Aneuploidy May Predict NSCLC Immunotherapy Response

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Research presented at the virtual AACR Annual Meeting 2021 suggests a potential role for aneuploidy as a biomarker for immune checkpoint inhibitor (ICI) response in non-small-cell lung cancer (NSCLC) patients. 

“Cancer aneuploidy is associated with somatic mutation rate, expression of proliferative genes, and altered immune signaling”, explained lead investigator João Alessi, from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA. 

Next-generation sequencing (NGS) analysis was used to assess 1582 NSCLC patients for aneuploidy, defined as the number of chromosomal arm alterations. 

Median aneuploidy score did not significantly differ between never smokers and those who were current or former smokers, nor between patients with squamous or nonsquamous histology, but patients with stage I tumours had significantly lower median aneuploidy scores than patients with stage II, III or IV disease. 

In addition, patients with PD-L1 expression of at least 50% had significantly lower median aneuploidy scores than those with PD-L1 expression of less than 1%, and there was a “very weak, positive correlation” between aneuploidy score and tumour mutational burden (TMB), observed João Alessi. 

Furthermore, there was a significant correlation between aneuploidy and the presence of key oncogene drivers, with the highest median aneuploidy scores found among patients with NTRK, EGFR, ALK and RET alterations, and the lowest in those with activating BRAF, MET and KRAS alterations. 

When the team analysed data from a cohort of 299 patients treated with ICI therapy, the response rate was significantly higher among the 79 patients with an aneuploidy score of 2 or less versus the 220 patients who had a score above 2, at 43.0% versus 19.1%. 

Moreover, the patients with low versus high aneuploidy had significantly better median progression-free survival (PFS; 6.2 vs 3.2 months, hazard ratio [HR]=0.74) and overall survival (21.0 vs 13.8 months, HR=0.73). 

Low aneuploidy continued to be a significant predictor for PFS, but not overall survival, after adjusting for ECOG performance status, TMB, PD-L1 expression and line of treatment, the presenter commented. 

By contrast, analysis of a cohort of first-line platinum-based chemotherapy-treated NSCLC patients did not show a significant difference in objective response rate or PFS between those with low and high aneuploidy scores.  

To explore the mechanism by which aneuploidy score might impact advanced tumour response to immunotherapy, the team looked at CD8+ T cells and PD-1-positive immune cells in 35 patients with a low score and 65 patients with a high score. 

This revealed that low aneuploidy tumours were “enriched” with CD8+ cells and PD-1-positive cells compared with high aneuploidy tumours in the intratumoural space alone and when combined with the tumour-stroma interface. 

“NSCLCs with low aneuploidy have a distinct immune microenvironment and more favorable outcomes to ICIs”, João Alessi summarised. 

“Given the burgeoning number of recommended molecular tests for NSCLC, NGS testing offers an opportunity for aneuploidy assessment”, the presenter suggested. 

Reference  

Abstract 26. Alessi JV, Ricciuti B, Li YY, et al. Association of aneuploidy score with clinical outcomes to immunotherapy in NSCLC. AACR Annual Meeting 2021; 10–15 April