CTNNB1 ( β -catenin) mutations in NSCLC: clinicogenomic characteristics, prognostic value and implications for therapy

Abstract Although mutations in CTNNB1 have long been associated with cancer, their impact in patients with non-small cell lung cancer (NSCLC) is not well understood. Beyond a potential role in the acquired resistance setting of EGFR-mutant NSCLC, little is known about the clinical and molecular characteristics of NSCLC patients harboring these mutations. Here, we identify 302/15,688 (1.9%) NSCLC patients with CTNNB1 mutations. These mutations frequently co-occur with EGFR and KRAS mutations and are associated with a favorable prognosis (mOS, 45.8 months overall; 19.7 months KRASmut). Patients benefit significantly from immune-checkpoint-blockade, but non-intuitively,PD-L1 TPS ≥50%(4/6 treated with monotherapy) survive the shortest. We show that patients with proposed CTNNB1 resistance mutations to EGFR-directed therapy have significantly shorter mOS when treated with targeted therapy, compared to non-resistant CTNNB1 mutations. This study highlights unique clinicogenomic features and the nuanced impact of CTNNB1 mutations on therapeutic outcomes. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study did not receive any funding. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethikkommission of medizinische Fakultaet der Unversitaet zu Koeln gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data and code are available online at github.com/moritzgls/CTNNB1-Paper-M-Glaser-et-al.