Authors: Jamie Mills, Valerie Gunchick, Jiaqi Shi, Aaron M. Udager, Timothy Frankel, Vaibhav Sahai, Mark Zalupski
Published: 2023-06-04
DOI: 10.1200/jco.2023.41.16_suppl.e16001
Source: Full article
e16001 Background: Undifferentiated carcinoma (UC) is a rare subtype of pancreatic carcinoma and can present with or without osteoclast-like giant cells (OGC). This 2010 delineation complicates interpretation of prior studies comparing UC to pancreatic ductal adenocarcinomas (PDAC). Limited retrospective data suggest UC-OGC tumors correspond to younger age, larger size, and worse prognosis compared to UC. The role of OGC is hypothesized to alter the immune microenvironment of tumors, leading to different response to therapy compared to PDAC. Methods: The aim of the study was to assess the clinical outcomes, histology (H&E), targeted genomics panel, transcriptomics (RNA panel and CIBERSORT-X), and multiplex immunofluorescence (mIF) to assess the tumor immune milieu in a cohort of adult patients with UC or UC-OGC compared to PDAC. Results: We identified 32 patients with UC and 15 with UC-OGC treated at Michigan Medicine between 2005 and 2021. The demographics, presenting symptoms, tumor size, and CA 19-9 were similar between cohorts. In patients with advanced cancers, median survival was 2.6 months (N = 22) vs 8.13 months (N = 2) for UC and UC-OGC, respectively (p = 0.27). R0 resection was completed in 10 (31%) patients with UC compared to 13 (87%) with UC-OGC; median survival was 17.0 months vs 145.0 months, respectively (p = 0.03). Genomic landscape of UC and UC-OGC was similar to PDAC (TCGA; N = 159), with KRAS and TP53 mutations at similar rates. However, the transcriptome revealed significantly increased M2 macrophages and CD4-8- (γδ) T-cells with significantly decreased regulatory T-cells (Tregs) in UC/UC-OGC (N = 10) compared to PDAC (p < 0.05). These data were corroborated by mIF with significantly reduced Tregs (p < 0.046) and trend toward increased M2 macrophages (p < 0.055) in UC/UC-OGC (N = 17), but not CD8+ T cells, which were significantly enriched in PDAC (p < 0.0001; N = 17). Conclusions: Overall, this study demonstrates significantly longer survival in patients with UC-OGC compared to UC in both advanced and resected patients. Increased pro-tumorigenic M2 macrophage infiltration and decreased Tregs in the tumor immune milieu of UC/UC-OGC suggests a potential role of macrophage inhibitors and other immune-modulatory therapies in combination with chemotherapy for these rare variants of pancreatic cancer.