Abstract 26: Association of aneuploidy score with clinical outcomes to immunotherapy in NSCLC
Authors: Alessi João Victor , Ricciuti Biagio , Li Yvonne Y. , Gupta Hersh , Lamberti Giuseppe , Recondo Gonzalo , Nishino Mizuki , Sholl Lynette M. , Cherniak Andrew D. , Lindsay James , Sharma Bijaya , Pfaff Kathleen , Felt Kristen , Rodig Scott , Awad Mark M. 
Published: July 2021

Abstract
Introduction: Cancer aneuploidy, an unbalanced number of chromosomes, is associated with somatic mutation rate, expression of proliferative genes, and altered immune signaling. Whether aneuploidy impacts clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC is unknown.
Methods: In NSCLCs which underwent targeted next-generation sequencing (NGS), we retrospectively analyzed the aneuploidy score (AS), defined as the sum of the number of altered chromosome arms, among patients treated with immune checkpoint inhibitors. An unbiased recursive partitioning (URP) algorithm was used to investigate an optimal AS cut-off with respect to objective response rate (ORR). Multiplexed immunofluorescence (mIF) to quantify CD8+, FOXP3+, PD-1+ immune cells, and PD-L1 was performed to determine differences in tumor immune cells subsets according to AS cut-off.
Results: Among 279 patients with NSCLC treated with ICIs, the median AS was 6 (range 0 to 23). The AS was significantly lower among patients with a partial response to ICI compared to those with stable or progressive disease (4 vs 7, P=0.004). An unbiased recursive partitioning analysis identified an AS of 2 as the strongest discriminator of objective response to ICI. Compared to patients with an AS &gt;2 (N= 207, 74.2%), patients with AS ≤2 (N=72, 25.8%) had a significantly higher overall response rate (ORR 43.0% vs 19.8%, P&lt;0.001), a significantly longer median progression free survival (mPFS 6.2 months vs 2.9 months, HR: 0.70 [95% CI: 0.52-0.94], P=0.02), and a significantly longer median overall survival (mOS 19.8 months versus 13.8 months, HR: 0.66 [95% CI: 0.47-0.94], P=0.02) to treatment with ICIs. After adjusting for other variables such as performance status, presence of oncogenic driver mutation, PD-L1 expression, tumor mutational burden, and line of treatment, AS was significantly associated with improved mPFS (HR: 0.72 [95% CI: 0.52-0.99], P=0.04) and mOS (HR: 0.64 [95% CI: 0.44-0.94], P=0.02). Among 179 NSCLCs profiled by multiplex immunofluorescence, compared to cancers with an AS &gt;2, those with low aneuploidy (AS ≤2) had significantly higher numbers of CD8+, FOXP3+, PD-1+ immune cells, and PD-1+ CD8+ T cells, both intratumorally and when looking at the total numbers of cells within the tumor and the tumor-stroma interface. There was no significant difference in PD-L1 expression levels or tumor mutational burden on tumor cells or on immune cells according to aneuploidy score.
Conclusion: NSCLCs with low aneuploidy have a distinct immune microenvironment and more favorable outcomes to ICIs.
Citation Format: João Victor Alessi, Biagio Ricciuti, Yvonne Y. Li, Hersh Gupta, Giuseppe Lamberti, Gonzalo Recondo, Mizuki Nishino, Lynette M. Sholl, Andrew D. Cherniak, James Lindsay, Bijaya Sharma, Kathleen Pfaff, Kristen Felt, Scott Rodig, Mark M. Awad. Association of aneuploidy score with clinical outcomes to immunotherapy in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 26.