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PubMed2026

Co-Occurring EGFR L858R Mutation and HER2 Amplification in NSCLC Identified by Stepwise Molecular Profiling.

BACKGROUND The coexistence of multiple oncogenic drivers in non-small cell lung cancer (NSCLC) is a rare and diagnostically challenging molecular configuration. Conventional polymerase chain reaction (PCR)-based testing may fail to detect co-occurring genomic alterations, potentially limiting therapeutic options, particularly in resource-constrained settings. CASE REPORT We describe the case of a 54-year-old non-smoking woman diagnosed with Stage IIIA lung adenocarcinoma in 2020. Initial PCR-based molecular testing was negative for EGFR mutations. Following disease progression with brain metastases and severe chemotherapy toxicity, stepwise molecular profiling in a resource-limited setting identified HER2 (ERBB2) amplification via fluorescence in situ hybridization (FISH). The patient achieved 23 months of clinical and radiological stabilization on trastuzumab. Subsequent next-generation sequencing (NGS) analysis of archived tissue revealed a previously undetected estimated glomular filtration rate (EGFR) L858R mutation. In late April 2025, new lesions appeared in the lungs, indicating disease progression. Based on the previously verified EGFR L858R mutation, the treatment strategy was revised and gefitinib was initiated in May 2025. CONCLUSIONS This case illustrates that co-occurring EGFR and HER2 alterations can remain undetected following initial limited molecular testing, and that stepwise molecular profiling in a resource-constrained setting can facilitate identification of therapeutically actionable targets. The sequential clinical responses observed are consistent with the biological relevance of both alterations, although broader conclusions regarding diagnostic strategy or driver hierarchy cannot be drawn from a single observation.

Humans↗

PubMed2026

The impact of EGFR subtype combined with TP53 co-mutation status on survival outcomes with front-line osimertinib in non-small cell lung cancer (NSCLC).

BACKGROUND: Osimertinib is a standard therapy for EGFR-mutant NSCLC. However, markers to better identify those at risk for poor outcomes are needed. This is the largest study to date evaluating the impact of EGFR subtype combined with TP53 co-mutation status on survival endpoints with front-line osimertinib. METHODS: Patients from a U.S. clinical-genomic database with advanced EGFR-mutant NSCLC receiving front-line osimertinib were studied. Real-world progression-free survival (rwPFS) and overall survival (OS) were determined using Kaplan-Meier methods, and multivariable Cox regression compared outcomes after accounting for relevant clinical covariates. RESULTS: Of 606 patients, 277 (46%) had EGFR L858R, 384 (63%) had TP53 co-mutations, and 186 (30.7%) had both. Bearing L858R vs. exon 19 deletions (rwPFS: hazard ratio [HR] 1.4, P = 0.001; OS: HR 1.3, P = 0.01) or a TP53 co-mutation vs. wildtype (rwPFS: HR 1.5, P < 0.001; OS: HR 1.6, P < 0.001) predicted inferior outcomes. Especially short median rwPFS (10.1 vs. 21.4 months, HR 2.2, P < 0.001) and OS (21.3 vs. 53.4 months, HR 2.3, P < 0.001) were observed in patients with both markers (L858R/TP53-mutant) as compared to neither (exon 19 deletion/TP53-wildtype). CONCLUSIONS: Having EGFR L858R or a TP53 co-mutation were independent predictors of inferior rwPFS and OS with front-line osimertinib. Patients with both unfavorable alterations had the shortest survival. Risk stratifying using a combination of these markers can assist in identifying patients for novel trials or approved intensified therapies.

Humans↗

PubMed2026

Osimertinib With or Without Chemotherapy in Advanced Non-Small Cell Lung Cancer With EGFR and Concurrent TP53 Mutations: A Randomized Clinical Trial.

IMPORTANCE: Combination therapy has emerged as a promising therapeutic approach for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, its clinical benefit-risk profile remains a focus of ongoing debate. Identifying patients most likely to derive benefit from such regimens remains an unmet clinical need. OBJECTIVE: To prospectively compare the efficacy and safety of first-line osimertinib plus chemotherapy with osimertinib monotherapy for patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, open-label, phase 3 study conducted at 17 sites in China. Between March 25, 2021, and July 11, 2024, a total of 294 eligible patients with treatment-naive, stage IV or recurrent nonsquamous NSCLC harboring concurrent TP53 and EGFR-sensitizing mutations were enrolled. INTERVENTIONS: Patients were randomized (1:1) to receive osimertinib plus chemotherapy (pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy of osimertinib plus pemetrexed; n = 146) or osimertinib monotherapy (n = 148). MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, response, safety, and quality of life. RESULTS: Among 294 enrolled patients, the median age was 57 years (range, 26-79 years), and 159 (54.1%) were female. The data cutoff date was November 11, 2025. At a median follow-up of 25.1 months for the osimertinib-chemotherapy group and 26.1 months for the osimertinib monotherapy group, median progression-free survival was significantly longer with osimertinib plus chemotherapy than with osimertinib monotherapy (34.0 vs 15.6 months; difference, 18.4 months [95% CI, 9.9-22.3]; hazard ratio, 0.44 [95% CI, 0.32-0.60]; P < .001). This benefit was consistent across prespecified subgroups, including those with brain metastases and L858R mutations. The overall survival data remained immature (30.6% maturity); however, a trend toward overall survival benefit with combination therapy was observed. The incidence of grade 3 or higher treatment-related adverse events was higher in the combination group, with no new safety signal identified. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, osimertinib plus chemotherapy significantly increased progression-free survival among patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. These findings provided a clinical rationale for individualized combination strategies in the management of patients with EGFR-mutated NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04695925.

Adult↗

PubMed2026

pKAKA: a protein language model for prioritizing kinase-disrupting variants in diseases.

Protein kinases are pivotal regulators of cellular signaling, and their genetic variations are frequently implicated in diseases. Although numerous kinase mutations have been identified as drivers of altered activity, with a few successfully targeted therapeutically, the functional impact of most variants remains uncharacterized. To bridge this gap, we curate a comprehensive dataset that contains 2553 experimentally validated kinase activity-related key alterations (KAKAs) from the literature. While many mutations outside canonical functional regions are known to affect kinase activity, systematic methods to predict their functional consequences are lacking. Consequently, we develop a computational method to predict potential KAKAs, leveraging transfer learning on the pre-trained protein language model ProtBert. Our model, termed pKAKA, achieves an impressive AUC score of 0.9593 and outperforms the AlphaMissense benchmark in comparative testing. Systematic analysis of kinase missense mutations underscores the critical role of KAKAs in pathogenesis, with highlights including JAK2 V617F in atherosclerotic cardiovascular disease, LRRK2 G2385R in Parkinson's disease, EGFR L858R in lung adenocarcinoma, and EGFR G598V in glioma. Overall, this study significantly advances our understanding of how mutations that influence kinase activity contribute to disease mechanisms.

Humans↗

PubMed2026

Integrated multi-omic profiling enables recurrence risk stratification beyond pathological stage in resected EGFR-mutant lung adenocarcinoma.

BACKGROUND: Early-stage EGFR-mutant lung adenocarcinoma (LUAD) demonstrates heterogeneous outcomes after curative surgery, yet adjuvant treatment decisions are guided by pathological stage alone. Following the ADAURA trial, adjuvant osimertinib is the standard of care for resected stage IB-IIIA EGFR-mutant LUAD; however, real-world data demonstrate that up to 40% of patients remain disease-free at five years without adjuvant osimertinib, underscoring the need for improved risk stratification. PATIENTS AND METHODS: We performed integrated clinical, genomic and transcriptomic profiling of 400 patients with resected stage IA-IIIA EGFR-mutant LUAD. EGFR-mutant recurrence risk models integrating clinical, genomic and transcriptomic data were developed and validated across one internal and three external cohorts. RESULTS: Genomic instability, including TP53 co-mutations, copy number alterations and APOBEC-associated mutational signatures, increased with pathological stage. RBM10 co-mutations were enriched in tumours with L858R mutations and correlated with upregulation of WNT signalling and epithelial-mesenchymal transition. Transcriptomic features outperformed clinical or genomic variables alone in predicting recurrence risk, and a multi-omic model demonstrated superior and reproducible performance, achieving a median concordance index of 75.4% across four independent validation cohorts. The multi-omic model stratified recurrence risk within individual pathological stages, including stage I disease, and identified patients most likely to benefit from adjuvant EGFR TKI. CONCLUSIONS: These findings define the molecular heterogeneity of early-stage EGFR-mutant LUAD and support multi-omic risk stratification to inform adjuvant EGFR TKI decisions beyond pathological stage. Prospective validation in larger cohorts will be required to confirm these findings.

Journal Article↗

PubMed2026

Distinct spatial immune microenvironment features of different EGFR mutation subtypes in early-stage lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinoma (LUAD), yet their influence on the spatial tumor immune microenvironment (TIME) in early-stage disease remains unclear. We characterized the spatial TIME in 144 treatment-naïve, early-stage LUADs using integrated genomic sequencing and multiplex immunohistochemistry (mIHC). Although EGFR-mutant tumors overall displayed reduced CD8 + T-cell infiltration compared with EGFR-wild-type tumors, substantial heterogeneity was observed among EGFR subtypes. Specifically, L858R and rare-variant subtypes exhibited higher tumor mutational burden, greater CD8 + T-cell density, and enrichment of T-cell-dominant cellular neighborhoods relative to 19del subtype, consistent with a comparatively immune-infiltrated phenotype. In contrast, 19del tumors showed lower T-cell infiltration. TP53 co-mutation was also associated with enhanced CD8 + T-cell infiltration. These cross-sectional findings identify hypothesis-generating spatial immune phenotypes across EGFR-mutant LUAD subtypes; their potential relevance to perioperative treatment selection requires prospective validation in outcome-annotated treatment cohorts.

Humans↗

PubMed2026

Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer after Progression on First-line Osimertinib: Phase II ORCHARD Study.

PURPOSE: Osimertinib is the standard of care for first-line treatment for epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment. PATIENTS AND METHODS: ORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFRm NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile after progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a prespecified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS data was also assessed. RESULTS: This study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histogenomic landscape after first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 86% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed. CONCLUSIONS: This comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes. See related commentary by Gupta et al., p. 3718.

Humans↗

PubMed2026

Genomic Analysis and Clinical Correlation of Non-Small Cell Lung Cancer with Special Reference to Brain Metastasis.

BACKGROUND: Next-generation sequencing (NGS) has improved genomic analysis depth in precision oncology. This study analyzed genomic biomarker testing in stage IV NSCLC, focusing on brain metastasis and clinicopathological correlations. OBJECTIVE: To study molecular markers and clinicopathological correlations in stage IV NSCLC patients, with and without brain metastasis. METHODS: A total of 169 stage IV NSCLC patients were studied from April 2023 to May 2025. Demographic data, clinical presentations, and mutation analyses were assessed using NGS on tissue blocks or liquid biopsies. RESULTS: Among 169 patients, 41.42% (n = 70) had brain metastasis (NSCLC-BM), while 58.58% (n = 99) had no brain metastasis (mNSCLC). Median ages were 51.5 and 56 years, respectively. Adenocarcinoma comprised 95.27% (n = 161) of cases. The cerebral hemisphere was the most common intracranial metastatic site, while skeletal involvement was the most common extracranial site. Headache was the predominant neurological symptom. EGFR mutations were the most common overall. EGFR > TP53 > ALK > other mutations were observed in NSCLC-BM, while EGFR > TP53 > KRAS > other mutations were seen in mNSCLC. Mutation analysis stratified by smoking history (χ²(1) = 1.347, p = 0.245) and sex (χ²(1) = 0.0302, p = 0.862) was not statistically significant. The benefit of gefitinib plus chemotherapy in EGFR exon 19 and exon 21 L858R mutations was greater in mNSCLC (log-rank χ²(1) = 10.813, p = 0.001) than in NSCLC-BM (log-rank χ²(1) = 3.100, p = 0.078). Median survival was 11 months (95% CI: 7.506-14.494) for NSCLC-BM versus 21 months (95% CI: 8.365-33.635) for mNSCLC, with a statistically significant difference (log-rank χ²(1) = 8.639, p = 0.003). CONCLUSION: NSCLC-BM showed higher genomic biomarker enrichment (80% vs. 68.68%) but poorer outcomes than mNSCLC. EGFR was the most common targetable mutation, followed by ALK in NSCLC-BM and KRAS in mNSCLC.

Humans↗