Increased detection of NRG1 fusions in non-squamous non-small cell lung cancer using combined DNA and RNA sequencing in a real-world cohort.

NRG1 gene fusions are rare oncogenic drivers in non-squamous NSCLC, occurring in approximately 0.2-0.3% of cases and enriched in invasive mucinous adenocarcinoma (IMA). Their true incidence may be underestimated by DNA-only NGS. Following FDA approval of a bispecific HER2-HER3 antibody for NRG1 fusion-positive tumors, we evaluated the prevalence, clinicopathologic, and molecular characteristics of these cases in a real-world Brazilian cohort systematically profiled with integrated DNA and RNA sequencing. We retrospectively analyzed all non-squamous NSCLC samples tested at the centralized molecular laboratory of Oncoclínicas Medicina de Precisão (OCPM) from February 2022 to December 2025. Only tumors with successful paired DNA- and RNA-based NGS were included. Demographic, clinical, histologic, molecular, and outcome data were collected from institutional records. Among 1,536 patients, 12 (0.8%) harbored NRG1 fusions. Median age was 66 years; 83% were female. Six were former and five never-smokers. Eight of 12 had stage IV disease at diagnosis; central nervous system (CNS) metastases were present in 2 patients (25%). Ten tumors (83%) were IMAs, all PD-L1 negative and TMB-low. TP53 was the most frequent co-mutation (50%) and a co-occurring KRAS mutation was identified in one patient. CD74 (n = 5) and SLC3A2 (n = 3) were predominant fusion partners, with single cases involving WRN, LIPE, VAMP2, and SDC4. Among metastatic patients, first-line therapies included chemoimmunotherapy (n = 5), chemotherapy alone (n = 2), and radiotherapy for CNS disease (n = 1). None received HER2-HER3-directed therapy. After a median follow-up of 7.3 months, median overall survival for stage IV patients was 7.9 months (95% CI, 5.4-NA). NRG1 fusions were identified in 0.8% of NSCLC, exceeding historical estimates and underscoring the importance of RNA-based NGS for fusion detection. The clinical and molecular profile mirrored prior reports, with predominant female patients, IMA histology, PD-L1 negativity, and low TMB. Outcomes were poor in metastatic patients lacking access to targeted therapy, supporting the need for broader implementation of RNA sequencing and access to anti-HER3 agents.