Search

Background Cisplatin/gemcitabine is standard first-line treatment for patients with advanced biliary tract cancer (ABC). NUC-1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites. Methods Patients with untreated ABC, Eastern Cooperative Oncology Group performance status 0–1 received NUC-1031 (625 or 725 mg/m2) and cisplatin (25 mg/m2) on days 1 and 8, every 21 days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression-free survival (PFS), and overall survival (OS). Results Twenty-one patients (median age 61 years, n = 13 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC-1031 625 mg/m2 (n = 8 and expansion n = 7; median six cycles) or 725 mg/m2 (n = 6; median 7.5 cycles). Treatment was well tolerated; most common treatment-emergent grade 3–4 adverse events occurring in more than one patient with 625 mg/m2 NUC-1031 were increased gamma-glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg/m2, increased GGT, 67%, and fatigue, 33%. NUC-1031 725 mg/m2 was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3–10.1), and median OS was 9.6 months (95% CI, 6.7–13.1). The median estimates of area under the plasma concentration–time curve from time 0 to last measurable time and maximum concentration were highest for NUC-1031 (218–324 μg•h/mL and 309–889 μg/mL, respectively) and lowest for di-fluoro-deoxycytidine (0.47–1.56 μg•h/mL and 0.284–0.522 μg/mL, respectively). Conclusion This is the first study reporting on the combination of NUC-1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg/m2 NUC-1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: NCT02351765; EudraCT ID: 2015-000100-26). Implications for Practice The prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin/gemcitabine combination is standard first-line treatment for patients with ABC. NUC-1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC-08) demonstrated a favorable safety profile of NUC-1031 in combination with cisplatin for the first-line treatment of patients with ABC, and 725 mg/m2 NUC-1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling.

293 Background: NET-02 was a multi-centre, randomised (1:1), non-comparative phase II trial of nal-IRI/5-FU/folinic acid (ARM A) or docetaxel (ARM B) in pts with progressive PD-EP-NEC, aimed at selecting a treatment for evaluation in a phase III trial. Primary analysis (N = 58) showed ARM A, but not ARM B, achieved the target 6-month progression-free survival rate primary endpoint (McNamara et al. ASCO 2022). HRQoL was a secondary endpoint in NET-02. Methods: HRQoL was assessed using the EORTC QLQ-C30 and GINET21 (at baseline (BL), 6-weekly intervals and at disease progression). The mean change from BL was estimated for each scale by timepoint and treatment arm. Results are presented where there were ≥4 responses per time point. Scores were considered stable if they did not change by > 10 points from BL. The mean BL C30 scores for all pts were compared to United Kingdom (UK) population normative C30 data using a 2-sample t-test. Results: Fifty-four of 58 pts (93%) completed a BL questionnaire; of these, 39 (72%) completed ≥1 post-BL questionnaire, with 21 (51%) completing questionnaires at progression. Global health status (GHS) and all functional scales in ARM A remained stable from BL to intervals pre-progression, with a sustained improvement in role functioning observed post-BL. In ARM B, GHS and all C30 functional scales decreased by > 10 points between BL and week 18 (worsening of QoL). Both arms had a > 10-point increase from BL in constipation and diarrhoea in ≥1 post-BL time point. In ARM A, pain, insomnia and financial problems decreased from BL. No C30 symptom scales in ARM B were consistently lower post-BL. Patterns of change in GINET21 mean score were similar in both arms: body image, disease-related worries, information/communication, sexual function and social function all had a > 10-point reduction in score from BL (indicating improvement in symptoms/problems); endocrine and gastrointestinal symptoms remained stable; muscle/bone pain varied across time points, initially showing a reduction in pain followed by an increase, compared to BL. In comparison to the UK C30 norms (BL all pts), 11 of 15 C30 scales did not significantly differ (P > 0.05). Mean scores for fatigue and appetite loss were significantly higher than UK C30 norms (worse symptoms in pts from NET-02) (P = 0.03, P = 0.0003 respectively). However, emotional functioning and GHS were significantly better in pts from NET-02 (P = 0.001, P = 0.03 respectively). Role and social functioning were lower in pts from NET-02 (both P = 0.06) (poorer level of functioning). Conclusions: HRQoL was maintained and potentially improved with nal-IRI/5-FU/folinic acid, but not docetaxel. Compared to the UK general population, BL QoL did not substantially differ in pts from NET-02. Clinical trial information: NCT03837977.

Background/Aims: To assess health-related quality of life (HRQoL), treatment patterns, and clinical outcomes of adult (≥18 years) patients with advanced (unresectable or metastatic) pancreatic neuroendocrine neoplasms (PanNENs) treated with everolimus in routine clinical practice. Methods: In a prospective, non-interventional, multi-center study patients administered at least one 10 mg dose of everolimus were evaluated for change in HRQoL (EORTC QLQ-C30 Global Health Status scale) from baseline after 6 months treatment (primary endpoint). Secondary endpoints included disease-specific HRQoL measures (EORTC QLQ-G.I.NET21), clinical outcomes, everolimus treatment patterns, and safety. Results: Forty-eight patients were recruited (between August 2013 and March 2015); the median treatment duration was 27.8 months. EORTC QLQ-C30 Global Health score was not significantly different from baseline after 6 months of treatment (mean difference –1.9 points, p = 0.660, n = 30). In pairwise analyses, the only significant changes in HRQoL from baseline were for EORTC QLQ-C30 physical functioning score at month 3 (adjusted mean difference –8.8 points, p = 0.002, n = 36) and the EORTC QLQ-G.I.NET21 disease-related worries scores at months 1 and 2 (adjusted mean differences: –11.5 points [p = 0.001, n = 44] and –8.8 points [p = 0.017, n = 43], respectively). Disease progression or death was recorded in 44.4% (n = 20/45) patients during follow-up; median progression-free survival was 25.1 months and the cumulative survival rate at 3 years was 71%. No new safety signals were detected. Conclusions: The OBLIQUE study demonstrates that HRQoL is maintained in patients with PanNENs during treatment with everolimus in a UK real-world setting. This study adds to the limited HRQoL data available in this patient group.

IntroductionPoorly differentiated (PD), extrapulmonary (EP), neuroendocrine carcinomas (NECs) are rare but aggressive neuroendocrine neoplasms. First-line treatment for advanced disease is an etoposide and platinum-based chemotherapy combination. There is no established second-line treatment for patients with PD-EP-NEC, and this is an area of unmet need.Methods and analysisNET-02 is a UK, multicentre, randomised (1:1), parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive PD-EP-NEC. One hundred and two eligible participants will be randomised to receive either nal-IRI/5-FU/folinic acid or docetaxel. The primary objective is to determine the 6-month progression-free survival (PFS) rate. The secondary objectives of this study are to determine PFS, overall survival, objective response rate, toxicity, quality of life and whether neuron-specific enolase is predictive of treatment response. If either treatment is found to have a 6-month PFS rate of at least 25%, that treatment will be considered for a phase III trial. If both treatments meet this target, prespecified selection criteria will be applied to establish which treatment to take forward.Ethics and disseminationThis study has ethical approval from the Greater Manchester Central Research Ethics Committee (reference no. 18/NW/0031) and clinical trial authorisation from the Medicine and Healthcare Products Regulatory Agency. Results will be published in peer-reviewed journals and uploaded to the European Union Clinical Trials Register.Trial registration numbersISRCTN10996604,NCT03837977, EudraCT Number: 2017-002453-11

// Grzegorz J. Korpanty 1, 2, * , Lawson Eng 1, * , Xin Qiu 3, * , Olusola Olusesan Faluyi 1 , Daniel J. Renouf 4 , Dangxiao Cheng 5 , Devalben Patel 5 , Zhuo Chen 5 , Brandon C. Tse 5 , Jennifer J. Knox 1 , Lorin Dodbiba 1 , Jennifer Teichman 1 , Abul Kalam Azad 1 , Rebecca Wong 6 , Gail Darling 7 , David Reisman 8 , Sinead Cuffe 1, # , Geoffrey Liu 1, 5, 9, # , Wei Xu 3, # 1 Princess Margaret Cancer Centre, Department of Medicine, University Health Network, Toronto, ON, Canada 2 Canadian Cancer Trials Group, Department of Medicine, Queens University, Kingston, ON, Canada 3 Princess Margaret Cancer Centre, Department of Biostatistics, University Health Network, Toronto, ON, Canada 4 Department of Medical Oncology, University of British Columbia and British Columbia Cancer Agency, Vancouver, BC, Canada 5 Princess Margaret Cancer Centre, Department of Medical Biophysics, University Health Network, Toronto, ON, Canada 6 Princess Margaret Cancer Centre, Radiation Medicine Program, University Health Network, Toronto, ON, Canada 7 Department of Surgery, Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, ON, Canada 8 Department of Medicine in the College of Medicine, Division of Hematology and Oncology, University of Florida, Gainesville, FL, USA 9 Department of Epidemiology, Dalla Lana School of Pubic Health, Toronto, ON, Canada * Co-first authors # Co-senior authors Correspondence to: Geoffrey Liu, email: Geoffrey.Liu@uhn.on.ca Keywords: chromatin remodeling, polymorphism, cancer prognosis, esophageal cancer, brahma Received: October 20, 2016 Accepted: February 22, 2017 Published: March 03, 2017 ABSTRACT Purpose: Brahma (BRM) is a critical catalytic subunit of the SWI/SNF chromatin remodeling complex; expression of BRM is commonly lost in various cancer types. BRM promoter polymorphisms (BRM-741; BRM-1321) are associated with loss of BRM expression, and with cancer risk/survival. We evaluated these two polymorphisms in the overall survival (OS) of esophageal adenocarcinoma (EAC) patients. Results: Of 270 patients, 37% were stage IV. Minor allele frequencies were 47−49%; 15% were double-homozygotes. When compared to the wild-type genotype, the homozygous variant of BRM-741 carried an adjusted OS hazard ratio (aHR) of 1.64 (95% CI:1.1−2.4); for BRM-1321, the aHR was 2.09 (95% CI:1.4−3.0). Compared to the double wild-type, carrying homozygous variants of both promoter polymorphisms (double-homozygote) yielded an aHR of 2.21 (95% CI:1.4−3.6). Directions/magnitudes of associations were similar in subsets by age, gender, smoking status, use of platinum agents, and disease stage, and for progression-free survival. Materials and Methods: In a cohort of EAC patients of all stages (84% male; median age of 64 years), two BRM polymorphisms were genotyped. Cox proportional hazards models, adjusted for known prognostic variables, estimated the association of polymorphisms with OS. Conclusions: BRM polymorphisms were associated with OS in EAC in this study. Validation studies are warranted.

Background: Previous observations suggest suboptimal ‘real world’ survival outcomes for advanced pancreatic adenocarcinoma. We hypothesized that centralisation of advanced pancreatic adenocarcinoma management would improve chemotherapy treatment and survival from the disease. Methods: The data was prospectively collected on all cases of advanced pancreatic adenocarcinoma reviewed through Clatterbridge Cancer Centre according to two groups; 1 October 2009–31st Dec 2010 (devolved care) or 1 January 2013–31 March 2014 (centralised care). Analysis included treatment received, 30-day chemotherapy mortality rate and overall survival (OS). Results: More patients received chemotherapy with central care (67.0% (n=115) vs 43.0% (n=121); P=2.2 × 10−4) with no difference in 30-day mortality (20.8% vs 25%; P=0.573) but reduced time to commencement of chemotherapy (18 vs 28 days, P=1.0 × 10−3). More patients received second-line chemotherapy with central care (23.4% vs 1.9%, P=1.4 × 10−4), while OS was significantly increased with central care (median: Five vs three months, HR 0.785, P=0.045). Exploratory analysis suggested that it was those with a poorer performance status, elderly or with metastatic disease who benefited the most from transition to central care. Conclusions: A centralised clinic model for advanced pancreatic cancer management resulted in prompt, safe and higher use of chemotherapy compared with devolved care. This was associated with a modest survival benefit. Prospective studies are required to validate the findings reported and the basis for improved survival with centralised care.

Polymorphisms in miRNA and miRNA pathway genes have been previously associated with cancer risk and outcome, but have not been studied in esophageal adenocarcinoma outcomes. Here, we evaluate candidate miRNA pathway polymorphisms in esophageal adenocarcinoma prognosis and attempt to validate them in an independent cohort of esophageal adenocarcinoma patients. Among 231 esophageal adenocarcinoma patients of all stages/treatment plans, 38 candidate genetic polymorphisms (17 biogenesis, 9 miRNA targets, 5 pri‐miRNA, 7 pre‐miRNA) were genotyped and analyzed. Cox proportional hazard models adjusted for sociodemographic and clinicopathological covariates helped assess the association of genetic polymorphisms with overall survival (OS) and progression‐free survival (PFS). Significantly associated polymorphisms were then evaluated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months, respectively. GEMIN3 rs197412 (aHR = 1.37, 95%CI: [1.04–1.80]; P = 0.02), hsa‐mir‐124‐1 rs531564 (aHR = 0.60, 95% CI: [0.53–0.90]; P = 0.05), and KIAA0423 rs1053667 (aHR = 0.51, 95% CI: [0.28–0.96]; P = 0.04) were found associated with OS. Furthermore, GEMIN3 rs197412 (aHR = 1.33, 95% CI: [1.03–1.74]; P = 0.03) and KRT81 rs3660 (aHR = 1.29, 95% CI: [1.01–1.64]; P = 0.04) were found associated with PFS. Although none of these polymorphisms were significant in the second cohort, hsa‐mir‐124‐1 rs531564 and KIAA0423 rs1053667 had trends in the same direction; when both cohorts were combined together, GEMIN3 rs197412, hsa‐mir‐124‐1 rs531564, and KIAA0423 rs1053667 remained significantly associated with OS. We demonstrate the association of multiple miRNA pathway polymorphisms with esophageal adenocarcinoma prognosis in a discovery cohort of patients, which did not validate in a separate cohort but had consistent associations in the pooled cohort. Larger studies are required to confirm/validate the prognostic value of these polymorphisms in esophageal adenocarcinoma.

499 Background: Regorafenib was the first treatment to demonstrate a survival benefit in patients with HCC after progression on sorafenib. The RESORCE trial found that regorafenib improved overall survival with acceptable toxicity, in patients with disease progression on sorafenib who tolerated ≥400mg sorafenib daily and had Child-Pugh A liver function. Methods: We performed a multicentre, retrospective, observational study of patients with HCC receiving regorafenib in the UK, following its availability in April 2018. Results: Data on a total of 104 patients were included from April 2018–August 2019, and 80.8% were male. Age was collected in 85 patients, with a median of 68 years (range 22–86). 23.5% had NAFLD, 21.2% had ALD, 12.9% had HBV, and 3.5% had HCV. Prior management included sorafenib (100%), TACE (30.8%), resection (12.9%). Duration of sorafenib treatment was evaluable in 99/104 patients, and reported a median of 8.7 months (range 1.8–76.6). Duration of regorafenib treatment was evaluable in 92/104 patients, and reported a median of 3.9 months (range 0.0–15.7). Following treatment with regorafenib, 6 patients (5.8%) achieved partial response, 37 (35.6%) achieved stable disease and 45 (43.3%) had progressive disease as the best response. 15 (14.4%) were not assessed and 1 (1.1%) had mixed response. Survival data is immature with 62/101 (61.4%) patients alive at the time of census with median survival currently 6.5 months. Fatigue was the most frequent AE, with 69/88 patients (85.2%) for all grades. 12/88 patients (14.8%) had Grade 3 fatigue. Other significant AEs include hand-foot syndrome (6/85 patients [7.3%] had Grade 3) and diarrhoea (4/83 patients [4.9%] had Grade 3). Conclusions: The population in our real-world experience of regorafenib for HCC had a similar duration of prior sorafenib to those in the RESORCE trial. However, there was different balance of aetiologies with a lower proportion of patients with HBV and HCV. The rate of partial response is similar to the RESORCE trial with fewer patients achieving stable disease. The incidence of fatigue was higher, but the incidence of hand-foot syndrome and diarrhoea were lower. Further expansion and follow-up of this population is warranted.

Cholangiocarcinoma which is often diagnosed late due to non-specific clinical presentation is the most common biliary tract malignancy. In general, accurate staging is crucial to identifying patients with early disease who may be amenable to surgery with curative intent or locally advanced disease for which locoregional treatment approaches may be relevant. Furthermore, accurate diagnosis is crucial to guiding systemic treatment in the adjuvant or palliative setting. Findings on detailed radiological examination with CT and/or MRI could be suggestive of the diagnosis and sufficient for staging, while laparoscopy is at times necessary to exclude intra-abdominal metastases. However, the role of PET requires further evaluation. Invasive techniques such as ERCP, SpyGlass endoscopy and PTC have been found useful for biliary tract evaluation and for therapeutic relief of biliary tract obstruction. These biliary intervention techniques and EUS-FNA have also been found useful for obtaining a confirmatory histological diagnosis. This chapter subsequently discusses the diagnosis and staging of cholangiocarcinoma in some detail with some future perspective.

Esophageal cancer and its treatment can cause serious morbidity/toxicity. These effects on health-related quality of life (HRQOL) can be measured using disease-specific scales such as FACT-E, generic scales such as EQ-5D-3L, or through symptoms. In a two-year cross-sectional study, we compared HRQOL across esophageal cancer patients treated in an ambulatory clinic and across multiple disease states, among patients with all stages of esophageal cancer. Consenting patients completed FACT-E, EQ-5D, a visual analog scale, and patient reported (PR)-ECOG. Symptom complexes were constructed from FACT-E domains. Responses were categorized by disease state: pre-, during, and post-treatment, surveillance, progression, and palliative chemotherapy. Spearman correlation and multivariable linear regression characterized these associations. In total, 199 patients completed 317 questionnaires. Mean FACT-E and subscale scores dropped from baseline through treatment and recovered during post-treatment surveillance (P < 0.001); EQ-5D health utility scores (HUS) displayed a similar pattern but with smaller differences (P = 0.07), and with evidence of ceiling effect. Among patients with stage II/III esophageal cancer, mean EQ-5D HUS varied across disease states (P < 0.001), along with FACT-E and subscales (P < 0.001). Among patients with advanced disease, there was no significant difference between baseline and on-treatment total scores, but improved esophageal cancer-specific scales were noted (P = 0.003). Strong correlation was observed between EQ-5D and FACT-E (R = 0.73), along with physical and functional subscales. In addition, the association between FACT-E and EQ-5D HUS was maintained in a multivariable model (P < 0.001). We interpret these results to suggest that in a real-world clinic setting, FACT-E, EQ-5D HUS, and symptoms were strongly correlated. Most HRQOL and symptom parameters suggested that patients had worse HRQOL and symptoms during curative therapy, but recovered well afterwards. In contrast, palliative chemotherapy had a neutral to positive impact on HRQOL/symptoms when compared to their baseline pre-treatment state.

Polymorphisms in the vascular endothelial growth factor (VEGF)/angiogenesis pathway have been implicated previously in cancer risk, prognosis and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP (single nucleotide polymorphism) approach to identify new VEGF pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA and 33 FLT1) selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis and median OS and PFS were 20 and 12 months, respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio, aHR = 0.69, 95% confidence interval (CI): 0.53-0.90; P = 5.9E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR = 1.44, 95% CI: 1.04-1.99; P = 0.03 and aHR = 1.50, 95% CI: 1.01-2.24; P = 0.045, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR = 1.59, 95% CI: 1.04-2.44; P = 0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma, whereby each variant allele confers a 45-60% increased risk of mortality. Validation and evaluation of this association in other cancer sites are warranted.

Background No prognostic classification is currently used for patients treated with systemic therapies for Hepatocellular Carcinoma (HCC). Methods We retrospectively analysed data from patients treated with sorafenib for HCC from five centres in France and in the United Kingdom (UK). The training set comprised data from two centres and the validation set from three. Variables independently associated with Overall Survival (OS) in the training set were used to build the SAP (Sorafenib Advanced HCC Prognosis) score. The score was tested in the validation set, then compared with other prognostication systems. Results The training set and validation set included 370 and 468 patients respectively. In the training set, variables independently associated with OS in multivariable analysis were: performance status (PS) >0, alpha-fetoprotein (AFP) >400 ng/ml, tumour size >7 cm, bilirubin >17 μmol/l and albumin

TPS4158 Background: The prognosis for pts with PD-EP-NEC is poor. First-line treatment for advanced disease is etoposide/platinum-based chemotherapy, analogous to that of high grade lung NEC, with no standard second-line treatment, and is an area of unmet need. Methods: This is a multi-centre, randomised, phase II trial of nal-IRI; 80mg/m2 intravenously (IV) over 90 mins, prior to 5-FU; 2400 mg/m2 infusion over 46 hrs and folinic acid, Q14 days, or docetaxel; 75mg/m2 IV over 60 mins, Q21 days, as second-line therapy in pts with progressive PD-EP-NEC (Ki-67 > 20%), with the overall aim of selecting a treatment for continuation to a phase III trial. The standard arm is that used in high-grade lung NEC, of which docetaxel is a second-line therapy option (NCCN guidelines) and combination regimens such as Irinotecan/5-FU are a second-line therapy option currently used without trial evidence for this subset of pts. Pts must have had prior treatment with first-line platinum-based chemotherapy, have documented disease progression and have an ECOG performance status of ≤2. This study plans to recruit 102 pts from 16 UK centres (over 37 mths). Primary endpoint is 6-mth progression-free survival (PFS) rate; trial is designed to have an 80% chance of demonstrating that the one-sided 95% confidence interval of the 6 mth PFS rate excludes 15%, if the true rate is at least 30%, where 30% is the required level of efficacy, and a rate of < 15% would give grounds for rejection. If both treatment arms exceed the required level of efficacy to warrant further evaluation in a phase III trial, treatment with the higher PFS rate at 6 mths will be selected. Secondary endpoints include overall survival, objective response rate, toxicity, quality of life, serum neuron-specific enolase. Exploratory endpoints include quantification of circulating tumour cells (CTCs), circulating tumour deoxyribonucleic acid (ctDNA) and molecular profiling of CTCs, ctDNA and tumour tissue, and generation of CTC-derived xenografts. This trial is open and has enrolled 6 pts at time of submission. Clinical trial information: 10996604.

There are very few xenograft models available for the study of esophageal (E) and gastro-esophageal junction (GEJ) cancer. Using a NOD/SCID model, we implanted 90 primary E and GEJ tumors resected from patients and six endoscopic biopsy specimens. Of 69 resected tumors with histologically confirmed viable adenocarcinoma or squamous cell carcinoma, 22 (32%) was engrafted. One of 11 tumors, considered to have had a complete pathological response to neo-adjuvant chemo-radiation, also engrafted. Of the 23 patients whose tumors were engrafted, 65% were male; 30% were early stage while 70% were late stage; 22% received neo-adjuvant chemo-radiation; 61% were GEJ cancers. Engraftment occurred in 18/54 (33%) adenocarcinomas and 5/16 (31%) squamous cell carcinomas. Small endoscopic biopsy tissue had a 50% (3/6) engraftment rate. Of the factors analyzed, pretreatment with chemo-radiation and well/moderate differentiation showed significantly lower correlation with engraftment (P

Summary Background The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. Methods We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m 2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m 2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. Findings Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5–31·5) compared with 25·5 months (22·7–27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68–0·98], p=0·032). 608 grade 3–4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3–4 adverse events in 196 of 366 patients in the gemcitabine group. Interpretation The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. Funding Cancer Research UK.

TPS537 Background: Single agent gemcitabine still remains an appropriate choice for patients with metastatic pancreatic adenocarcinoma who are not suitable for combination therapy. Known resistance factors, such as low hENT1 and dCK, and CDA overexpression limit gemcitabine’s efficacy. NUC-1031 (Acelarin), is designed to overcome this resistance and deliver significantly higher intracellular levels of the active agent, dFdCTP, than gemcitabine. In Phase I studies Acelarin has shown activity in a range of metastatic cancers, including pancreatic, biliary and ovarian cancers. This Phase III study is designed to show superiority of Acelarin over gemcitabine in patients unsuitable for combination chemotherapy. Methods: To date, 85 patients have been randomised in this multicentre, Phase III study comparing Acelarin with gemcitabine first-line in patients with metastatic pancreatic adenocarcinoma. Patients must have a Performance Status of 0-2 and be unsuitable for combination chemotherapy. To detect a hazard ratio of 0.705 between the two arms, 270 events must be obtained from 328 patients, assuming a median survival of 6 months in the control arm. Currently, pts are being recruited at 27 centres. Patients receive either 825mg/m2 Acelarin or 1000mg/m2 gemcitabine on Day 1, 8 and 15 of a 28-day cycle until disease progression. The primary outcome measure is Overall Survival. Secondary outcome measures include Progression Free Survival, Response Rate, Disease Control Rate and Toxicity. Translational research will explore the use of biomarkers for predictive benefit of Acelarin over gemcitabine. Clinical trial information: ISRCTN16765355.

4077 Background: Better understanding of the biology of esophageal cancer may help improve its treatment. The SWI/SNF chromatin remodeling complex is an important regulator of gene expression that has been linked to cancer development and outcome. Expression of Brahma (BRM), a critical catalytic subunit of SWI/SNF, is lost in a variety of solid tumors. Two novel BRM promoter polymorphisms (BRM -741 and BRM -1321) have been correlated with BRM loss and elevated cancer risk in upper aerodigestive cancers (Wang et al, Carcinogenesis, 2012) and more recently in lung cancer outcome (Cuffe et al, ESMO, 2012) by our research teams. Objectives: We evaluated BRM polymorphisms and their role in the survival of esophageal cancer patients. Methods: 223 histologically-confirmed esophageal adenocarcinoma patients of all stages were evaluated. The two BRM polymorphisms utilized Taqman genotyping. Cox proportional hazards models adjusted for clinical prognostic variables and determined the association of polymorphisms with overall survival (OS) and progression free survival (PFS). Adjusted hazard ratio (aHR) and 95% confidence intervals (CI) were calculated. Results: Among our patients, 85% were male; the mean age was 63 years. 37% had stage IV advanced tumors. The median PFS was 1.03 years, while median OS was 1.82 years. After adjustment for known prognostic clinical variables, carrying homozygous variants of both BRM polymorphisms (double homozygotes) was associated with a worse outcome: aHR 1.84 (1.06-2.34, p=0.03) for OS and aHR 1.93 (1.10-2.48, p=0.02) for PFS. The direction and magnitude of associations were similar in subsets of patients by age, gender, smoking status, use of platinum agents, and disease stage. Non-significant trends in the same direction but of aHR magnitudes 1.34-1.54 were seen in the patients who carried one homozygous variant or who were double heterozygotes. Conclusions: We report the initial association of BRM polymorphisms with survival in esophageal cancer. We plan to explore additional relationships and validate these findings in other datasets.

6607 Background: Health utility scores (HUS) are an increasingly important tool to help determine the cost-effectiveness of therapies worldwide. The EQ-5D-3L is a validated tool for deriving HUS, with reference data in numerous populations, but there is limited information on the role that individual symptom complexes (SC) play in determining HUS in Esophageal cancer (EC) patients. Methods: A cross-sectional survey of EC patients at Princess Margaret Cancer Centre (2012-2014) assessed EQ-5D-3L and FACT-E. EQ-5D scores were converted to HUS using Canadian references. SC were developed: domains from FACT-E were identified and grouped to represent symptoms such as pain, dysphagia, fatigue, dyspnea, nausea and loss of appetite. Multivariable regression analysis was performed to assess associations between SC and HUS, adjusting for age, sex, and stage of disease. Results: Of 197 patients, median age was 67 (range 32-93) years, 76% were male, with stage I/II-IVA/IVB (6%/66%/28%) disease. Mean (SE) HUS were 0.90...

149 Background: Health Utility scores (HUS) are an increasingly important tool in helping to determine the cost-effectiveness of therapies worldwide. The EQ-5D is a validated HUS questionnaire, with reference data in numerous populations. Previously, HUS in esophageal cancer (EC) were based on limited datasets, and the relationship between HUS and either quality of life (QOL, through the validated FACT-E) or esophageal-specific symptoms such as dysphagia, has not been studied. Methods: This cross-sectional survey of EC patients at Princess Margaret Cancer Centre (2012-2014) assessed EQ-5D, FACT-E, a Visual Analog Scale (VAS), patient reported performance status (PRO-ECOG), and dysphagia scoring. EQ-5D scores were converted to HUS using Canadian references. Correlation analyses were performed between HUS and global FACT-E scores, global dysphagia scores, and specific esophageal symptom scores included in FACT-E. Results: Of 198 patients, median age was 67 (range 32-93) years, 76% were male, with localized (LD stage 1, 6%), regional (RD, stage II-IVA, 62%), and metastatic (MD, stage IVB, 27%) disease. Mean + SEM EQ-5D HUS was 0.80+0.01 (all patients), 0.90+0.05 (LD), 0.82+0.01 (RD), and 0.73+0.03 (MD) [p=0.03]. Mean FACT-E total score was 130, mean total FACT-G score was 80, and mean ECS score was 49. There was a strong correlation between FACT-E total scores and EQ-5D HUS (r=0.73, p

e15067 Background: Advanced gastroesophageal malignancies are associated with significant morbidity and a median survival of less than a year. Platinum containing regimens (such as the epirubicin, ...

Introduction: Polymorphisms within miRNA and in genes regulating miRNA biogenesis can regulate a variety of cancer pathways in EC patients. Comprehensive pathway analyses of miRNA-related genes were performed on EC outcomes. Methods: 324 EC patients from Princess Margaret Hospital (Toronto, Canada) were screened for 62 single nucleotide polymorphisms (SNPs) in 21 miRNA or miRNA biogenesis pathway genes. Multivariate Cox-proportional hazard models, adjusted for key prognostic factors evaluated the association of each SNP with overall survival (OS) and progression free survival (PFS). Significant SNPs were further analysed for joint effects, and also in subgroup and pathway analyses. All results were internally validated through bootstrapping. Results: Five polymorphisms belonging to the miRNA biogenesis pathway and one in a miRNA were nominally associated with OS or PFS, where adjusted hazard ratios (aHR) were between 1.23-1.41 for each comparison; p=0.003-0.04: AGO1 (rs595961; chromosome (chr) 1), GEMIN3 (rs197412; chr1) CD86 (rs17281995; chr 3) hs-miRNA-26a1 (rs7372209; chr 3), GEMIN4 (rs7813 and rs910924; chr 17). Joint effect analysis of SNPs in the same chromosome found additive effects of these risk alleles (RA) on outcome: chr 1 (2-4 vs 0-1: aHROS=1.82 [1.21-2.75], p=0.004), chr 3 (3-4 vs 0: aHROS=4.07 [1.91-8.67], p=0.003), chr 17 (4 vs 0: aHRPFS=2.21 [1.13-4.31], p=0.02). Pathway based analysis found each additional RA conferring a strong additive effect on OS (per 2 RA: aHR=1.50 [1.25-1.81], p=1.9x10E-5). Results on PFS were similar, with aHRPFS per 2RA of 1.51 [1.26-1.82], p=1.3x10E-5. Internal validation found consistent results for all analyses. Exploratory subgroup analysis identified two SNPs that had differential effects on OS based on histology: for adenocarcinomas, the aHR for KIAA0423 (rs1053667) was 0.51 [0.28-0.96], p=0.03, while for squamous cell carcinomas, the aHR was 7.36 [2.07-26.1], p=0.002. Similarly, for DICER (rs13078), aHRadenocarcinoma=0.96 [0.72-1.28], p=0.78 vs aHRsquamous=2.51[1.21-5.21], p=0.01). In subset analyses, hsa-mir-30a (rs1358379), hsa-mir-492 (rs2289030), hsa-mir-499 (rs3746444), and DGCR8 (rs1640299) were significantly associated with different outcomes by nodal status. Conclusion: We identified the miRNA biogenesis pathway as having an important role in the prognosis of EC patients, with a 50% increase in death or disease progression when carrying two additional miRNA risk alleles. Although some of the identified polymorphisms have been previously associated with risk or prognosis in other cancer disease sites, we report for the first time, their associations with esophageal cancer prognosis. Citation Format: Lawson Eng, Olusola O. Faluyi, Xin Qiu, Dangxiao Cheng, Daniel J. Renouf, Lorin Dodbiba, Sevtap Savas, Sharon Marsh, Jennifer J. Knox, Gail E. Darling, Rebecca KS Wong, Wei Xu, Geoffrey Liu, Abul K. Azad. Polymorphisms in microRNA (miRNA) pathways and survival in esophageal cancer (EC) patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2562. doi:10.1158/1538-7445.AM2013-2562 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

32 Background: Better understanding of the biology of esophageal cancer may help improve its treatment. MicroRNAs (miRs) regulate mRNA and can exert some influence on carcinogenesis. Identification of the microRNAs which regulate esophageal cancer development could potentially yield alternative therapeutic options. Objectives: We evaluated polymorphisms in miRs, miR biogenesis, binding sites of miR and their role in the survival of esophageal cancer patients. Methods: 324 esophageal cancer patients of all stages and histological subtypes were evaluated. Using Illumina Custom GoldenGate, 43 polymorphisms in miR pathways were evaluated. Cox proportional hazards models adjusted for clinical prognostic variables and determined the association of polymorphisms with overall survival (OS) and progression free survival (PFS). Adjusted hazard ratio (aHR) and 95% confidence intervals (CI) were calculated. Results: Among our patients, 83% were male while the mean age was 65 years. 73% had adenocarcinomas while 33.6% had advanced tumors (Stage IV). The median PFS was 1.20 years, while median OS was 2.17 years. After adjustment for clinical variables, a 5’UTR polymorphism in pri-mir26a-1 (rs7372209) was significantly associated with reduced PFS [aHR=0.78, CI:0.62-0.98, p=0.04] and OS [aHR 0.71 (0.56-0.89), p=0.003]. Three other polymorphisms were significantly associated with OS but not PFS: these included two polymorphisms of miR processing genes, DDX20 (rs197412) [aHR 1.31 (1.04-1.64), p=0.02] and EIF2C1 (rs595961) [aHR 0.76 (0.60-0.97), p=0.03] as well as the CD86 3’UTR C>G (rs17281995) polymorphism, which has been predicted to affect the binding of miR337, miR582, miR200a, miR184, and miR212 [aHR 1.38 (1.03-1.85), p=0.03]. Conclusions: We report the initial association of miR related polymorphisms with survival in esophageal cancer. We plan to explore additional relationships and validate these findings in other datasets.

4058 Background: The prognosis of PC is poor with limited response to standard chemotherapy. Prior randomized studies of cisplatin and gemcitabine in PC demonstrated no additional benefit over gemcitabine alone. Preclinical data and case reports suggest that BRCA mutant PC may have increased sensitivity to Pt-chemo. Our case series characterizes the benefits of Pt-chemo in germline BRCA mutant PC. Methods: Patients with PC and germline BRCA mutations were identified using the Ontario Pancreatic Cancer Study and Pharmacy databases. Review of clinical records provided demographic, treatment and survival data. Radiology review assessed responses to chemotherapy. RNA was extracted from tumor samples for gene expression studies using a panel of DNA repair genes and Nanostring technology. BRCA loss of heterozygosity (LOH) was also investigated. Results: We identified 14 PC patients with BRCA mutations (8 BRCA2, 6 BRCA1). 11 of these had metastatic disease of which 5 received Pt-chemo. Of the 5 treated with Pt-chemo, there were 3 partial responses (PR) and 2 complete responses (CR) using Recist criteria. For the remaining 6 not treated with Pt-chemo, there was 1 PR with gemcitabine. Additionally, two patients with locally advanced disease at diagnosis became resectable following Pt-chemo. Overall survival was superior for patients receiving Pt-chemo (33.0±25.6 vs 7.3±4.5 months; p=0.04). Gene expression and LOH results will be presented. Conclusions: Responses and survival associated with Pt-chemo observed in our case series of BRCA mutant PC adds to existing data supporting the use of Pt-chemo in this subgroup. Despite the low (2 to 5%) prevalence of BRCA mutations in PC, the benefits gained from personalizing treatment using Pt-chemo supports BRCA testing in selected patients.

646 Background: As demonstrated in the primary analysis of NET-02, nal-IRI/5-FU/folinic acid, but not docetaxel, met the primary endpoint of 6 month (mo) progression-free survival (PFS) rate in pts with progressive PD-EP-NEC. Here, the final results are presented. Methods: This was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI (70mg/m2 free base)/5-FU (2400 mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75mg/m2), Q21 days (ARM B), as 2L therapy in pts with progressive PD-EP-NEC, aimed at selecting a treatment for continuation to a phase III trial. On disease progression, pts in both arms could receive further systemic treatment as recommended by their physicians. Primary endpoint was 6 mo PFS rate; 80% power to demonstrate the one-sided 95% confidence interval (CI) of the 6 mo PFS rate excluded 15%, if the true rate was ≥30% (required level of efficacy); a rate of

4005 Background: The prognosis for pts with PD-EP-NEC is poor. A recognised first-line (1L) treatment for advanced disease is etoposide/platinum-based chemotherapy; there is no standard second-line (2L) treatment (area of unmet need). Methods: This was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI (70mg/m2 free base)/5-FU (2400 mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75mg/m2), Q21 days (ARM B), as 2L therapy in a planned 102 pts with progressive PD-EP-NEC, aimed at selecting a treatment for continuation to a phase III trial. Pts with histologically-confirmed PD-EP-NEC (Ki-67>20%; Grade 3, WHO 2019), who had prior 1L platinum-based chemotherapy and radiological disease progression or discontinuation of 1L therapy due to intolerance, with an ECOG performance status ≤2 were eligible. Randomisation was stratified by Ki-67, ECOG PS, presence of liver metastases, and response to previous platinum-based therapy. Primary endpoint was 6 month (mo) progression-free survival (PFS) rate; 80% power to demonstrate the one-sided 95% confidence interval (CI) of the 6 mo PFS rate excluded 15%, if the true rate was at least 30%, where 30% was the required level of efficacy; a rate of