NRG1 fusions in solid tumors.

Abstract

3132 Background: NRG1 fusions are rare but actionable genomic drivers that occur across a growing number of tumor types. NRG1 has an EGF-like domain that serves as a ligand for ErbB (HER3) receptors, thereby inducing heterodimerization, usually with HER2, and subsequent activation of relevant downstream signaling pathways. Agents targeting the HER2/HER3 pathway have shown early clinical promise in NRG1 fusion-positive cancers: currently zenocutuzumab has FDA Fast Track Designation for tumors harboring NRG1-fusions. Here, we update the incidence and characterization of NRG1 fusions across tumor types. Methods: Samples were submitted for clinical molecular profiling at Caris Life Sciences via Caris MI Tumor Seek (Phoenix, AZ). Gene fusion detection was performed on mRNA isolated from a formalin-fixed paraffin-embedded tumor sample using the Illumina NovaSeq platform (Illumina, Inc., San Diego, CA) and Agilent SureSelect Human All Exon V7 bait panel (Agilent Technologies, Santa Clara, CA). All NRG1 fusions with ≥ 3 junction reads were identified for manual review and for characterization of fusion class, intact functional domains, domain prediction, breakpoints, frame retention and co-occurring alterations by next-generation sequencing. Results: In an analysis of 169,273 tumor specimens, 261 unique tumors with an NRG1 fusion were identified for an overall incidence of 0.154% across tumors. NRG1 fusions were most frequently detected in NSCLC, breast cancer, ovarian cancer, pancreatic ductal adenocarcinoma, colorectal cancer, cholangiocarcinoma, prostate cancer, bladder and urothelial cancers, esophagogastric cancers and less commonly, prostate cancer, soft tissue sarcoma, anal cancer, salivary gland cancers, head and neck cancer, small intestine cancer, small cell lung cancer, endometrial cancer, thyroid cancer, neuroendocrine cancer, high grade glioma, and melanoma. The highest incidence was in breast cancer (0.301%), followed by cholangiocarcinoma (0.263%), NSCLC (0.232%), carcinoma of unknown primary (0.215%), pancreatic ductal adenocarcinoma (0.190%), ovarian cancer (0.174%), bladder cancer (0.148%), esophageal cancer (0.145%) and vulvar cancers (0.145%). There were 153 unique NRG1 fusion partners. The most common fusion partner was CD74 (12.37%), followed by SLC3A2 (8.13%), ATP1B1 (4.59%), and RBPMS (4.24%). Conclusions: NRG1 fusions are rare but actionable genomic events with significant heterogeneity of tumor type and fusion partner.