Integrated Genomic and Immunophenotypic Classification of Pancreatic Cancer Reveals Three Distinct Subtypes with Prognostic/Predictive Significance.

Purpose: Current clinical classification of pancreatic ductal adenocarcinoma (PDAC) is unable to predict prognosis or response to chemo- or immunotherapy and does not take into account the host reaction to PDAC cells. Our aim is to classify PDAC according to host- and tumor-related factors into clinically/biologically relevant subtypes by integrating molecular and microenvironmental findings.Experimental Design: A well-characterized PDAC cohort (n = 110) underwent next-generation sequencing with a hot spot cancer panel while next-generation tissue microarrays were immunostained for CD3, CD4, CD8, CD20, PD-L1, p63, hyaluronan-mediated motility receptor (RHAMM), and DNA mismatch repair proteins. Previous data on FOXP3 were integrated. Immune cell counts and protein expression were correlated with tumor-derived driver mutations, clinicopathologic features (TNM 8th edition, 2017), survival, and epithelial-mesenchymal transition (EMT)-like tumor budding.Results: Three PDAC subtypes were identified: the "immune escape" (54%), poor in T and B cells and enriched in FOXP3+ regulatory T cells (Treg), with high-grade budding, frequent CDKN2A, SMAD4, and PIK3CA mutations, and poor outcome; the "immune rich" (35%), rich in T and B cells and poorer in FOXP3+ Tregs, with infrequent budding, lower CDKN2A and PIK3CA mutation rate, and better outcome and a subpopulation with tertiary lymphoid tissue (TLT), mutations in DNA damage response genes (STK11 and ATM), and the best outcome; and the "immune exhausted" (11%), with immunogenic microenvironment and two subpopulations-one with PD-L1 expression and a high PIK3CA mutation rate and a microsatellite-unstable subpopulation with a high prevalence of JAK3 mutations. The combination of low budding, low stromal FOXP3 counts, presence of TLTs, and absence of CDKN2A mutations confers significant survival advantage in patients with PDAC.Conclusions: Immune host responses correlate with tumor characteristics, leading to morphologically recognizable PDAC subtypes with prognostic/predictive significance. Clin Cancer Res; 24(18); 4444-54. ©2018 AACRSee related commentary by Khalil and O'Reilly, p. 4355.

Tumour budding in pancreatic cancer revisited: validation of the ITBCC scoring system.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with rising incidence. Biomarkers that would help the prognostic stratification of patients are needed urgently. Although tumour budding (BD) is a strong and independent prognostic factor in PDAC it is not included in histopathology reports, due partly to the lack of a standardised scoring system. The aim of the present work is to assess the reliability and reproducibility of the BD scoring system proposed recently by the International Tumour Budding Consensus Conference (ITBCC) 2016 in a well-characterised PDAC cohort (n = 120) with complete clinicopathological and follow-up information. METHODS AND RESULTS: BD was scored independently by two pathologists on haematoxylin and eosin-stained PDAC sections by assessing the densest budding area at ×20 magnification (one hot-spot, 0.785 mm2 ), regardless of intra- or peritumoural localisation, and assigned to four categories: BD0: no buds; BD1: one to four buds; BD2: five to nine buds; and BD3: ≥ 10 buds. Findings were correlated to patient and tumour characteristics and interobserver agreement was assessed. The weighted kappa value for BD category was 0.62 (0.5-0.73), indicating strong agreement. Increasing BD category (BD3 versus BD0-2) correlated with higher grade (P = 0.002) and shorter overall [OS, P < 0.0001, hazard ratio (HR) = 3.234, 95% confidence interval (CI) = 1.95-5.37] and disease-free survival (DFS, P = 0.0135, HR = 1.974, 95% CI = 1.15-3.39). BD (BD3 versus BD0-2) was an independent prognostic factor for OS and DFS, after adjusting for tumour-node-metastasis (TNM) stage by using both the 8th American Joint Committee on Cancer (AJCC) edition (OS: P = 0.0031, HR = 2.298, 95% CI = 1.32-0.99; DFS: P = 0.0458, HR = 1.713, 95% CI = 1.01-2.91) and the 7th AJCC edition (OS: P < 0.0001, HR = 2.795,95% CI = 1.71-4.57 and DFS: P = 0.00786, HR = 1.643, 95% CI = 0.95-2.86). CONCLUSIONS: ITBCC scoring is a simple, reliable and reproducible method to evaluate BD in PDAC and facilitates its documentation in histopathology reports, allowing the prognostic stratification of PDAC patients.