When a pathology report returns invasive mucinous adenocarcinoma (IMA), the histologic subtype itself should prompt a deliberate pause—and a harder look at the molecular workup.

IMA is a clinicopathologically distinct variant comprising approximately 3%–10% of all lung adenocarcinomas,[1] characterized by older age at diagnosis (median ~70 years), lighter smoking histories (median 15 vs 20 pack-years), and a notably immunologically cold profile with lower PD-L1 expression (median TPS 0% vs 5%) and reduced tumor mutational burden (6.8 vs 8.5 mut/Mb) compared to nonmucinous adenocarcinoma.[2]

These features collectively narrow the utility of immunotherapy, making precise molecular driver identification not just preferable but essential.

IMA limits immunotherapy—driver detection is critical

KRAS mutations are the dominant genomic event in IMAs, present in 70%–76% of cases, and their identification on a standard DNA-based panel can create a false sense of molecular completeness. IMA carries a disproportionate burden of NRG1 fusions (the second most common driver at approximately 7%–9%) and the consequences of missing this rearrangement are significant.

NRG1-rearranged IMAs behave more aggressively, with significantly worse recurrence-free survival compared to KRAS-mutant IMAs (P < 0.0001).[3][4] Responses to cytotoxic chemotherapy, immunotherapy, and standard targeted agents in NRG1 fusion-positive NSCLC have been consistently disappointing.[5] Zenocutuzumab, a HER2/HER3-targeting bispecific antibody, now carries FDA approval specifically for this population—making accurate identification directly actionable.[6]

NRG1 IMA: Aggressive, now targetable

The enrichment of NRG1 fusions in IMA is well-documented across multiple cohorts. In the eNRGy1 global registry of 110 NRG1 fusion-positive NSCLC patients, IMA was the most frequent adenocarcinoma subtype at 57%, and a Brazilian cohort found that 10 of 12 NRG1-positive lung tumors (83%) were IMA.[7][8]

Critically, while NRG1 fusions are mutually exclusive with other drivers in approximately 94% of cases, a subset does harbor co-occurring alterations—including KRAS, EGFR, and ALK fusion. This means a positive KRAS or EGFR result on a DNA panel does not rule out a concurrent NRG1 rearrangement.[7]

DNA testing misses NRG1—RNA required

This co-occurrence risk, combined with a fundamental detection challenge, makes the case for RNA sequencing in all IMA diagnoses.

In IMA, the histology itself should be the trigger: Regardless of what the DNA panel shows, comprehensive molecular profiling inclusive of RNA sequencing should be standard practice to ensure no patient with a targetable—and now treatable—NRG1 fusion is overlooked.

Source – MDLinx

1. Chang WC, Zhang YZ, Nicholson AG. Pulmonary invasive mucinous adenocarcinoma. Histopathology. 2024;84(1):18-31. doi:10.1111/his.15064

2. Di Federico A, Hong L, Elkrief A, et al. Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors. Ann Oncol Off J Eur Soc Med Oncol. 2025;36(3):297-308. doi:10.1016/j.annonc.2024.11.014

3. Masago K, Kuroda H, Seto K, et al. Genomic Landscape of Resected Invasive Mucinous Adenocarcinoma of the Lung. Clin Lung Cancer. 2025;26(7):583-594.e4. doi:10.1016/j.cllc.2025.06.004

4. Chang JC, Offin M, Falcon C, et al. Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes. Clin Cancer Res Off J Am Assoc Cancer Res. 2021;27(14):4066-4076. doi:10.1158/1078-0432.CCR-21-0423

5. Drilon A, Duruisseaux M, Han JY, et al. Clinicopathologic Features and Response to Therapy of NRG1 Fusion-Driven Lung Cancers: The eNRGy1 Global Multicenter Registry. J Clin Oncol Off J Am Soc Clin Oncol. 2021;39(25):2791-2802. doi:10.1200/JCO.20.03307

6. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma. FDA. Published online December 4, 2024.

7. Drilon A, Duruisseaux M, Han JY, et al. Clinicopathologic Features and Response to Therapy of NRG1 Fusion-Driven Lung Cancers: The eNRGy1 Global Multicenter Registry. J Clin Oncol Off J Am Soc Clin Oncol. 2021;39(25):2791-2802. doi:10.1200/JCO.20.03307

8. Araújo BJ, Visani F, Paes RD, et al. Increased detection of NRG1 fusions in non-squamous non-small cell lung cancer using combined DNA and RNA sequencing in a real-world cohort. Lung Cancer. 2026;215:109370. doi:10.1016/j.lungcan.2026.109370