NRG1 fusion found? These 3 questions determine next steps
Industry Buzz
For NRG1 fusions, the type of test used is not a minor detail—it determines whether the fusion is found at all. DNA-based NGS panels look for the precise genomic breakpoint, but NRG1's large intronic regions place most breakpoints outside the capture footprint of DNA standard panels.
—Mya Tran, PharmD, BCOP
When a molecular report comes back showing a gene fusion, the work is not done. There is a critical interpretive step—one that requires the oncologist to answer three questions: Is this fusion oncogenic? Was it detected by the right assay? And does it represent the dominant biology of this tumor?
Is this fusion actually driving the cancer?
Not every fusion spotted on a molecular test is actively driving cancer growth. For a fusion to be dangerous, the new abnormal protein it creates needs the right structure to switch on cancer-promoting signals inside the cell.
For NRG1 fusions specifically, the fused protein must retain an intact EGF-like domain—the key structure that enables NRG1 to bind HER3, triggering HER2–HER3 heterodimerization and downstream activation of growth signaling. Without this domain, the fusion is likely non-functional and not worth targeting. []
The challenge is that DNA-based reports often cannot confirm whether this domain is intact, which leads directly to the second question.
Related: AACR 2026: 3 shifts in cancer research oncologists can’t ignoreWas the right test used?
For NRG1 fusions, the type of test used is not a minor detail—it determines whether the fusion is found at all. DNA-based NGS panels look for the precise genomic breakpoint, but NRG1's large intronic regions place most breakpoints outside the capture footprint of DNA standard panels. []
In fact, up to 67% of NRG1 fusions in lung cancer were missed entirely by DNA and identified only by RNA sequencing. DNA panels may occasionally detect NRG1 fusions when a common partner gene. []
RNA-based sequencing detects fusions regardless of where the break happened in the DNA. It also confirms that the fusion is active, properly formed, and retains the critical EGF-like domain, giving a much clearer picture of whether the fusion is truly actionable and providing a functionally confident result that DNA alone cannot deliver.[]
Related: IMA histology should trigger RNA sequencing in NSCLC—here’s whyIs the fusion driving the tumor, or along for the ride?
Even a structurally intact, properly detected fusion requires one further check: is it clonal—present throughout the tumor and contribute as a major cancer driving force?—or subclonal, appearing in only a fraction of cells and does not contribute much to cancer growth?
A fusion with a low variant allele frequency relative to other somatic alterations, or one that is inconsistently detected across samples, should raise suspicion for subclonality. In such cases, the fusion may represent a resistance mechanism or a minor subpopulation rather than the tumor's foundational biology. []
Putting it all together
For NRG1 fusions—now targetable with FDA-approved zenocutuzumab—interpretation requires confirming the fusion is structurally capable of driving cancer, verifying it was detected by a test that can actually find and characterize it, and checking that it represents what the tumor is fundamentally depending on to grow. []
Getting this right is not just scientific precision. It is what determines whether the right patient receives the right treatment.
Related: The hidden population: How many NRG1 fusion-positive patients are we missing?