Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients

Abstract

Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival. We observe alterations in genes with potential therapeutic utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, with recurrence by ctDNA detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.

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Figure 1. Schematic of next-generation sequencing and ctDNA analyses

Next-generation sequencing analyses were performed for tumour specimens obtained from pancreatic ductal adenocarcinoma patients using either whole-exome or targeted analyses focused on 116 genes, Genomic alterations were evaluated for potential clinical utility or as prognostic indicators. Somatic mutations identified through genomic analyses were used to evaluate patient plasma for detection of ctDNA at the time of diagnosis or after surgical intervention.

Figure 2. Recurrent genetic alterations in pancreatic cancer and their effect on disease outcome

(a) Representation of the mutations identified in chromatin modifying and other recurrently mutated genes, Each patient sample is indicated as a grey box with mutations indicated in green or black. (b) Analyses of overall survival revealed that patients wild type for MLL gene alterations (n=87) had a significantly lower median survival compared with those with mutated MLL genes (n=14; median survival 15.3 months versus not reached respectively, P=0.0063, log-rank test), (c) Similar analyses revealed significantly improved survival in patients with mutations in either MLL or ARID1A genes (n=20) compared with those that were wild type for any of these genes (n=81).

Figure 3. Detection of residual disease using computed tomography (CT) imaging and ctDNA analyses

(a) Patients with detectable ctDNA after surgical resection (n=10) were more likely to relapse and die from disease compared with those with undetectable ctDNA (n=10). The median time to recurrence as determined by CT imaging was 9.9 months for individuals with detectable ctDNA and was not reached for those without detectable ctDNA (P=0.0199, log-rank), (b) Comparison between the time to detection of recurrence using ctDNA and standard-of-care CT imaging revealed that the average time to recurrence was 3.1 months for individuals with detectable ctDNA and 9.6 months for those patients with positive imaging results (n=9, P=0.0004, paired t-test).