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Pushing out the frontiers through oncology research

This year’s keynote address was delivered by Dr Eileen O’Reilly, a medical oncologist based in Memorial Sloan-Kettering Cancer Centre (MSKCC) in New York. Dr O’Reilly, an Irish native and graduate of Trinity College, is Associate Director for Clinical Research, David M Rubenstein Centre for Pancreatic Cancer in Memorial Sloan-Kettering.

Dr O’Reilly is the Principal Investigator of multiple phase 1, 2 and 3 trials in pancreatic cancer and has authored/co-authored numerous articles, editorials and book chapters. Her major research focus and clinical activities include pancreatic and hepatobiliary malignancies, and her research initiatives include integration of molecular and genetic-based therapies for the treatment of pancreatic cancer, along with development of adjuvant and neoadjuvant therapies and identification of biomarkers that may be used to select therapy. Her talk for the meeting was titled ‘New therapeutic directions in pancreas adenocarcinoma’.

Front-line therapies

Dr O’Reilly said newly-diagnosed patients with good functional status are typically treated with cytotoxic regimens. The two active front-line regimens are FOLFIRINOX and gemcitabine/nab-paclitaxel.

Dr O’Reilly said that clinical trial data on FOLFIRINOX, which consists of five chemotherapy agents, was a significant breakthrough in the treatment of the disease. The trial showed a median overall survival of 11.1 months was obtained for patients with metastatic pancreatic cancer on the FOLFIRINOX arm.

“These data were practice-changing for pancreas cancer and reinvigorated the field, showing that there is room for manoeuvre in this disease,” Dr O’Reilly told attendees. “It is probably the biggest single survival impact that has been [seen] with any regimen, in any state, in pancreas cancer.”

However, Dr O’Reilly said that as FOLFIRINOX is associated with toxicity burdens, patients should be selected judiciously for the regimen.

She then spoke about data from the MACT trial assessing gemcitabine/nab-paclitaxel, which consisted of a broader performance status group and was not limited by age, unlike the FOLFIRINOX population, during its trial. The trial found the regimen was associated with a median overall survival of eight-and-a-half months.

“It is a little bit less than FOLFIRINOX, but if you take similar groups of people who have similar disease patterns, similar performance status with metastatic pancreas cancer and give them either one of these regimens, they would probably do pretty similarly,” according to Dr O’Reilly.

She said gemcitabine/nab-paclitaxel was probably now used a “little more widely” than FOLFIRINOX, partially because it applies to a broader base of patients and it is potentially easier to add novel agents to the regimen than with FOLFIRINOX.

Dr O’Reilly stressed there is no clear data as to which is the best regimen and that work was ongoing to provide guidance in this regard.

She posed the question as to why pancreatic cancer was so hard to treat. She suggested it was because of the “hostile hypervascular environment” consisting of a strong stromal component. A lack of immune cells and targetable suppressor genes (although there are some promising areas of research) are other impediments to developing new treatments.

PEGPH20

Speaking specifically about the microenvironment, Dr O’Reilly said one of the features of the stroma is a high level of hyaluronan, which is a glycosaminoglycan, which impedes drug delivery. She said an enzyme called PEGPH20, which is pegylated for delivery over time, has been shown to deplete hyaluronan, to alter interstitial pressure and to improve drug delivery. A recent randomised, phase 2, controlled trial looked at the addition of PEGPH20 in an unblinded fashion, combined with gemcitabine and nab-paclitaxel in untreated metastatic pancreatic cancer and examined progression-free survival and outcome by hyaluronan level. 

Data from the trial presented in 2015 showed benefits for patients with a high level of hyaluronan being treated with the three-drug combination compared with gemcitabine/nab-paclitaxel on its own.

Dr O’Reilly said these benefits came at the expense of higher levels of thrombotic events in the pegylated enzyme group, resulting in a low-molecular-weight heparin prophylactic strategy, which reduced negative events. The full results of the trial are due to be presented at this year’s American Society of Clinical Oncology (ASCO) meeting.

It has led to another randomised phase 2 trial examining FOLFIRINOX used with and without PEGPH20, as well as a phase 3 trial examining gemcitabine and nab-paclitaxel with and without PEGPH20. The latter trial is essentially mimicking the completed phase 2 trial, but exclusively uses biomarker-positive patients with high levels of hyaluronan.

“That [PEGPH20] is probably the single most promising agent that I would say in terms of novel drugs that is in the clinic at the moment,” according to Dr O’Reilly.

Genetics

The next topic Dr O’Reilly moved on to was genetics. She stated that between 7-to-15 per cent of pancreatic cancer, maybe higher, will arise due to genetics.

“It is not something that is routinely looked for but we think this is a way we need to go, not just for the individual from the treatment perspective but maybe the bigger implication that family might be at risk, not just of pancreas cancer, but of other disease,” said Dr O’Reilly.

She described the MSK-IMPACT [Integrated Molecular Profiling Actionable Cancer Targets] next-generation sequencing system.

In its first iteration, initiated in January 2014, MSK-IMPACT included full exon coverage of 341 genes, in addition to select intronic regions to enable detection of actionable fusions. Since February 2015, a second iteration of MSK-IMPACT was implemented, expanding coverage to a total of 410 genes. The system analyses not only somatic gene mutations, but germline (inherited) mutations also. Dr O’Reilly said screening for the latter type of mutations already holds promise in the area of pancreatic cancer.

“This is a novel way of doing genetic testing,” Dr O’Reilly said.

“What we do is, for each new patient who comes into the clinic, we will discuss with them whether they are interested in learning whether there might be an underlying predisposition, talking about the implication for them and their family. We walk them through this and have them watch a short video to augment their understanding of what they are consenting to because, as you well know, these are complex topics.”

One area of particular promise is germline BRCA and pancreatic cancer. It is estimated that of an unselected patient population with pancreatic cancer, between 5-to-7 per cent will have an underlying BRCA1 or BRCA2 mutation. The mutations are statistically more common in people with Ashkenazi heritage, where presence of BRCA 1 or 2 may be nearer to 5-to-16 per cent.

In patients with familial pancreatic cancer, defined as families with two or more first-degree relatives of pancreatic cancer, BRCA 1 or 2 is present at 5-to-19 per cent, while in families with a history of breast and ovarian cancer, 5-to-10 per cent carry the BRCA 1 or 2 mutation. In the Ashkenazi setting, the three common mutations are the two founder mutations of BRCA1 and the one founder mutation in BRCA2.

People who carry a germline BRCA mutation who go on to develop pancreatic cancer are diagnosed about 10 years younger than the average.

The average age of diagnosis for sporadic pancreas cancers is in the early 70s, while for BRCA-related pancreatic cancer, average age of diagnosis is in the early 60s.

Dr O’Reilly said BRCA-deficient cells lack homologous repair abilities and use alternative pathways to repair DNA damage. These alternative pathways are highly unstable and lead to apoptosis, cell death and chromosomal damage.

She discussed research examining the addition of a PARP inhibitor, which prevents cancer cells from repairing their damaged DNA, to platinum-based therapy.

Immunotherapy

Finally, Dr O’Reilly talked about immunotherapy and pancreatic cancer. She said the area was challenging, not just for pancreatic cancer but also other GI cancers. “So what are the problems in pancreas cancer?” she asked. “Part of it is the environment of this disease, part of it is that the immune environment is very negatively predisposed to respond, so there are some immune cells involved but they tend not to be optimal effector immune cells. A number of the strategies are trying to see if you can get more T cells into the tumour and get the right T cells into the tumour.”

A number of studies are currently evaluating the potential of immune therapy in pancreatic cancer, with Dr O’Reilly adding that combination approaches appear key.

“We need better biomarkers for potential response in pancreas cancer and combination approaches are the current way to go; for a small number, there may be a delayed response potential,” Dr O’Reilly stated.

Awards

At the end of the meeting, the ISMO Fellowship and Bursary Awards were announced. The MSKCC Fellowship winner was Dr Niamh Keegan of Beaumont Hospital, Dublin.

The bursary winners were: Dr Megan Greally, Mater Misericordiae University Hospital, Dublin; Dr Hazel O’Sullivan, St James’s Hospital, Dublin; Dr Caitriona Healy, Mercy University Hospital, Cork;  Dr Niamh Fitzgerald, St James’s Hospital; Dr Niamh Peters, St James’s Hospital; Dr Michael McCarthy, University Hospital Limerick; Dr Rachel Kearns, Cork University Hospital; Dr Ciara McNevin, Beaumont Hospital; Dr Dara Clarke, Mater Misericordiae University Hospital; Dr Caitriona Goggin, Cork University Hospital; Dr Amanda Lavan, Cork University Hospital; Dr Fergus Keane, Mater Misericordiae University Hospital; Dr Jack Gleeson, Beaumont Hospital; and Dr Jane Sui, Cork University Hospital. The findings of five of these studies are discussed below.

Dr Greally delivered her presentation on a contemporary multi-modal management for colorectal cancer (CRC). A retrospective review of the clinical, radiological and histological records was performed for consecutive patients with CRC who were referred for input from the tertiary multidisciplinary colorectal cancer team for the period 2012-2016. Patients with stage I and II disease were excluded from analysis unless they were referred for adjuvant systemic therapy for high-risk features.

The researchers identified 325 patients, of whom the median age was 65 years (24-to-97 years). Elderly patients (>69 years) accounted for 30 per cent of the cohort (n=98). The commonest primary site was the rectum, accounting for 37.8 per cent (n=122), followed by sigmoid, 22.6 per cent (n=73) and caecal tumours, 13.6 per cent (n=44). Left-sided tumours occurred in 73.4 per cent (n=237) of patients and 24.5 per cent (n=79) had right-sided disease.

A total of 223 (68.5 per cent) had stage II or III disease at diagnosis. Of those, 86 patients relapsed (38.6 per cent). The median disease-free interval (DFI) was 14 months. Elevated platelet count, C-reactive protein, lymphovascular space invasion and peri-neural invasion positivity were all associated with a higher risk of relapse. De novo metastatic disease occurred in 31 per cent (n=102). Of all patients with stage IV disease, 23.9 per cent (n=45) are currently disease-free, having undergone curative intent surgery.

Median overall survival (OS) for all patients with stage IV disease was 42 months. Median survival was 32 months for right-sided tumours and 46 months for left-sided (p=0.59).

Regarding RAS status, OS for RAS wild type (WT) patients was not reached (NR), 36 months for KRAS WT patients and 31 months for RAS mutant patients.

Data pertaining to surgical management in stage IV disease was available for 181 patients; 61.8 per cent (n=112) had metastasectomies and median OS for this group was 94 months versus 16 months for patients who did not undergo surgery. When patients referred from other institutions are excluded, 42.5 per cent (n=92) underwent metastasectomy, with a median OS of 50 months vs 14 months for those who did not undergo surgery (p<0.001).

The study found increasing lines of therapy were positively associated with survival. Patients who received no systemic therapy had a median OS of six months vs 25 months for two lines of therapy. Median OS was NR for those who received four lines of therapy. Median OS for those receiving pseudoadjuvant chemotherapy after resection of metastatic disease was 50 months.

“This ‘real world’ data shows overall survival to be improving, due in large part to enhanced multidisciplinary care, better access to surgical interventions, sequencing of chemotherapeutic and targeted therapies and aggressive use of salvage surgery following recurrences,” according to the authors.

“Our findings provide support for the long-term benefit of surgical metastasectomy for stage IV disease, when feasible.”

Dr Healy’s study was titled ‘An Irish regional cancer centre experience of impact of incidental pulmonary nodules detected during treatment for early-stage breast cancer’.

For the study, a retrospective review of breast multidisciplinary referrals for neoadjuvant or adjuvant chemotherapy from 2009-2015 in Cork University Hospital was undertaken. 

A total 937 patients were referred to medical oncology. A total of 322 patients had staging thoracic imaging. Of these, 75 patients (23 per cent) had an incidental pulmonary nodule/nodules. Also, 20 patients did not have follow-up thoracic imaging but continued on clinical follow-up and are alive and well and followed in the adjuvant setting.  Some 38 patients had imaging surveillance of pulmonary nodules, which ultimately resolved or displayed stability over time. Ten patients developed metastatic disease, of whom four patients developed pulmonary metastatic disease. A total of three patients had newly-detected primary malignancy (one thyroid, two lung). Some four patients are having ongoing radiological surveillance.  The average number of follow-up scans was 1.6 scans per patient.

The study ultimately found that 5.3 per cent (n=4) of breast cancer patients who had pulmonary nodules detected upon routine staging ultimately developed pulmonary metastatic disease. Follow-up surveillance of pulmonary nodules was variable.

The vast majority of pulmonary nodules detected were benign. “This results in significant burden on the radiology department, as well as increased anxiety for the patient. In clinical practice, a standardised, multidisciplinary algorithm should be applied to ensure appropriate follow-up of pulmonary nodules in this specific cohort,” the authors stated.

Dr Clarke presented on an interesting case of a radiation-induced osteosarcoma against a background of Hodgkin’s disease. A 28-year-old Irish male was originally treated for a IIA classical Hodgkin’s lymphoma (cHL) in 2009 with ABVD x4 followed by mediastinal radiotherapy. He remained clinically and radiologically in remission from a lymphoma perspective. He subsequently developed progressive cervical pain from early 2016. He ultimately experienced a rapid deterioration and proceeded to MRI followed by emergent admission under neurospinal surgery. He had developed an extensively destructive lesion of C6 with vertebral instability, though he remained neurologically intact. Surgical stabilisation and open biopsy were performed, which demonstrated a high-grade osteosarcoma. Given his prior radiation field, this was determined to be a radiation-induced sarcoma. CT-staging demonstrated no evidence of metastatic disease. He was then commenced on induction chemotherapy with adriamycin/cisplatin (AC), alternating with high-dose methotrexate (HDMTX).

He achieved two cycles each of AC and HDMTX total adriamycin dose: 350mg/m2. The treatment course was complicated by neutropaenic port sepsis followed by a further septic episode (source not identified) with non-oliguric acute kidney injury requiring ICU admission but no haemodynamic supports or ventilation. CT restaging at end of neoadjuvant therapy demonstrated no evidence of metastases, with possible shrinkage of the primary. He has re-attended neurospinal surgery with a view to curative resection of the primary. He has remained generally well and neurologically intact to this point.

“Final decision regarding surgical candidacy and treatment plan from this point is outstanding,” according to the study.

Dr McCarthy delivered a presentation on ‘Outcomes in advanced renal cell cancer: A retrospective case series analysis’.

For the study, researchers performed a retrospective analysis of individuals diagnosed with advanced (unresectable/stage IV) RCC at University Hospital Limerick between 2008 and 2015. Anonymised data was extracted from electronic health records and analysed. Survival analysis, including Cox proportional hazards ratios and Kaplan-Meier curves, were then generated.

Overall, a total of 66 patients were identified. A total of 35 (53 per cent) received treatment and were included in the analysis. The ratio of men-to-women was approximately 2:1. The study showed 75 per cent of individuals were aged over 60 years at presentation. The most common site of haematogenous metastasis was lung, followed by bone and liver. Pazopanib (52 per cent) and sunitinib (48 per cent) were the commonest choices for first-line treatment. Forty-four per cent (15) of patients received more than one line of treatment. The median overall survival was 22.0 months.

There was no significant difference in survival between treatment in the first line with pazopanib and sunitinib (22.0 months versus 18.9 months, HR 1.27 95 per cent CI: 0.51-3.18; p=0.61). Individuals treated with nephrectomy had a longer median overall survival than those with no nephrectomy, although this difference was not statistically significant (22.3 months versus 12.4 months, HR 0.57 95 per cent CI: 0.25-1.31; p=0.186).

“While the median overall survival in our analysis (22.0 months) is lower than that reported in current clinical trials, our population included individuals with worse performance status,” according to the study.

“Pazopanib and sunitinib are equally effective first-line treatment options. The trend towards improved survival in patients treated with cytoreductive nephrectomy (although not statistically significant) is in keeping with published retrospective analyses.”

Dr Peters discussed a study investigating familial oesophageal cancer over a decade in Ireland. The independent records of two national referral services were reviewed: An oesophageal surgery database and a hereditary cancer genetics database.

A total of 1,238 patients with oesophageal cancer were seen at St James’s Hospital from 2005 to 2015, with some 641 patients (51 per cent) having a family history of malignancy. A total of 78 (6.3 per cent) reported a family history of oesophageal cancer, six (7.6 per cent) of whom had two or more first-degree relatives with oesophageal cancer and 10 (13 per cent) had both a first-degree and second-degree relative with oesophageal cancer. More male relatives were diagnosed with oesophageal cancer than female (59 per cent versus 41 per cent). The majority (24 per cent) with a family history were diagnosed at stage III; the majority (29 per cent) without a family history were diagnosed at stage II. Also 1,840 pedigrees from the genetic database were reviewed. No pedigree contained a proband with oesophageal cancer and 4.5 per cent (n=84) included at least one family member with oesophageal cancer. The median age at diagnosis was 64 years. Breast, colorectal and gastric were the most commonly associated cancers with median ages of 50, 59 and 64 years, respectively.

“More than half of patients presenting with oesophageal cancer report a family history of cancer, with likely hereditary and environmental components,” according to the study.

“Oesophageal cancer patients are rarely referred for genetic assessment, possibly due to treatment-related morbidity and poor clinical outcome.”

Speaking to the Medical Independent (MI), Consultant Oncologist in the Mater Misericordiae University Hospital and ISMO Meeting Co-ordinator, Prof John McCaffrey, said that this year’s meeting was “probably the best one yet”.

“The meeting has been going since 2005; we have had more presentations of the highest calibre this year than any other year that I can remember.”

Consultant Oncologist in Cork University Hospital and ISMO President, Dr Deirdre O’Mahony, agreed that the studies presented at this year’s meeting were of a very high standard.

“The calibre of the presentations was amazing,” Dr O’Mahony told MI. “We saw people at every level; we saw interns, SHOs, registrars, not only people who were established in their oncology career. I think it is a great opportunity for people to get exposure, not only through their presentations, but also through the greater oncology experience.”

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