated group compared to Abx treated group: 12.4 months (95 per cent CI, 1.9-22.9) vs 4.1 months (95 per cent CI, 2.6-5.6: p<0.001).

Similarly, OS among patients with no Abx usage was significantly higher: 28.2 months (95 per cent CI, not calculated) vs 12.5 months (95 per cent CI, 10.8-14.2: p<0.001).

Oncotype DX

The title of the presentation by Dr Tharmabala, St Vincent’s University Hospital, Dublin, was ‘Influence of oncotype DX in treatment decisions and economic impact’. This retrospective, observational study evaluated the impact of oncotype Dx on decision-making and also the economic impact of testing. A total of 1,099 patients were identified for this study between October 2011-March 2019.

A total of 246 patients were 50 years old or younger at the time of diagnosis, while 709 were 51 years or older. The majority of patients (n=782) had breast-conserving surgery. The majority (750) of patients had IDC histology. Pre-oncotype chemotherapy would have been recommended for 96 per cent of such patients. With the use of oncotype Dx, this reduced to 27 per cent being recommended for chemotherapy. The financial savings in this patient cohort were also discussed.

“The use of this test has revolutionised the treatment paradigm for early-stage breast cancer,” the study concluded.

Breast cancer

Breast cancer among immigrants in Ireland was the subject of the presentation by Dr Weadick, CUH. Patients diagnosed with breast cancer and discussed in the regional breast cancer multidisciplinary team meeting from January 2018 to August 2019, were identified.

Sixty patients not born in Ireland were identified, with a median age of 43 years (range 30-to-80). Eighteen countries of origin were identified, with 22 patients originating from the UK. Eleven patients (18.3 per cent) did not speak English and required a translator, all resulting in delays throughout their treatment. Eighty patients of Irish birth were identified, with a median age of 63 years (range 31-92). There was no difference between stage at presentation; 66 per cent of the immigrant population presented with stage I or II disease, comparable to 60 per cent of the Irish population. Of those in the age range eligible for cancer screening, one patient (5 per cent) not born in Ireland was diagnosed through screening, compared with four (18.2 per cent) of the Irish population.

“These results demonstrate that although there is no difference between stage at presentation, there are factors that negatively affect the treatment of their cancer,” according to Dr Weadick.

“Despite being eligible for breast cancer screening, only 5 per cent of the immigrant population presented via this pathway. Further research is required to investigate how many of these patients were enrolled in screening programmes. Eleven patients did not speak English and required a translator; all experienced delays during their treatment plans secondary to communication failures. These figures highlight aspects of patient care that can be improved upon to improve patient safety and outcomes.”

Cannabis use in cancer

Dr Coyne, Beaumont Hospital, spoke about his study, which involved an assessment of cannabis use in Irish patients with cancer.

A total of 200 questionnaires were distributed to patients attending Beaumont’s oncology day unit, with 175 completed and returned in full.

A total of 41/175 (23.6 per cent) of the surveyed patients at some point in their life had used a form of cannabis, while 26/175 (14.9 per cent) were actively taking cannabis or cannabidiol (CBD) during their treatment (15 female, 11 male). Of these patients, 20/26 (77 per cent) believed it would cure or slow the growth of cancer, and 7/26 (26.9 per cent) believed it would help treat cancer-related symptoms. The majority of patients obtained cannabis through a friend or family member. Patients spent between €50 to over €500 in a six-month period on cannabis/cannabis products.

“A significant portion of patients are taking CBD/cannabis products as part of their treatment,” the study noted.

“Currently, there is no definitive evidence to suggest that cannabis has any anti-cancer effect or benefit on cancer-related side-effects and symptoms compared to current standards. Further study is required to understand utilisation patterns and how to incorporate these findings into patient-cantered cancer care.”

The winners of the ISMO poster presentations were as follows: Dr Mairi Lucas, Mater Hospital; Dr Rachel Clarke, Mater Hospital; Dr Ruth Kiernan, St James’s Hospital; and Dr Amyen Abbass, CUH.

The meeting’s keynote address was delivered by Dr David Solit, Medical Oncologist, Memorial Sloan Kettering Cancer Centre, US, who spoke about ‘Defining the actionable genome’.