NRG1 fusion-positive solid tumors: clinical detection, genomic landscape, and real-world data in pancreatic cancer
Menée à l'aide de données clinicopathologiques issues de registres médicaux et portant sur 76 531 patients atteints d'un cancer, cette étude identifie des cas de cancer du pancréas avec fusion du gène NRG1, analyse les caractéristiques cliniques et histopathologiques de ces tumeurs puis examine les méthodes de détection et le pronostic
Background : NRG1 fusions are unique oncogenic drivers that activate the HER3/HER2/PI3K pathway. The FDA granted Accelerated Approval to a HER2/HER3 antibody, zenocutuzumab, for treatment of NRG1 fusion-positive (NRG1+) non-small-cell lung and pancreatic cancer (PDAC). The optimal detection methods and clinicopathologic features of patients with NRG1+ cancer have not been systematically studied. We review NRG1+ cancer and focus on outcomes in PDAC.
Methods : NRG1+ patients at Memorial Sloan Kettering were identified using institutional databases. Clinicopathologic data were extracted from the medical record. NRG1+ PDAC cases underwent review of radiology, pathology, treatment data, and assessment of progression-free and overall survival.
Results : Out of 76,531 patients, 48 NRG1+ cases were identified. The most common tumor types were lung (60%), PDAC (21%), and breast (10%). Approximately half (46%) received HER2 and/or HER3-directed therapy. Patients were identified by RNA (n = 34), DNA (n = 11), or both (n = 3). RNA was superior to DNA for fusion identification. Twenty-one fusion partners were detected, most commonly CD74 (40%) and ATP1B1 (10%). Lung cancers were otherwise driver-negative and PDAC were KRAS wild-type. NRG1+ PDAC exhibited distinct histopathologic and clinical features. Median age was 48.5 years, median PFS on 1st-line chemotherapy was 12.6 months (n = 7; 95% CI 2.9-NR), and median OS from diagnosis was 39.6 months (n = 9; 95% CI 23.2-NR).
Conclusions : NRG1 fusions are a newly described clinically actionable target in solid tumors. We report the landscape of NRG1+ cancers and highlight the importance of RNA testing. NRG1+ PDAC is enriched in younger patients with KRAS wild-type disease and has a unique biology.
Journal of the National Cancer Institute , article en libre accès, 2025