Bridging NSCLC treatment gaps: ‘The clinical stakes of missing an NRG1 fusion are not abstract’
Industry Buzz
Many platforms deprioritize RNA, pursuing it only if tissue remains adequate after DNA processing. This sequential logic [limits] detection of RNA-dependent targets—none more so than NRG1 fusions, whose heterogeneous breakpoints fall within large intronic regions standard NGS can't reliably capture.
—Mya Tran, PharmD, BCOP, precision oncology clinical pharmacist
In locally advanced/metastatic NSCLC, the foundation of precision oncology rests on molecular profiling—yet the very samples upon which that profiling depends are frequently inadequate for the task asked of them.
The growing mismatch in NSCLC molecular profiling
The majority of metastatic NSCLC cases diagnosed via minimally invasive techniques—CT-guided percutaneous biopsy, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), or fine needle aspiration—yield small specimens with inherently limited tumor content.
When specimen is collected from bone metastases, which is a common site of metastases in NSCLC, the challenge compounds: Decalcification protocols routinely degrade both DNA and RNA, compromising downstream sequencing quality before testing even begins.[][]
Against this backdrop of limited material, the biomarker landscape continues to expand, demanding not just DNA-based mutation profiling, but RNA sequencing for fusion detection and IHC for protein expression markers such as PD-L1, HER2, and MET.[]
Related: IMA histology should trigger RNA sequencing in NSCLC—here’s whyInstitutional pressures create risk
The tension between sample reality and clinical necessity has never been greater. Institutional pressures to deliver rapid results have led many centers to adopt reflex small-panel DNA testing as a first-line strategy, prioritizing turnaround time over comprehensiveness.
While clinically understandable, this approach carries a meaningful risk: tissue exhaustion. Once a small biopsy specimen is consumed by an upfront limited panel, the opportunity for broader profiling—including RNA sequencing—may be permanently lost.
Liquid biopsy offers a non-invasive complement, but is not a replacement for tissue testing. Circulating tumor DNA is limited by low tumor fraction in a significant subset of patients, and critically, most commercially available liquid biopsy platforms lack an RNA sequencing component entirely, rendering them poorly suited to detect fusion events.[] Biomarkers requiring tissue-based IHC cannot be captured at all through ctDNA testing. The practical consequence is that oncologists are frequently forced to make treatment decisions on incomplete molecular information—a compromise that carries real clinical cost.
'The clinical stakes are not abstract'
RNA sequencing deserves particular emphasis as a vulnerable point in the testing workflow. RNA is inherently less stable than DNA and degrades more readily, especially in small or suboptimally preserved samples.[] Although concurrent DNA/RNA co-extraction is increasingly available, many platforms still deprioritize RNA, pursuing it only if tissue remains adequate after DNA processing.
This sequential logic, while pragmatic, systematically disadvantages the detection of RNA-dependent targets — none more so than NRG1 fusions, whose highly heterogeneous breakpoints fall within large intronic regions that standard DNA-based NGS cannot reliably capture.[][]
The clinical stakes of missing an NRG1 fusion are not abstract. Median overall survival for stage IV NRG1 fusion-positive NSCLC is only 15.5 months, responses to chemotherapy, immunotherapy, and conventional targeted therapy have been consistently poor, and many patients present with aggressive disease burden that leaves little room for sequential testing or repeat biopsy at progression.[]
Zenocutuzumab (Bizengri), now FDA-approved for NRG1 fusion-positive cancers, offers a meaningful therapeutic option — but only for patients whose rearrangement has been identified.[] This demands a deliberate rethinking of testing strategy: Thoughtful biopsy planning to maximize sample adequacy, tumor enrichment through microdissection where feasible, and upfront comprehensive profiling that incorporates RNA sequencing alongside DNA from the outset — not as a contingency, but as a standard.