Neuregulin 1 (NRG1) gene fusions represent a rare but increasingly important class of oncogenic drivers across solid tumors. These fusions activate the HER3–HER2 signaling axis, leading to downstream PI3K pathway activation and tumor growth. The clinical relevance of NRG1 fusions has recently been underscored by the FDA’s Breakthrough Therapy Designation for the HER2/HER3–targeted bispecific antibody zenocutuzumab in patients with NRG1 fusion–positive cancers, including non–small-cell lung cancer and pancreatic ductal adenocarcinoma (PDAC).
Despite this regulatory milestone, key questions remain unanswered. The optimal diagnostic approach for identifying NRG1 fusions, their genomic diversity, and the clinicopathologic characteristics of affected patients—particularly in pancreatic cancer—have not been systematically defined. To address these gaps, investigators from Memorial Sloan Kettering Cancer Center conducted a comprehensive analysis of NRG1 fusion–positive cancers, with a focused evaluation of real-world outcomes in PDAC.
The article was published online in the Journal of the National Cancer Institute (JNCI) on December 13, 2025 under the title “NRG1 Fusion–Positive Solid Tumors: Clinical Detection, Genomic Landscape, and Real-World Data in Pancreatic Cancer.”
The study was authored by Alison M. Schram, MD; Soo-Ryum Yang, MD; Genessa Kahn; Rogelio Velasco, MD; Matteo Repetto, MD; Richard Kinh Gian Do, MD, PhD; Sara DiNapoli, PhD; Purvil Sukhadia, MS; Megan Troxel, MS; Kerem Ozcan, MD; Zeynep Tarcan, MD; Marc Ladanyi, MD; James J. Harding, MD; Alexander Drilon, MD; Olca Basturk, MD; and Eileen M. O’Reilly, MD, and is available as an open-access publication.
You can also read about Zenocutuzumab: Uses in Cancer, Side Effects, Dosages, Expectations, and More on OncoDaily.
Methods and Endpoints
This retrospective study identified patients with NRG1 fusion–positive tumors from institutional molecular profiling databases at Memorial Sloan Kettering. Clinical, pathologic, and genomic data were extracted from electronic medical records.
Detection methods for NRG1 fusions were evaluated, including DNA-based next-generation sequencing, RNA-based sequencing, or both. Fusion partners were catalogued to characterize the genomic landscape. For patients with NRG1 fusion–positive PDAC, detailed review of radiologic findings, histopathology, systemic therapies, and outcomes was performed.
Key clinical endpoints included progression-free survival (PFS) on first-line chemotherapy and overall survival (OS) from diagnosis in the PDAC cohort.
Results
Among 76,531 patients profiled, 48 NRG1 fusion–positive cases were identified, confirming the rarity of this alteration. Lung cancer was the most common tumor type (60%), followed by pancreatic ductal adenocarcinoma (21%) and breast cancer (10%). Nearly half of all patients received HER2- and/or HER3-directed therapy, reflecting growing clinical adoption of targeted strategies in this molecular subset.
RNA-based sequencing emerged as the most effective detection method, identifying the majority of cases, while DNA-only testing missed a substantial proportion of fusions. In total, 21 distinct fusion partners were observed, with CD74 being the most frequent, followed by ATP1B1, highlighting significant genomic heterogeneity.
Biologically, NRG1 fusion–positive tumors showed distinct molecular features. Lung cancers were otherwise devoid of canonical oncogenic drivers, and pancreatic cancers were uniformly KRAS wild-type—a notable finding given the near ubiquity of KRAS mutations in PDAC.
NRG1 fusion–positive PDAC demonstrated a unique clinical phenotype. Patients were substantially younger than typical PDAC populations, with a median age of 48.5 years. Outcomes also appeared more favorable than expected for pancreatic cancer. Median progression-free survival on first-line chemotherapy was 12.6 months, and median overall survival from diagnosis reached 39.6 months, although confidence intervals were wide due to small patient numbers. These findings suggest a biologically distinct and potentially more indolent disease course in this subgroup.
Conclusion
This large institutional analysis establishes NRG1 fusions as a clinically actionable oncogenic driver across multiple solid tumors and provides critical insights into their detection and biology. RNA-based sequencing is essential for reliable identification and should be prioritized when NRG1 fusions are suspected.
In pancreatic cancer, NRG1 fusion–positive disease defines a rare but distinct molecular subtype characterized by younger age, KRAS wild-type status, and unexpectedly prolonged survival. As targeted therapies such as zenocutuzumab enter clinical practice, systematic molecular testing and prospective studies will be crucial to optimize patient selection and fully realize the therapeutic potential of NRG1-directed strategies.
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