Deconstructing pancreatic cancer using next generation-omic technologies–from discovery to knowledge-guided platforms for better patient management

Comprehensive molecular landscaping studies reveal a potentially brighter future for pancreatic ductal adenocarcinoma (PDAC) patients. Blood-borne biomarkers obtained from minimally invasive “liquid biopsies” are now being trialled for early disease detection and to track responses to therapy. Integrated genomic and transcriptomic studies using resectable tumour material have defined intrinsic patient subtypes and actionable genomic segments that promise a shift towards genome-guided patient management. Multimodal mapping of PDAC using spatially resolved single cell transcriptomics and imaging techniques has identified new potentially therapeutically actionable cellular targets and is providing new insights into PDAC tumour heterogeneity. Despite these rapid advances, defining biomarkers for patient selection remain limited. This review examines the current PDAC cancer biomarker ecosystem (identified in tumour and blood) and explores how advances in single cell sequencing and spatially resolved imaging modalities are being used to uncover new targets for therapeutic intervention and are transforming our understanding of this difficult to treat disease

The value of source data verification in a cancer clinical trial

Background Source data verification (SDV) is a resource intensive method of quality assurance frequently used in clinical trials. There is no empirical evidence to suggest that SDV would impact on comparative treatment effect results from a clinical trial. Methods Data discrepancies and comparative treatment effects obtained following 100% SDV were compared to those based on data without SDV. Overall survival (OS) and Progression-free survival (PFS) were compared using Kaplan-Meier curves, log-rank tests and Cox models. Tumour response classifications and comparative treatment Odds Ratios (ORs) for the outcome objective response rate, and number of Serious Adverse Events (SAEs) were compared. OS estimates based on SDV data were compared against estimates obtained from centrally monitored data. Findings Data discrepancies were identified between different monitoring procedures for the majority of variables examined, with some variation in discrepancy rates. There were no systematic patterns to discrepancies and their impact was negligible on OS, the primary outcome of the trial (HR (95% CI): 1.18(0.99 to 1.41), p = 0.064 with 100% SDV; 1.18(0.99 to 1.42), p = 0.068 without SDV; 1.18(0.99 to 1.40), p = 0.073 with central monitoring). Results were similar for PFS. More extreme discrepancies were found for the subjective outcome overall objective response (OR (95% CI): 1.67(1.04 to 2.68), p = 0.03 with 100% SDV; 2.45(1.49 to 4.04), p = 0.0003 without any SDV) which was mostly due to differing CT scans. Interpretation Quality assurance methods used in clinical trials should be informed by empirical evidence. In this empirical comparison, SDV was expensive and identified random errors that made little impact on results and clinical conclusions of the trial. Central monitoring using an external data source was a more efficient approach for the primary outcome of OS. For the subjective outcome objective response, an independent blinded review committee and tracking system to monitor missing scan data could be more efficient than SDV

Management and Outcome of 64 Patients with Pancreatic Serous Cystic Neoplasms

Background: The optimal management approach to pancreatic serous cystic neoplasms (SCNs) is still evolving. Methods: Consecutive patients with SCN managed at the Liverpool Pancreas Cancer Centre between 2000 and 2013 were retrospectively reviewed. Results: There were 64 patients consisting of 39 women (60.9%) and 25 men (39.1%). Forty-seven patients (73.4%) had surgical removal and 17 (26.6%) were observed. The possibility of a non-SCN malignancy was the predominant indication for resection in 27 (57.4%) patients. Postoperative morbidity occurred in 26 (55.3%) patients with 2 (4.3%) deaths. An increased risk of resection was associated with patient's age (p = 0.011), diagnosis before 2009 (p < 0.001), pain (p = 0.043), possibility of cancer (p = 0.009) and a solid SCN component on imaging (p = 0.002). Independent factors associated with resection were a diagnosis before 2009 (p = 0.005) and a solid SCN component (p < 0.001). Independent factors associated with shorter time to surgical resection were persistent pain (p = 0.003) and a solid SCN component (p = 0.007). Conclusion: There was a reduction in the proportion of resections with the application of an observe-only policy for asymptomatic patients with more definite features of SCN. Improved criteria are still required in the remainder of patients with uncertain features of SCN in deciding for intervention or surveillance

Pancreatic cancer incidence and survival and the role of specialist centres in resection rates in England, 2000 to 2014: A population-based study.

BACKGROUND: The aim was to compare population-based survival for exocrine pancreatic cancer in England in the 23 regions covered by specialist centres. The centres were initiated in 2001, covering populations of 2-4 million. METHODS: We examined incidence for adults diagnosed with a pancreatic exocrine cancer during 1995-2014 and age-standardised net survival up to five years after diagnosis for patients diagnosed during 2000-2013. We examined variation in regional resection rates and survival for patients diagnosed during 2010-2013. The data were extracted from the National Cancer Registration and Analysis Service. RESULTS: Age-standardised annual incidence rates of exocrine pancreatic cancer increased from 17.1 per 100,000 during 1995-1999 to 18.7 during 2010-2014. Age-standardised one-year and five-year net survival increased from 17.9% and 3.6%, respectively, for 2000-2009, to 21.6% and 4.2% during 2010-2013. There were 2086 (8.9%) resections among 23,415 patients diagnosed with an exocrine tumour in 2010-2013. The proportion ranged from 5.1% to 19.6% between centres. Among resected patients, survival was 73.0% at one year and 20.2% at five years. Of the total 2118 resected patients, 18 (0.9%) were at stage 1; 34 (1.6%) at stage 2; 791 (37.3%) at stage 3 and 140 (6.6%) at stage 4, although 53.6% of stage information was missing. Five-year survival was 2.1% for those who were not resected. The number of resections performed in each centre was not correlated with one-year survival. CONCLUSIONS: Despite improvements in the management of pancreatic cancer in England with the introduction of specialist centres, resection rates remain relatively low, and survival remains lower than in comparably wealthy countries

Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial

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