Multiplex proximity ligation assay to identify potential prognostic biomarkers for improved survival in locally advanced pancreatic cancer patients treated with stereotactic body radiation therapy

Publication date: Available online 12 October 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Avani D. Rao, Yufei Liu, Rie von Eyben, Charles C. Hsu, Chen Hu, Lauren M. Rosati, Arti Parekh, Kendall Ng, Amy Hacker-Prietz, Lei Zheng, Timothy M. Pawlik, Daniel A. Laheru, Elizabeth M. Jaffee, Matthew J. Weiss, Dung T. Le, Ralph H. Hruban, Ana De Jesus-Acosta, Christopher L. Wolfgang, Amol K. Narang, Daniel T. Chang, Albert C. Koong, Joseph M. Herman
Purpose/ObjectivesIn locally advanced pancreatic cancer (LAPC), the role of stereotactic body radiotherapy (SBRT) is evolving. Non-invasive seromarkers are needed to define prognosis. A proximity ligation assay (PLA) can evaluate expression levels of proteins that may correlate with outcomes. Herein, seromarker levels were explored for associations with outcomes in LAPC patients who received chemotherapy and SBRT.Materials/MethodsSerum from LAPC patients in two prospective trials of hypofractionated SBRT (5-6.6 Gyx5) was collected pre-SBRT. PLA quantified the expression levels of 36 pancreatic cancer-specific candidate seromarkers: Axl, BMP2, Ca 125, CA19-9, CEA, CXCL-1/6/9/10, EGFR, Gas6, Her2, IGF2, IGFBP-2/3/7, IL-6/6Ra/7/8/12, mesothelin, MMP-1/2/3/7, osteopontin, PDGFRa, PDK1, PF4, RegIV, SPARC, TGFβ, VEGF-A/D, and YKL40. Seromarker values were log transformed due to log-normal distribution of the values and Cox regression analysis was performed to assess for any association with overall survival. The Benjamini-Hochberg method was used to control for a false discovery rate (FDR) of only 10%.ResultsSixty-four patients with LAPC were included. No clinical factors (including surgical resection, receipt of pre-SBRT chemotherapy, receipt of post-SBRT chemotherapy, performance status, and age) or potential biomarkers in the panel were associated with improved survival in this cohort after application of the FDR correction. Potential prognostic factors for improved survival for future investigation included surgical resection (p=0.007, adjusted p=0.153) and the serum expression of IL-8 (p=0.006, adjusted p=0.153), CA19-9 (p=0.031, adjusted p=0.377), and MMP1 (p=0.036, adjusted p=0.377).ConclusionThese data explore the expression of a panel of proteins in pre-SBRT serum of LAPC patients in the context of a conservative false discovery rate correction. None of the clinical factors or expression levels of the serum proteins were found to be associated with survival; however, IL8, CA19-9, and MMP1 were highlighted as possible candidates warranting inclusion in future seromarker studies in the ongoing efforts to identify tools for risk stratification and treatment allocation in LAPC.



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