Abstract PO-008: Multi-omic Profiling of primary pancreatic adenocarcinomas obtained from the APACT adjuvant trial of nab-paclitaxel + gemcitabine vs gemcitabine
Authors: Lila Thomas , Biankin Andrew , Browne Andrew , Reiss David J. , Lu Brian , Pierce Daniel , Ratushny Alexander , Tsai Kao-tai , Lata Sneh , Kamalakaran Sitharthan , Babak Tomas , Fox Brian , Danziger Sam , Mavrommatis Konstantinos , Trotter Matthew W. B. , Chang David , Towfic Fadi 
Published: November 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a difficult disease to treat, with few therapies available that target specific patient subgroups. Translational studies in pancreatic cancer can be technically challenging due to biopsy specimen characteristics including low tumor cellularity and dense fibrotic stroma. Resected primary pancreatic tumors obtained during the phase 3 APACT clinical trial (NCT01964430 adjuvant nab-paclitaxel + gemcitabine versus gemcitabine monotherapy n = 866) are a unique resource for characterizing molecular and immune subtypes among PDAC tumors and their association with treatment outcomes in the adjuvant chemotherapy setting. Tumor-infiltrating immune cells were assessed in serial sections of 453 tumors by dual-chromogen immuno-histochemical (IHC) staining (CD4 CD8 CD20 CD163 CMAF CD56 FoxP3 PD-1 PD-L1). Image alignment, segmentation, and spatial localization of stained cells relative to a pan-cytokeratin staining-based tumor epithelial mask was performed using a commercial analysis platform. Expression profiles were obtained for 515 macrodissected tumor biopsy regions by RNA-seq. Transcriptional subtypes were assigned based on schema previously reported by Moffit and Bailey, and molecular pathway correlates were characterized using gene set enrichment analysis. Based on immunochemical staining, higher intratumoral CD8+ or lower CD163+ cell densities were associated with modestly longer disease-free or overall survival in patients treated with nab-paclitaxel plus gemcitabine. The combination of both high CD8+ and low CD163+ cell density was notably associated with longer overall survival compared to other subjects treated with the combination regimen (mOS&gt;55months versus 36 months HR=0.46 p=&lt;0.01) Transcriptional subtyping of tumors, based on schema such as those previously reported by Moffit et al or Bailey et al, identified groups defined by anticipated signatures. Classical/progenitor subtypes differentially expressed genes involved in oxidative respiration and endodermal cell fate, while basal/squamous subtypes showed high expression of signatures for hypoxia, mesenchymal transformation, and TGFb signaling. Longer overall survival in subjects treated with nab-paclitaxel plus gemcitabine as compared to gemcitabine monotherapy was seen principally in subjects with tumors of Moffit classical (HR=0.59 P=0.01) and Bailey progenitor (HR=0.42 P&lt;0.01) subtypes. The observations highlighted provide insight into primary PDAC tumor characteristics that are associated with treatment-specific outcomes to nab-paclitaxel based adjuvant chemotherapy. Future work will combine data described here with mutational and genetic studies in progress as well as with other public, proprietary, or commercial data sources. In combination, we anticipate that these data may be useful in identifying patient subsets and molecular mechanisms that might be targeted by novel combination therapies for improved treatment of pancreatic cancer.
Citation Format: Thomas Lila, Andrew Biankin, Andrew Browne, David J. Reiss, Brian Lu, Daniel Pierce, Alexander Ratushny, Kao-tai Tsai, Sneh Lata, Sitharthan Kamalakaran, Tomas Babak, Brian Fox, Sam Danziger, Konstantinos Mavrommatis, Matthew W. B. Trotter, David Chang, Fadi Towfic. Multi-omic Profiling of primary pancreatic adenocarcinomas obtained from the APACT adjuvant trial of nab-paclitaxel + gemcitabine vs gemcitabine [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-008.