A Gene Mutation Signature Predicting Immunotherapy Benefits in Patients With NSCLC
Authors: Angela Y Hu
Dong Pan
Chuan-Yuan Li
Scott J Antonia
Journal: Journal of Thoracic Oncology (2021)
Discipline: CLINICAL MEDICINE
Keywords: Gene mutation signature; Immunotherapy; NSCLC; Predictive biomarker; Tumor mutational load.
Affiliations: Department of Dermatology, Duke University Medical Center, Durham, North Carolina., Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina., Department of Medicine, Duke University Medical Center, Durham, North Carolina; Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina., Department of Dermatology, Duke University Medical Center, Durham, North Carolina; Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina. Electronic address: .

Abstract:  Introduction: Identification of patients who can benefit from immune checkpoint blockade (ICB) therapy is key for improved clinical outcome. Recently, U.S. Food and Drug Administration approved tumor mutational burden (TMB) high (TMB-H or TMB ≥ 10) as a biomarker for pembrolizumab treatment of solid tumors. We intend to test the hypothesis that mutations in select genes may be a better predictor of NSCLC response to ICB therapy than TMB-H. Methods: We compiled a list of candidate genes that may predict for benefits from ICB treatment by use of data from a recently published cohort of 350 patients with NSCLC. We then evaluated the influences of different mutation signatures in the candidate genes on ICB efficacy. They were also compared with TMB-H. The predictive powers of different mutation signatures were then evaluated in an independent cohort of patients with NSCLC treated with ICB. Results: A compound mutation signature, in which two or more of the 52 candidate genes were mutated, accounted for 145 of 350 patients with NSCLC and was associated with considerable ICB treatment benefits. Specifically, the median duration of overall survival was 36 versus 8 months in NSCLC in those with two or more versus none of the 52 genes mutated. Moreover, those patients with the compound mutation signature but had low TMB (&lt;10) achieved significant overall survival benefits when compared with those without the signature but had TMB-H (≥10). Finally, in an independent cohort of 156 patients with ICB-treated NSCLC, the median duration of progression-free survival was 8.3 months versus 3.5 months in those with the compound mutation signature versus those with none mutated in the 52 genes. Conclusions: A genetic signature with mutations in at least two of 52 candidate genes was superior than TMB-H in predicting clinical benefits for ICB therapy in patients with NSCLC. 

Retracted: No

PubPeer comments:
 We had a nice discussion of this paper at an online journal club today https: twitter.com wilsonpoon status 1240657838906761218 The model used to fit the data have a lot of parameters whilst the original data sets are limited. The approach is useful because it allows to interpolate and compare the data at the same time for different studies even if that time point was not included. But the significance and usefulness of the measured parameters themselves is somewhat limited. Maybe some of the other participants to the discussion will add more comments? Also, I noticed that several of the papers referenced have comments on PubPeer because of potential duplication of images. There is an argument that such papers should be removed from the analysis if the concerns are warranted. I recommend that everyone, especially people doing metaanalysis of papers use PubPeer and install the plugin in their web browsers Ref 197: https: pubpeer.com publications 9553E0C63DF60DDBDFE26E590CD12F Ref 160 https: pubpeer.com publications 390137155358F260205156E7F5AAD2 Ref 127 https: pubpeer.com publications C20F471D73D0767CB6AEE86DD18851 Ref 98 https: pubpeer.com publications 2E5D6FEB7F767D69F7F6AF3941871B ,