MDLinxIMA Histology Should Trigger RNA Sequencing in NSCLC—Here’s Why

Invasive mucinous adenocarcinoma (IMA), 3%–10% of lung adenocarcinomas, carries a disproportionate burden of NRG1 fusions alongside dominant KRAS mutations. With zenocutuzumab now FDA-approved for NRG1-rearranged NSCLC, histology-triggered RNA sequencing becomes clinically actionable.

Clinical Considerations

• IMA shows an immunologically cold profile with median PD-L1 TPS 0% and TMB 6.8 mut/Mb, narrowing immunotherapy utility.
• KRAS mutations dominate at 70%–76%, but NRG1 fusions appear in 7%–9% as the second most common driver in IMA.
• NRG1-rearranged IMAs show significantly worse recurrence-free survival versus KRAS-mutant IMAs (P < 0.0001) and respond poorly to chemotherapy and immunotherapy.
• DNA-based NGS misses NRG1 fusions because breakpoints fall within large intronic regions; RNA sequencing is required for reliable detection.

Practice Applications

• Integrate RNA sequencing into IMA molecular workup regardless of DNA panel results.
• Recognize that positive KRAS or EGFR findings do not exclude concurrent NRG1 rearrangement.
• Avoid sequential testing delays that defer RNA panels until DNA results return.
• Consider zenocutuzumab for confirmed NRG1 fusion-positive disease after identification.

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