| dc.description.abstract | Title Diagnostic and prognostic clinical and molecular biomarkers for duodenal adenocarcinoma. Aim I explored the clinical and immunohistochemical features in the largest cohort of duodenal adenocarcinoma (DA) to identify diagnostic, predictive or prognostic biomarkers purposes. Method UK Duodenal Cancer Study Group (UKDCSG) is an ethically approved multicentre (seven sites, 2005-15) retrospective collection of clinical data (n=180) and samples of primary DA undergoing resection (n=124). We performed immunohistochemistry and immunofluorescence on specially constructed tissue microarray (TMA) and analysed with an automated, unbiased image software (QuPath). Results One hundred eighty patients with DA had a median age of 65 (58 – 72 IQR) years, 55% male, and a median follow-up of 29 (11-72 IQR) months demonstrated a median survival of 44 months (95%CI 36-52) despite adjuvant treatment being administered to only 30% of cases. Of the protein biomarker analysis (MMR/CDX2/CK7/CK10/Aurora-A/Beclin-1/CD4/CD8), 70 patients where matched clinical samples were available; several had significant differences in expression comparing tumour and normal duodenum, but none of them demonstrated an impact on OS. However, 25% of the cases had MMR deficiency/ MSI-H features. Reduced CD20 infiltration showed significant prognostic impact (HR 0.78 (95% C.I. 0.63-0.97), p=0.02). CD3 density infiltrate was lower in the tumour compared to the normal duodenum (p<0.0001). Lower CD3 infiltrate had an improved prognostic outcome (log-rank p=0.0345, HR=3.2 (95% C.I. 1.52-7.06)). Tumour characteristics and known prognostic features correlated with the immune markers (CD3/CD20/CD4/CD8) in DA were only statistically significant in CD8 density for resection margin (p=0.0451). Delta changes in CD3, CD8, and CD4 expression did demonstrate a significant difference (p=0.0233, p=0.0013 and p=0.0055, respectively), but this difference did not have prognostic impact. Delta change of CD20 expression (HR 0.782 95% C.I. 0.630 to 0.970; p=0.025) was significantly associated with improved overall survival. Combining the MMR status with the immune infiltrate showed only CD8 expression had a statistically significant result (p=0.0323); however, there did not appear to be a prognostic impact (p=0.7839). Further multivariate analysis showed that age (HR 1.104, 95% C.I. 1.037 to 1.175; p=0.002), perineural invasion (HR 3.988 95% C.I. 1.486 to 10.703; p=0.006), lymph node ratio (HR 10.965 95% C.I. 1.381to 87.064; p=0.023) and N2 status (HR 2.51 (95%CI 1.10-5.73), p=0.03) were significantly associated for overall survival. Conclusion This study highlights the possible importance of immune infiltration and the microenvironment in DA. This could have significant clinical application with immunotherapies in DA. This study also showed the implementation of a semi-automated, unbiased software for scoring IHC and IF markers. UKDCSG, the largest cohort of DA, would enable the validation and discovery of predictive and prognostic biomarkers in the future by creating a robust, comprehensive analytical pipeline. | en_US |
