Abstract 2911: Immune related melanoma gene expression profile predicts neoadjuvant ipilimumab clinical benefit
Authors: Tarhini Ahmad A. , Lin Yan , Lin Hui-Min , Sander Cindy , Framboise William A. La , Kirkwood John M. 
Published: May 2015

Abstract
Background
Patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab in a previously reported study (ASCO 2012). Gene expression profiles of tumors of treated patients were investigated for their therapeutic predictive value.
Methods
Patients were treated with ipilimumab (10mg/kg IV every 3weeks x2 doses) bracketing surgery. Tumor specimens were obtained at baseline and at definitive surgery (week 6-8). Gene expression profiling was performed on the tumor biopsies of 32 patients using U133A 2.0 Affymetrix gene chips. Significance Analysis of Microarrays (SAMR) was performed to test the association of each gene with outcome. Pathway analysis was performed using Ingenuity Pathway Analysis software. The Benjamini and Hochberg method was used to adjust for multiple testing in the pathway analysis.
Results
Pathway analysis identified biologically relevant pathways enriched with genes that are significantly associated with clinical outcome at baseline in relation to progression free survival (PFS) and disease non-progression (NP) as well as early on-treatment outcomes (PFS and overall survival, OS). These pathways and the top associated molecules were notably immune related and highly statistically significant. Pathways associated with clinical outcome overlapped between baseline and on-treatment specimens as well as across clinical endpoints tested. Table1 summarizes the top canonical pathways identified at baseline (PRE) and on-treatment (POST) and their association with PFS, NP and OS.
Conclusions
Gene expression profiling identified pathways and genes related to inflammation and autoimmunity that significantly predict clinical benefit from neoadjuvant ipilimumab at baseline and early on-treatment. These findings warrant further investigation in relation to ipilimumab and other immunotherapeutics. (Supported by NIH award P50CA121973 and BMS)
Table 1.Pathways identified at baseline and on-treatment and their association with PFS, NP and OSPathwaysPRE/PFS (Adjusted P)PRE/NP (Adj. p)POST/PFS (Adj. p)POST/OS (Adj. p)Antigen Presentation0.00024.2x10-050.0043.1x10-05Cytotoxic T Lymphocyte-mediated Apoptosis of Target Cells0.00043.9x10-070.0040.0009T Helper Cell Differentiation0.0010.00050.050.023B Cell Development7.0x10-121.1x10-132.3x10-064.3x10-07iCOS-iCOSL Signaling in T Helper Cells0.0064.2x10-070.110.11OX40 Signaling0.0071.3x10-050.0050.0002CD28 Signaling in T Helper Cells0.048.3x10-050.040.15IL-4 Signaling0.020.00080.060.002PKCÎ¸ Signaling in T Lymphocytes0.048.0x10-050.140.04Nur77 Signaling in T Lymphocytes0.030.00010.030.008SLE Signaling1.5x10-054.3x10-06Allograft Rejection Signaling0.00034.3x10-060.0040.0006Autoimmune Thyroid Signaling0.0044.5x10-050.0210.003
Citation Format: Ahmad A. Tarhini, Yan Lin, Hui-Min Lin, Cindy Sander, William A. La Framboise, John M. Kirkwood. Immune related melanoma gene expression profile predicts neoadjuvant ipilimumab clinical benefit. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2911. doi:10.1158/1538-7445.AM2014-2911