Australian Pancreatic Genome Initiative Research Articles

HPB P06 The clinical and molecular landscape of early onset pancreatic cancer

Abstract Background The incidence of Pancreatic ductal adenocarcinoma (PC) is rising in the western world. There is a particularly concerning trend in the rapid increase in incidence of early onset PC (EOPC). The reason for this, and the implications of EOPC is not well understood. The aim of this study was to investigate the clinical outcomes of patients with EOPC and the molecular heterogeneity between EOPC and late onset disease. Methods Clinical, pathological and survival outcome data was obtained from 2 large independent prospective cohorts curated by the Australian Pancreatic Genome Initiative (APGI) and the West of Scotland pancreatic unit (Glasgow Royal Infirmary). Patients were categorised into 2 age groups, < 50 and >50 years at time of diagnosis. Clinicopathological and outcome data were compared between groups. Molecular data was obtained from the APGI’s contribution to the International Cancer Genome Consortium, this included transcriptomic, genomic and immunohistochemical data. Molecular subtypes, gene expression signatures, mutational signatures, and tumour microenvironment data was compared between groups. Results N=851 patients were identified and n=71 (8%) were < 50 years old. EOPC was associated with earlier recurrence (10.9 vs 14.2 months, P=0.011) and higher incidence of liver recurrence (50% vs 37%, P=0.031). There were no differences in validated clinicopathological variables. Despite an increased proportion of patients with EOPC receiving adjuvant chemotherapy (P=0.020), recurrence was earlier in those that completed > 3 cycles (12.6 vs 16.0 months, P=0.022). There is enrichment of the poor prognostic squamous (basal) subtype (42% vs 28%) in EOPC. There were no differences in the incidence of germline mutations to account for the early onset of disease. Conclusions EOPC appears to be increasing in incidence and is associated with earlier recurrence and more aggressive disease pattern. This appears to be associated with resistance to adjuvant chemotherapy and more aggressive, adverse molecular pathology. The onset of early disease cannot be explained by inherited genomic aberrations. Ongoing mutation signature, gene expression and microenvironmental data analysis will be presented upon acceptance of this abstract.

C-reactive protein is a prognostic biomarker in pancreatic ductal adenocarcinoma patients.

The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is approximately 11% and has only improved marginally over the last three decades. For operable PDAC, resection and adjuvant FOLFIRINOX chemotherapy is standard of care. There is growing interest in perioperative regimens to improve outcomes. The non-randomized Phase II study "Gemcitabine and Abraxane for resectable Pancreatic cancer" (GAP) demonstrated the feasibility of perioperative gemcitabine/abraxane. Long-term survival in PDAC requires an effective immune response; hence, we undertook this translational study of the GAP trial cohort to identify immune-oncology biomarkers for clinical use. We combined Nanostring nCounter technology with immunohistochemistry to investigate the correlation between gene expression and overall patient survival. Findings were investigated in samples from the International Cancer Genome Consortium (ICGC, n=88) and the Australian Pancreatic Genome Initiative (APGI, n=227). We confirmed that human equilibrative nucleoside transporter 1 (hENT1) expression was not a prognostic marker in PDAC but patients with high levels of hENT1 were more likely to live longer than 24 months post-surgery. Additionally, CD274 (PD-L1) and two novel biomarkers of survival, cathepsin W (CTSW) and C-reactive protein (CRP), were identified in the GAP cohort (n=19). CRP expression was confirmed in data from the ICGC. Although PD-L1 and CTSW proteins were not significant across all three cohorts, results show that low CRP mRNA and protein expression are associated with longer overall survival in all three patient groups. PDAC patients with long survival have higher hENT1 expression levels. Furthermore, CRP expression is a biomarker of poor prognosis following perioperative chemotherapy and resection in PDAC patients and thus may be useful for identifying patients who could benefit from more aggressive adjuvant strategies.

The Right Treatment Strategy for the Right Patient: A Biomarker-Driven Approach to Neoadjuvant vs. Surgery-First Management of Resectable and Borderline Resectable Pancreatic Cancer.

Simple SummaryRoutine neoadjuvant therapy for resectable and borderline resectable pancreatic cancer is gaining popularity, but its true oncological benefit remains disputed. Whilst the genotypic and phenotypic heterogeneity of pancreatic cancer is becoming increasingly appreciated, there is currently no method to determine whether certain patients will benefit from a neoadjuvant approach and whether others will benefit from a surgery-first approach. In this study, a previously validated prognostic triple biomarker panel is shown to predict genetic subtypes and clinical phenotypes of pancreatic cancer and also the optimal treatment strategy (neoadjuvant vs. surgery-first) for patients with resectable and borderline resectable pancreatic cancer.The genomic heterogeneity of pancreatic ductal adenocarcinoma (PDAC) is becoming increasingly appreciated. We aimed to evaluate the ability of a triple biomarker panel (S100A4, Ca-125, and mesothelin) to predict: (i) genetic PDAC subtypes; (ii) clinical phenotypes; and (iii) the optimal treatment strategy (neoadjuvant vs. surgery-first) in resectable and borderline resectable PDAC. Patients who underwent resection for resectable and borderline resectable PDAC were included from one single-institutional cohort and one multi-institutional cohort from the Australian Pancreatic Genome Initiative (APGI). Tumors were immunohistochemically evaluated for S100A4, Ca-125, and mesothelin, and a subset from the APGI cohort underwent RNA sequencing. This study included 252 and 226 patients from the single institution and the APGI cohorts, respectively. Triple-negative biomarker status correlated with non-squamous PDAC genotypes (p = 0.020), lower rates of distant recurrence (p = 0.002), and longer median overall survival (mOS) with the surgery-first approach compared with neoadjuvant treatment (33.3 vs. 22.2 mths, p = 0.038) in resectable PDAC. In contrast, the triple-positive disease was associated with longer mOS with neoadjuvant treatment compared with the surgery-first approach (29.5 vs. 13.7 mths, p = 0.021) in resectable and borderline resectable PDAC. In conclusion, the triple biomarker panel predicts genetic PDAC subtypes, clinical phenotypes, and optimal treatment strategies in resectable and borderline resectable PDAC.

MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. It is phenotypically heterogeneous with a highly unstable genome and provides few common therapeutic targets. We found that MCL1, Cofilin1 (CFL1) and SRC mRNA were highly expressed by a wide range of these cancers, suggesting that a strategy of dual MCL-1 and SRC inhibition might be efficacious for many patients. Immunohistochemistry revealed that MCL-1 protein was present at high levels in 94.7% of patients in a cohort of PDACs from Australian Pancreatic Genome Initiative (APGI). High MCL1 and Cofilin1 mRNA expression was also strongly predictive of poor outcome in the TCGA dataset and in the APGI cohort. In culture, MCL-1 antagonism reduced the level of the cytoskeletal remodeling protein Cofilin1 and phosphorylated SRC on the active Y416 residue, suggestive of reduced invasive capacity. The MCL-1 antagonist S63845 synergized with the SRC kinase inhibitor dasatinib to reduce cell viability and invasiveness through 3D-organotypic matrices. In preclinical murine models, this combination reduced primary tumor growth and liver metastasis of pancreatic cancer xenografts. These data suggest that MCL-1 antagonism, while reducing cell viability, may have an additional benefit in increasing the antimetastatic efficacy of dasatinib for the treatment of PDAC.

From functional genomics to precision medicine: The therapeutic potential of targeting ROCK signaling in pancreatic cancer.

e15029 Background: Pancreatic cancer (PC) is a highly lethal disease with few effective treatment options for metastatic disease. PC is a genetically highly heterogeneous disease that lends itself to a personalised approach to translational research (Biankin et al. Nature. 2012 Nov 15;491(7424):399-405.). Genomic sequence data from the Australian Pancreatic Genome Initiative (APGI) has identified a subset of patients with ROCK-1 amplification. ROCK-1 is a downstream target of Rho, a small GTPase, which is involved in cell adhesion and motility and has been shown to play a role in cancer cell growth and invasiveness (S. Boeck, P. Stieber, et al. Oncology 2006; 70:255., Lane J, Martin T et al. Int J Onc 2008; 33:585-593.). Our aim is to identify biologically and clinically relevant, targetable phenotypes for PC by examining therapeutic efficacy of two ROCK-1 inhibitors, Y-27632 and fasudil in model systems with aberrant Rho/ROCK signaling. Methods: Using extensively characterised model systems of PC, including unique primary patient derived xenografts (PDX) and patient derived cell lines (PDCL) established in the laboratory, we are examining the efficacy of individualized rationally designed combination therapies based on targeting Rho/ROCK signaling. Using innovative techniques, including organotypic assays, we are examining the effect of the targeted approach on cell proliferation, migration, invasion and metastasis in relevant models of PC. Results: Here we demonstrate significant differential sensitivity of pancreatic PDXs and PDCLs with aberrant Rho/ROCK signaling to ROCK combination therapy when compared with standard therapy, gemcitabine. Finally, these compounds impair invasiveness of human pancreatic tumour cells, suggesting that ROCK-1 is a targetable phenotype for the treatment of PC. Conclusions: By carefully defining the key cancer subtypes and expanding our knowledge about the interplay of the key regulators and activators of the Rho/ROCK pathway, the promise of ROCK inhibitors for PC therapy may be realized. As fasudil is already in clinical use for the treatment of cerebral vasospasm, this work may be quickly translated to the clinic.