Burden of copy number alterations predicts outcomes in immune checkpoint blockade treated gastrointestinal cancer patients

Author:Zhihao Lu, Huan Chen, Shuang Li, Xi Jiao, Lihong Wu, Henghui Zhang, Lin Shen

Background: Despite the great achievements made in immune checkpoint blockade (ICB) in cancer therapy, how to identify patients who may benefit from ICB still remains one of the central questions, especially in gastrointestinal (GI) cancer. 

Methods: To address this, we analyzed FFPE tumor specimens from 73 patients with metastatic GI cancers who were treated with ICB. All patients were randomly assigned into discovery (60%) and validation (40%) cohorts. Overall, tumor mutation burden (TMB) and copy number alterations (CNAs) were determined by using the whole-exome sequencing platform. FFPE samples of 65 patients were analyzed via a multiplex RNA immune oncology sequencing panel. 

Results: Here we show that lower burden of copy number alteration (CNA) was observed in responders to immunotherapy in both discovery and validation cohorts. More importantly, lower burden of CNA in GI cancers were associated with improved objective response, clinical benefit and overall survival. Efficacy also correlated with the higher TMB. Of note, a combinatorial biomarker of TMB and burden of CNA may better stratify responders from patients received immunotherapy. In addition, patients with lower burden of CNA revealed increased IFNγ and expanded immune signatures in our GI patient cohort and TCGA cohorts as well. 

Conclusions: Our results suggest that burden of CNA may expand the predictive and prognostic value of genomic determinants in identifying potential responders with GI cancer to immune checkpoint blockade therapy.