Abstract 2860: miR-21 overexpression assessed by in situ hybridisation is an independent predictor of survival in patients with resected pancreatic ductal adenocarcinoma

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival of only 3%. Surgery is the only curative option but only 15-20% of patients are suitable and post-operative recovery is long, with significant early mortality and a 5-year survival of around 20%. Thus not all patients benefit from surgery and prognostication and subsequent stratification of patients to surgical or non-surgical management could be better. Initial staging currently relies on imaging; the main pathological prognostic factors are not known until after resection. Initial diagnosis usually involves pancreatic cytology samples. Prognostication is possible in such samples using biomarkers such as miR-21. Prognostication on cytology is not yet clinically routine, perhaps because previous research methodology has involved tissue extracts e.g. RT-PCR and not in situ techniques, as often preferred by pathologists. Our aim was to study the expression of miR-21 in resected PDAC by in situ hybridisation and its relationship to clinico-pathological parameters including prognosis. Methods: We studied PDACs from 69 patients, using tissue microarrays (TMAs). Chromogenic in situ hybridisation (CISH) for miR-21 was performed using an EXIQON kit. Staining was scored based on intensity as: negative or weak (low expression); or moderate or strong (high expression). Kaplan-Meier survival curves were generated for progression free survival (PFS) and overall survival (OS) and correlated with miR-21 scores using univariate and multivariate COX proportion hazard models. Results: miR-21 expression on CISH was cytoplasmic and mainly in neoplastic PDAC epithelium and stroma; further analysis used epithelial expression data only. miR-21 was highly expressed in 39 (56%) patients; miR-21 was low or absent in 30 (44%) patients. Median PFS was 9 months (3.8-14.2, 95% CI) and 19 months (12.1-26.9, 95% CI) in the high and low expression groups respectively (P<0.002). Median OS was 15 months (12.9-18.1, 95% CI) and 24 months (18.5-28.8, 95% CI) in the high and low expression groups respectively (P<0.001). On univariate analysis with standard clinico-pathological factors, miR-21, tumor grade and lymph node invasion were prognostic for PFS and OS; on multivariate analysis, only high miR-21 was prognostic, being associated with poor PFS (HR 1.8, p<0.01) and OS (HR 2.1, p<0.01). Conclusion: High epithelial expression of miR-21 assessed by CISH is independently predictive of poorer overall and progression-free survival in patients with PDAC. Prognostication using miR-21 in diagnostic cytology samples is theoretically possible. CISH enables tissue localisation of the biomarker, in this case miR-21. Use of CISH might facilitate adoption of such stratification methods and enable improved allocation of patients with into surgical or non-surgical treatment groups. Note: This abstract was not presented at the meeting. Citation Format: Asif Ali, Elisa Giovannetti, Niccola Funel, Roderick Ferrier, Jennifer Morton, Karin A. Oien. miR-21 overexpression assessed by in situ hybridisation is an independent predictor of survival in patients with resected pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2860. doi:10.1158/1538-7445.AM2014-2860

miRNAs in pancreatic cancer progression and metastasis

“…who found consistently reduced let-7 expression levels in lung cancer patients significantly associated with worse survival outcomes post-tumour resection [ 147 , 148 ]. Following this, a large clinical study involving a total of 686 patients, showed that high miR-21 expression in PDAC tumours was significantly correlated with shorter overall survival, along with other clinical features of advanced development, such as high tumour grade and presence of lymph node metastasis [ 149 ]. However, those patients with high miR-21 expression are also predicted to have an increased survival benefit after receiving gemcitabine-based adjuvant chemotherapy as compared to low miR-21 patients.…”

The Multifaceted Role of miR-21 in Pancreatic Cancers

“…In addition to making the diagnosis, the level of miR-21 can reflect treatment efficacy in pancreatic cancer [ 120 ]. Patients with lower miR-21 expression after treatment have been found to have a longer median survival period compared to those with persistently high expression [ 121 ]. The diagnostic potential, prognostic value, and implications for therapeutic strategies indicate that the foundation of miR-21 in PDAC will continue to be a pivotal area of research, shaping both diagnostic and therapeutic paradigms in managing pancreatic ductal adenocarcinoma…”

“…Several retrospective studies have investigated the importance of miR-21 as a prognostic biomarker. The results have shown that high levels of miR-21 expression are associated with significantly decreased overall survival and disease-free survival in PDAC patients [ 121 , 130 ]. For instance, in the study of 76 patients diagnosed with pancreatic cancer, Ali S. et al identified that increased miR-21 was significantly associated with worse survival and chemotherapy resistance [ 131 ].…”

“…Furthermore, in an international multicenter study of 686 PDAC patients, miR-21 was analyzed using tissue microarrays and correlated with clinical pathologies. The miR-21 overexpression was significantly associated with increased tumor size (>2 cm) and lymph node metastasis [ 121 ].…”

Targeting miRNA and using miRNA as potential therapeutic options to bypass resistance in pancreatic ductal adenocarcinoma

“…The tissue expression of miR-21 was evaluated by chromogenic in situ hybridization (CISH). By applying this method to tissue microarrays of well-annotated PDAC cohorts of patients, the researchers showed that the epithelial expression of miR-21 is an independent robust prognostic biomarker in PDAC, prompting prospective trials for further validation and application in the clinical setting [ 56 ]. The above-mentioned studies also showed that PDAC cells treated with gemcitabine and transfected with pre-miR-21 became less sensitive and had a decreased apoptosis induction, while transfection with anti-miR-21 enhanced the gemcitabine sensitivity.…”