Identifying targetable pathways in pancreatic cancer from endoscopic ultrasound-guided fine-needle aspirates (EUS/FNA): Providing a personalized approach to targeted therapy.

Abstract

4051 Background: Targeted therapy trials in pancreatic cancer patients have either failed or, at most, provided only marginal benefit. Identification of activated key signaling pathways would allow the optimal selection of patients for kinase inhibitor trials. Hence, we launched a study to profile targetable pathways from EUS/FNA samples using an ultrasensitive multiplexed protein microarray platform (CEER, Prometheus). Methods: Patients who underwent routine diagnostic FNA for a suspicious lesion in the pancreas underwent two dedicated passes for CEER profiling of the following phosphorylated (activated) key molecules: HER1, HER2, HER3, c-met, IGF-IR, PI3K, AKT, MEK, ERK, and other signaling proteins. Results: Of 100 participants, final cytology results were: 73 carcinomas, 8 indeterminate, 13 negative, and 5 neuroendocrine. Pathway activation was heterogeneous in patients with carcinoma. Among 61 pancreatic cancer patients with adequate HER evaluation, a high prevalence of HER3 activation (62%) was observed, and concomitant activation of two or more HER pathways was seen in 52% of patients. In particular, activation of HER2 and HER3 was noted in 23% of carcinoma patients. High concordance of HER, PI3K and AKT activation was seen. Conclusions: Our study confirmed the feasibility of profiling targetable pathways from FNA samples. Furthermore, it illustrates highly variable and concomitant pathway activation among pancreatic cancer patients, suggesting the feasibility of a personalized approach to targeted therapy. Future trials will need to be designed to explore the clinical benefit of combinations of HER-targeted agents in defined subsets of pancreatic cancer patients, and further evaluation of the HER3 pathway is especially warranted. An analysis of pathway interactions and prognostic effects is in progress. [Table: see text]