Highlights
- •High tumor mutation burden can be predictive of better response to immune checkpoint blockade but varies across cancers and has inconsistent definitions.
- •Genomic alterations in 16 genes that clustered into neuronal development/differentiation (PTPRD, NTRK3, ZFHX3, NOTCH3, EPHA5, EPHA7), receptor tyrosine kinase/phosphatase signaling (EPHA5, PTPRD, NTRK3, LATS1, PPM1D, EPHA7), and epigenetic regulation (ARID1A, TET1, SETD2, CREBBP, CIC, POLE) were associated with survival in patients treated with immune checkpoint blockade.
- •The ImmGA signature is predictive of response to immune checkpoint blockade.
Abstract
Background: High tumor mutation burden (TMB) and total mutation count (TMC) can be predictive
of better response to immune checkpoint blockade (ICB). Nevertheless, TMB and TMC
are limited by variation across cancers and inconsistent definitions due to different
profiling methods (targeted vs whole genome sequencing). Our objective was to identify
genomic alterations (GAs) associated with ICB response and builds a novel genomic
signature predictive of ICB response, independent of TMB/TMC.
Methods: This was a pan-cancer next generation sequencing (NGS)-association study using January
2014-May 2016 data from AACR Project Genomics Evidence Neo-plasia Information Exchange
(GENIE). Participants included 6619 patients with metastatic or un-resectable cancer
across 9 cancer types (including 1572 ICB-treated patients). GA data was collected
using next-generation sequencing (NGS) assays and downloaded from cbioportal.org.
Predictive analyses for ICB response were performed to develop the signature (ImmGA).
Results: GAs in 16 genes were associated with improved OS in ICB-treated patients (p < 0.005). 13 GAs were associated with an OS benefit in ICB-treated patients (Pinteraction < 0.05); these genes composed the ImmGA signature. High ImmGA score (≥2 alterations
out of 13 predictive GAs) was associated with better OS in ICB-treated patients (AHR:0.67,
95%CI [0.6–0.75], p = 1.4e−12), even after accounting for TMC (Pinteraction = 8e−16). High ImmGA was associated with better OS in ICB-treated patients across most cancers
and across different ICB treatment modalities.
Conclusion: A novel signature predictive of ICB response (ImmGA) was developed from 13 GAs.
Further investigation of the utility of ImmGA for treatment and trial selection is
warranted.
Keywords
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Article info
Publication history
Published online: August 28, 2021
Accepted:
August 25,
2021
Received in revised form:
June 7,
2021
Received:
January 9,
2021
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
