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

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.