Coexistence of multiple oncogenic drivers in non-small cell lung cancer (NSCLC) is uncommon and can present diagnostic challenges. Limited or conventional molecular assays, such as targeted polymerase chain reaction (PCR) panels, may fail to detect co-occurring genomic alterations. Missed alterations can restrict therapeutic options, particularly in resource-constrained settings where comprehensive testing is not routinely available. This report describes a stepwise molecular profiling approach that identified both HER2 (ERBB2) amplification and an EGFR L858R mutation in a single patient with lung adenocarcinoma.
A 54-year-old woman, a lifelong non-smoker, was diagnosed with Stage IIIA lung adenocarcinoma in 2020. Initial molecular evaluation using PCR-based testing did not identify EGFR mutations. The clinical course included disease progression with the development of brain metastases and severe toxicity from chemotherapy, prompting reconsideration of therapeutic strategy and additional molecular analyses in a resource-limited clinical setting.
After progression and treatment-related complications, the care team pursued further molecular characterization using available modalities. Fluorescence in situ hybridization (FISH) testing on tumor tissue identified HER2 amplification. Based on this finding, HER2-directed therapy was introduced.
Subsequently, archived tumor material underwent broader profiling with next-generation sequencing (NGS). NGS analysis revealed a previously undetected EGFR L858R mutation. The EGFR mutation had been missed by the initial PCR-based assay; details about the specific PCR panel, limits of detection, or the timing and scope of tissue sampling were not reported in the abstract.
Following identification of HER2 amplification by FISH, the patient was treated with trastuzumab, resulting in clinical and radiological stabilization that lasted 23 months. During that period the disease was described as stabilized on imaging assessments.
In late April 2025, new pulmonary lesions were documented, indicating disease progression despite prior HER2-targeted control. With the EGFR L858R mutation confirmed by prior NGS of archived tissue, the treatment plan was revised and the patient was started on the EGFR tyrosine kinase inhibitor gefitinib in May 2025.
The sequential therapeutic responses — prolonged stabilization on trastuzumab followed by progression and switch to EGFR-targeted therapy — are presented as consistent with the biological activity of both oncogenic alterations in this individual patient.
This case illustrates several clinically relevant points for practice in settings with constrained molecular resources:
Initial PCR-based assays can fail to detect co-occurring actionable alterations such as an EGFR L858R mutation when used alone. The limitations of PCR panels versus broader methods were implicated but not detailed in the abstract.
Stepwise molecular profiling that incorporates additional techniques (here FISH followed by NGS) can uncover complementary or coexisting drivers—HER2 amplification by FISH led directly to HER2-targeted treatment, while later NGS identified EGFR L858R that informed a subsequent switch to an EGFR inhibitor.
The observed 23-month period of disease stabilization on trastuzumab supports that HER2 amplification was a clinically actionable driver in this patient. Later emergence of new lung lesions and initiation of gefitinib based on the EGFR L858R finding suggests the EGFR alteration was also biologically relevant.
Resource-limited environments may benefit from a pragmatic, sequential testing strategy that uses available assays to identify actionable alterations; however, single-case observations cannot define the optimal testing algorithm or the relative hierarchy of concurrent drivers.
Limitations and missing details noted in the source abstract include lack of information on the specific PCR assay used initially, allele fraction or quantitative metrics from NGS, timing and site of the tissue sampled for each test, and objective response criteria or detailed imaging timelines beyond the reported stabilization period.
In this single-case report of Stage IIIA lung adenocarcinoma, stepwise molecular profiling in a resource-constrained setting identified HER2 amplification by FISH and later an EGFR L858R mutation by NGS. The patient experienced 23 months of clinical and radiologic stabilization on trastuzumab, followed by disease progression and initiation of gefitinib after detection of EGFR L858R. The case underscores that limited initial molecular testing can miss co-occurring, therapeutically actionable alterations and that sequential use of complementary assays can meaningfully influence management. The authors emphasize that broader conclusions about diagnostic sequencing or driver dominance cannot be drawn from a single observation.