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PubMed2026

Detection of a Rare Intra-ALK Inversion and ALK Rearrangement in a Lung Adenocarcinoma Patient by FoundationOne Liquid CDx and Successful Treatment with Alectinib: Case Report.

A 50-year-old woman with stage IVB lung adenocarcinoma tested negative for driver mutations using the Oncomine Dx Target Test Multi-CDx system (Thermo Fisher Scientific, Waltham, MA). After undergoing chemotherapy and immunotherapy, FoundationOne Liquid CDx (Foundation Medicine, Inc., Cambridge, MA) identified a rare EML4-ALK gene rearrangement. Treatment with alectinib led to rapid clinical improvement and sustained disease control for more than 7 months. This case highlights the value of next-generation sequencing-based profiling in detecting rare actionable alterations missed by standard tests. We also include a discussion on why the EML4-AKL fusion was not detected in the usual test.

ALK-EML4 rearrangement↗

PubMed2025

Integration of ALK gene mutations and targeted therapies in pediatric high-risk neuroblastoma: advancements in precision oncology.

INTRODUCTION: Neuroblastoma (NB) is the most common extracranial solid tumor in children. High-risk neuroblastoma remains a therapeutic challenge, with a 5-year survival rate of 60%. The anaplastic lymphoma kinase (ALK) oncogene plays a critical role in the pathogenesis of neuroblastoma, with mutations frequently observed in high-risk cases. In this review we explored the genomic landscape of high-risk neuroblastoma, focusing on ALK mutations and their role in disease progression. We have also discussed the efficacy of ALK-targeted therapies and potential combination strategies to overcome resistance. METHODS: A comprehensive literature search was conducted to collect peer-reviewed publications related to neuroblastoma's biology, classification, and treatment. Articles published between 1980 and 2025 were identified using databases such as PubMed, Scopus, Web of Science, and ClinicalTrials.gov. RESULTS: Neuroblastoma tumorigenesis implicates ALK mutations, particularly at ALK p.R1275Q, ALK p.F1174L, and ALK p.F1245C, with an enrichment in stage 4 tumors and younger patients. Several ALK inhibitors, like crizotinib, ceritinib, lorlatinib, repotrectinib, and alectinib, have shown different levels of success, but resistance to these treatments is still a big challenge. New treatment methods that combine farnesyltransferase inhibitors (FTIs) with ALK tyrosine kinase inhibitors (TKIs) are showing potential in improving how well the treatment works and in stopping the cancer from coming back. CONCLUSION: Precision oncology offers a novel and potentially more effective approach for treating high-risk neuroblastoma. While ALK inhibitors have shown promise, resistance mechanisms necessitate the development of combination therapies and next-generation inhibitors. Future research should focus on optimizing targeted treatment strategies to improve survival outcomes in pediatric patients with ALK-positive neuroblastoma.

ALK inhibitors↗

PubMed2025

Efficacy of amivantamab, a bi-specific antibody targeting EGFR and MET, in ALK-rearranged non-small-cell lung cancer cell lines.

BACKGROUND: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective in treating ALK-rearranged non-small-cell lung cancer (NSCLC). However, at least 40% of patients develop acquired resistance during treatment. Adaptive or acquired resistance to ALK TKIs could be mediated through epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling. Sixteen percent of acquired resistance cases are linked to bypass signaling. METHODS: In this study, we evaluated the effects of amivantamab, a bi-specific antibody targeting both EGFR and MET, on ALK-rearranged NSCLC cells. We investigated the effect of amivantamab on the ALK-rearranged NSCLC cell lines H3122, ABC-19, and ABC-11. RESULTS: Combining alectinib with amivantamab resulted in greater inhibition of cell growth inhibition in H3122 and ABC-19 cells compared to alectinib alone, but not in ABC-11 cells. EGFR TKI erlotinib showed similar efficacy in H3122 and ABC-19 cells, whereas MET TKI tepotinib was ineffective in both, suggesting that the efficacy of amivantamab is through EGFR inhibition. Unlike H3122 and ABC-19 cells, ABC-11 cells were resistant to EGFR/MET signaling inhibition. Interestingly, amivantamab enhanced alectinib efficacy against ABC-11 cells in the presence of peripheral blood mononuclear cells (PBMCs), despite showing no effect alone without PBMCs, suggesting action through non-signal inhibitory mechanisms. Finally, we treated alectinib-resistant cellswith alectinib, with or without amivantamab, and found that amivantamab restored the sensitivity of these cells to alectinib. CONCLUSION: The bi-specific antibody amivantamab, which targets EGFR and MET, enhanced the efficacy of alectinib through both signal and non-signal inhibitory mechanisms in ALK-rearranged NSCLC cells.

Humans↗

PubMed2026

EML4-ALK Variant-Specific Genetic Interactions Shape Lung Tumorigenesis.

UNLABELLED: Diverse fusions of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) are oncogenic drivers in lung adenocarcinoma. EML4-ALK variants have distinct breakpoints within EML4, but their functional differences remain poorly understood. In this study, we use somatic genome editing to generate autochthonous mouse models of EML4-ALK-driven lung tumors and show that variant 3 (V3) is more oncogenic than variant 1 (V1). By using multiplexed genome editing and quantifying the effects of 29 putative tumor-suppressor genes on V1- and V3-driven lung cancer growth, we show that many tumor-suppressor genes have variant-specific effects on tumorigenesis. Pharmacogenomic analyses further suggest that tumor genotype can influence therapeutic responses. Analysis of human EML4-ALK-positive lung cancers also identified variant-specific differences in their genomic landscapes. These findings suggest that EML4-ALK variants behave more like distinct oncogenes than a uniform entity and highlight the dramatic impact of oncogenic fusion partner proteins and coincident tumor-suppressor gene alterations on the biology of oncogenic fusion-driven cancers. SIGNIFICANCE: EML4-ALK-driven lung cancer is treated as a uniform disease despite the presence of distinct fusion variants in patients. Our findings show that EML4-ALK variants are functionally distinct, which may have implications for the treatment of this cancer type and highlights the need to consider differences among variants of other oncogenic fusions.

Animals↗

PubMed2026

Feasibility and Efficacy of Lorlatinib in Japanese Patients With Relapsed/Refractory ALK-Aberrant Neuroblastoma.

Lorlatinib, a third-generation ALK inhibitor, was administered off-label to five heavily pretreated patients with relapsed or refractory ALK-aberrant neuroblastoma. ALK alterations included F1174L, R1275Q, BEND5::ALK fusion, and ALK amplification; three patients had MYCN amplification. Best responses were three partial responses and two disease progressions. The longest progression-free survival (6.7 months) occurred in a patient with F1174L and non-amplified MYCN, whereas rapid progression was observed in two MYCN-amplified cases. Lorlatinib was generally well tolerated with manageable adverse events. These findings suggest that lorlatinib is a feasible therapeutic option in ALK-aberrant neuroblastoma and that clinical heterogeneity in treatment response warrants further investigation.

Humans↗

PubMed2026

Pediatric intracranial inflammatory myofibroblastic tumor harboring DCTN1::ALK fusion: a case report with radiologic-pathologic-molecular correlation.

Central nervous system inflammatory myofibroblastic tumors are rare; pediatric DCTN1::ALK fusion cases are exceptionally uncommon. Here, we present an eight-year-old boy who presented with headache, vomiting, and a rapidly enlarging right frontal scalp mass. An MRI showed a dural, extra-axial lesion with mass effect. Histology confirmed IMT, and ALK immunohistochemistry was positive; next-generation sequencing (NGS) identified DCTN1 (exon 1-27)-ALK (exon 20-29) fusion, and FISH confirmed ALK rearrangement (33/100 nuclei). Genomic metrics showed tumor mutational burden (TMB) of 0.94/Mb, microsatellite stability, and CNV burden of 2.1%. He underwent near total resection followed by alectinib; to our knowledge, this is the first reported young pediatric (<10 years old) CNS IMT with this fusion.

Humans↗

PubMed2026

Adjuvant alectinib versus chemotherapy in resected ALK-positive non-small-cell lung cancer (ALINA): health-related quality-of-life and safety outcomes from a randomised, open-label, phase 3 trial.

BACKGROUND: For patients with resected, ALK-positive non-small-cell lung cancer (NSCLC), adjuvant alectinib significantly improved disease-free survival versus platinum-based chemotherapy in the global, phase 3, open-label, randomised ALINA trial. We report safety and health-related quality-of-life (HRQoL) outcomes from the ALINA trial. METHODS: Eligible patients aged 18 years or older with resected, ALK-positive, stage IB (≥4 cm)-IIIA NSCLC (per the American Joint Committee on Cancer and the Union for International Cancer Control Cancer Staging Manual 7th edition) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) via a block-stratified randomisation method to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy for four 3-week cycles. Randomisation was stratified according to disease stage and race. The primary endpoint, previously reported, was disease-free survival. Safety was a secondary endpoint and HRQoL was an exploratory endpoint. Safety was assessed by the investigator as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5·0 until 28 days after the last alectinib dose or chemotherapy cycle. HRQoL was assessed via the Short-Form 36-item health survey version 2 (SF-36v2) questionnaire at baseline, every 3 weeks to week 12, then every 12 weeks until disease recurrence, consent withdrawal, death, or week 96. Norm-based scoring was applied; clinically meaningful changes were defined using the SF-36v2 manual. Safety was assessed in the safety-evaluable population and HRQoL in the intention-to-treat population. This study is registered with ClinicalTrials.gov (NCT03456076) and is ongoing. FINDINGS: Between Aug 16, 2018, and Dec 8, 2021, 257 patients were assigned to receive alectinib (n=130) or chemotherapy (n=127). 123 (48%) patients were male and 134 (52%) were female; 143 (56%) were Asian. The safety-evaluable population comprised 128 patients who received alectinib and 120 patients who received chemotherapy; median duration of safety follow-up was 24·8 months (IQR 22·0-24·9) in the alectinib group and 3·7 months (IQR 3·7-3·8) in the chemotherapy group. The safety of adjuvant alectinib was generally consistent with its known profile. The most common grade 3-4 adverse events were blood creatine phosphokinase increased (eight [6%] of 128), alanine aminotransferase increased (two [2%] of 128), and blood bilirubin increased (two [2%] of 128) in the alectinib group, and neutrophil count decreased (12 [10%] of 120), neutropenia (ten [8%] of 120), and nausea (five [4%] of 120) in the chemotherapy group. Serious treatment-related adverse events occurred in two (2%; one each with appendicitis and pneumonitis) of 128 patients in the alectinib group and eight (7%) of 120 patients in the chemotherapy group ( most common were gastrointestinal disorders in three [3%] patients). No deaths due to adverse events were reported in either group. There were fewer discontinuations due to adverse events with alectinib (seven [5%]) versus chemotherapy (15 [13%]). A clinically meaningful difference in improvement from baseline was seen at week 12 for bodily pain, role physical, mental health, social functioning, and vitality SF-36v2 domains with alectinib; improvements in physical and mental HRQoL were maintained over 2 years of active treatment (at week 96, mean Mental Component Summary score: 49·9 [SD 10·4]; mean Physical Component Summary score: 48·8 [SD 7·2]) and reached levels similar to the general population (population norm: 50). INTERPRETATION: For patients with resected ALK-positive NSCLC, adjuvant alectinib had a manageable safety profile; HRQoL improved and was maintained over 2 years of active treatment. Together with the disease-free survival benefit seen in ALINA, these data support adjuvant alectinib as an important new standard-of-care for patients with resected ALK-positive NSCLC. FUNDING: F Hoffmann-La Roche.

Adult↗

PubMed2026

Spatial transcriptomics of primary and metastatic ALK-rearranged NSCLC reveals site-specific adaptations.

INTRODUCTION: Genetic alterations and the tumor microenvironment (TME) influence treatment response in anaplastic lymphoma kinase-rearranged non-small cell lung cancer (ALK+ NSCLC). This study maps site-specific TME adaptations and exploratory risk-associated signatures in lymph node metastases (LNT) to investigate metastatic evolution. METHOD: We applied spatial transcriptomics to profile tumor (PanCK+) and stromal (PanCK-) compartments in a pilot cohort of 16 cases: primary lung tumors (LT, n = 3), LNT (n = 10), and brain metastases (BT, n = 3), with three site-matched non-tumor controls. LNT-derived prognostic signatures were evaluated using The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA LUAD) cohorts. RESULTS: Distinct, site-specific TME features were observed. LNT stroma was enriched in fibroblasts and macrophages, while tumor segments showed increased neutrophils. BT exhibited a macrophage-associated immunosuppressive TME. Tumor cells evolved divergently: LT retained pulmonary identity and showed trend towards translation-associated programs, LNT cells shifted toward senescence and epigenetic remodeling, and BT cells showed activation of Class A/1 (Rhodopsin-like) receptor, GPCR and drug metabolism pathways. In LNT, exploratory risk-associated differences were observed. Low-risk cases (n = 6) showed adaptive immune signatures, whereas high-risk cases (n = 4) showed enrichment for stromal MET signaling and stress-response pathways. Because treatment exposure differed markedly between the risk groups, these observations should be interpreted as hypothesis-generating. TCGA LUAD analysis suggested the broader biological relevance of immune-associated markers, but reflected general LUAD rather than ALK+ specific biology. Discordant associations for GCLC and TIMP1 underscored the importance of spatial context. CONCLUSION: Site-specific microenvironments may influence tumor adaptation across metastatic niches in ALK+ NSCLC. The exploratory risk-associated findings require validation in larger, uniformly treated cohorts.

Humans↗

PubMed2026

Anaplastic lymphoma kinase immunohistochemical positivity in high-grade pulmonary neuroendocrine carcinoma: an actionable signal or merely a shadow?

AIMS: Anaplastic lymphoma kinase (ALK) rearrangements are actionable drivers in non-small cell lung carcinoma (NSCLC), but the biological significance of ALK-immunohistochemistry (IHC) positivity in high-grade pulmonary neuroendocrine carcinoma (NEC) remains unclear. This study evaluated the diagnostic and therapeutic implications of discordant ALK IHC and genomic findings and the role of multimodal molecular testing in resolving them. METHODS: We retrospectively analysed eight South Asian patients (Indian and Nepali) with de novo high-grade pulmonary NEC and diffuse ALK immunoreactivity treated at a tertiary cancer centre in India. Comprehensive molecular profiling using DNA- and RNA-based next-generation sequencing (NGS) and ALK fluorescence in situ hybridisation (where tissue was adequate) was performed. Clinical outcomes and responses to ALK-targeted tyrosine kinase inhibitors (TKIs) were assessed. RESULTS: ALK IHC positivity was observed in 8 of 100 selectively tested cases among 319 high-grade pulmonary NECs diagnosed between 2019 and 2025. The cohort included seven SCLCs (one combined adenocarcinoma-SCLC) and one large-cell neuroendocrine carcinoma (LCNEC). Median age was 51 years; 75% were female and 87.5% never-smokers. Among five comprehensively profiled cases, true ALK rearrangements were confirmed in two (one LCNEC and one SCLC), both detectable only by RNA sequencing. Durable benefit from ALK-TKI therapy was seen only in the molecularly confirmed LCNEC case (>16 months), whereas ALK IHC-positive but NGS-negative cases progressed rapidly. CONCLUSIONS: True ALK rearrangements in high-grade pulmonary NEC are rare but highly actionable. ALK IHC alone is an unreliable predictor of therapeutic benefit. RNA-based sequencing is essential for fusion detection. Comprehensive molecular confirmation, with RNA sequencing as the preferred modality, should precede any initiation of ALK-targeted therapy in high-grade pulmonary NEC.

IMMUNOHISTOCHEMISTRY↗

PubMed2025

Novel strategies for rare oncogenic drivers in non-small-cell lung cancer: An update from the 2024 Annual ESMO meeting.

Across the landscape of oncogene-addicted non-small-cell lung cancer (NSCLC), various tyrosine kinase inhibitors (TKIs) have been introduced in the last twenty years. During the 2024 Annual ESMO meeting new therapeutic options were presented for EGFR exon 20 insertion mutation, ALK fusion and ROS1 fusion positive advanced stage NSCLC. For EGFR exon 20 insertion mutation positive NSCLC, results from REZILIENT-1, a single arm phase II study with zipalertinib, were presented, showing an objective response rate (ORR) of 50% in patients that were pretreated with amivantamab, and 25% in patients pretreated with amivantamab and an EGFR exon 20 insertion-directed TKI. The vast majority of these patients also received platinum-doublet chemotherapy. For ALK, results from ALKOVE-1, a single arm phase I/II study with NVL-655, a next generation ALK TKI, were presented. The ORR was 35 % in patients pretreated with ≥ 2 ALK TKIs including lorlatinib and 57 % in patients pretreated with ≥ 1 ALK TKI, excluding lorlatinib. The median number of prior anticancer therapies was 3. Intracranial responses were seen in lorlatinib naïve- and lorlatinib pretreated patients and toxicity was manageable. In addition, results of the first-line randomized phase III INSPIRE study were presented, in which iruplinalkib, an ALK and ROS1 selective TKI, is being evaluated versus crizotinib. Iruplinalkib showed a superior median PFS (36.8 versus 14.55 months for crizotinib), but no difference in 36-month overall survival (OS) rate. Finally, results from ARROS-1, a single arm phase I/II study with zidesamtinib, a ROS1 selective and TRK-sparing TKI, were presented. An ORR of 73% was obtained in patients that were pretreated with crizotinib and an ORR of 38% in patients pretreated with repotrectinib. In this review, we will discuss the relevant study results presented at ESMO 2024 for these three genomic drivers and hypothesize on their respective place in the sequence of treatment options.

Humans↗

PubMed2025

Immune landscape and novel therapeutic targets of epidermal growth factor receptor and anaplastic lymphoma kinase wild type never-smoker lung adenocarcinoma.

BACKGROUND: Never-smoker lung adenocarcinoma (NSLA) exhibits distinct immunosuppressive profiles and a lower tumor mutation burden compared with lung adenocarcinoma in smokers. These correlate with poor responses to immune checkpoint inhibitors. In this study, we aimed to elucidate the tumor-immune microenvironment of NSLA without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations and identify novel therapeutic targets. METHODS: We analyzed genome, transcriptome, and proteomic data from 102 NSLA tumor samples and 16 normal adjacent tissues. We classified tumors into distinct immune clusters (IC) based on gene signatures by profiling the tumor-infiltrating immune cells. RESULTS: The tumors were stratified into three ICs: hot, intermediate, and cold. Notably, only 21 (20.6%) patients exhibited hot IC enriched in cytotoxic T cells, natural killer cells, and B-cell signatures, which correlated with improved recurrence-free survival. Cold ICs (37.3%) exhibited higher myeloid-derived suppressor cell (MDSC) levels and M2 macrophage signatures, with poor immune cell infiltration and relatively low stimulatory cytokines and chemokines expression. CEACAM1, and NECTIN2 were upregulated in intermediate and cold ICs and correlated with MDSC and M2 macrophage infiltration. High expression of these genes was associated with poor survival outcomes. Protein-protein network analysis of 20 upregulated molecules associated with cancer- and driver-related proteins in cold IC identified XPO 1 as a key component. CONCLUSION: Our proteogenomic analysis highlighted the immunosuppressive properties of NSLA without EGFR and ALK alterations and identified novel therapeutic targets. These findings may provide novel treatment strategies that could improve the clinical outcomes of patients with NSLA.

Humans↗

PubMed2026

Comprehensive characterization of MET exon 14 skipping mutations in non-small cell lung cancer.

BACKGROUND: MET exon 14 skipping mutation (METΔex14) is a key driver event in non-small cell lung cancer (NSCLC) and can emerge as an acquired drug resistance mechanism to MET, EGFR or ALK inhibitors. The clinical and genomic features of METΔex14 in NSCLC require further characterization. METHODS: Our study included a total of 585 patients with METΔex14 + NSCLC, comprising 556 baseline samples, 53 samples from patients exhibiting resistance to MET inhibitors, and 16 samples from patients resistant to EGFR/ALK inhibitors. Genomic data from targeted next-generation sequencing (NGS) of tissue and/or plasma samples using GeneseeqPrime™ (a 425 pan-cancer gene panel) were analyzed. RESULTS: Overall, METΔex14 exhibited a prevalence of 1.02% (n = 585) in the screened NSCLC population, with a higher incidence in patients with a sarcomatoid histology. METΔex14 was predominantly detected at the splice donor site, though the non-coding region adjacent to the splice acceptor site contributed considerably to the complexity of METΔex14. Common concurrent alterations identified at baseline included those in TP53 (40.8%), CDK4 (16%) and EGFR (12.4%). Concurrent MET amplification and cell cycle pathway mutations were both associated with worse outcomes in patients treated with crizotinib, with significant co-occurrences observed also among these concurrent genomic variations. In addition, increased chromosomal instability and intra-tumoral heterogeneity correlated with a poorer response to crizotinib. Mechanisms of acquired resistance to MET inhibitors were primarily attributed to on-target MET D1228X/Y1230X mutations or off-target alterations within genes in the RTK/RAS/MAPK and PI3K/AKT/mTOR pathways. Intriguingly, our exploratory analysis also identified the FGFR3::TACC3 fusion as a potential resistance mechanism to savolitinib. Moreover, METΔex14 was identified in 16 patients following progression on EGFR and ALK inhibitors, highlighting the need for developing tailored therapeutic strategies to overcome resistance. CONCLUSIONS: This study provides a comprehensive characterization of METΔex14 in NSCLC, revealing its dual role as a primary driver of oncogenesis and a potential resistance mechanism to EGFR/ALK inhibitors. The identification of concurrent genetic alterations and potential resistance mechanisms enhances our molecular understanding of treatment responses. These findings highlight the need for further investigation into targeted therapies that consider the genomic complexity of METΔex14 to improve treatment efficacy and patient outcomes.

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↗

PubMed2025

Molecular Biomarker Testing Patterns and Turnaround Time in US Patients With Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Patients with advanced non-small cell lung cancer (aNSCLC) are recommended to undergo molecular testing for targetable genomic alterations. However, as high-throughput methods are increasingly used, long test turnaround time (TAT) may lead to lower receipt of appropriate targeted therapy. Guidelines recommend a 2-week TAT for ALK and EGFR testing, 2 prevalent pathogenic alterations with highly effective targeted therapies. PATIENTS AND METHODS: Using an electronic health record-derived, deidentified database, we conducted a retrospective cohort study of patients with aNSCLC diagnosed between 2011 and 2023 who received testing for ≥1 of 8 molecular markers. We assessed the number of biomarkers tested per patient, testing modality, and TAT (defined as the interval between specimen collection and result date) over time. We also evaluated patients with ALK/EGFR-altered aNSCLC who initiated early nontargeted treatment prior to test result availability, examining associations with TAT and clinical outcomes. RESULTS: The study sample comprised 33,945 patients, with a mean age of 68.2 years; 49.4% were female, 58.3% were White, and 83.4% reported a history of smoking. From 2011 to 2023, the mean number of biomarkers tested per patient (range, 2.0-6.8) and the use of next-generation sequencing (NGS) increased, whereas the mean TAT converged to 3 weeks. Fewer than half of the patients with ALK/EGFR-altered aNSCLC had a TAT of ≤2 weeks, and 1 in 8 initiated early nontargeted treatment. Longer TAT was associated with early nontargeted treatment when analyzed as both a continuous variable (odds ratio, 1.83 per week) and a binary variable (TAT >2 vs ≤2 weeks; odds ratio, 6.02). Early treatment was associated with worse median progression-free survival (9 vs 11 months) in patients with ALK/EGFR-altered aNSCLC. CONCLUSIONS: Biomarker testing and NGS use have increased over time in US patients with aNSCLC. TAT has plateaued and remains longer than recommended in consensus guidelines. Longer TAT was associated with early nontargeted therapy in patients with ALK+/EGFR+ aNSCLC, leading to suboptimal first-line treatment and poorer clinical outcomes.

Humans↗

PubMed2026

Genomic Diversity and Clinical Variability in Pediatric Primary Cutaneous Anaplastic Large Cell Lymphoma: A Case Series.

Primary cutaneous anaplastic large cell lymphoma (pcALCL) is a rare pediatric CD30-positive T-cell lymphoproliferative disorder with an excellent prognosis, but its genomic drivers are poorly defined. We report three children with skin-limited disease demonstrating striking molecular heterogeneity, including NPM::ALK, NUP214::FRK, and a novel PICALM::JAK2 fusion not previously described in pcALCL. Clinical courses ranged from spontaneous regression to systemic therapy, yet all achieved durable complete remission without progression over 31-50 months. These findings highlight previously unrecognized genomic diversity and expand the molecular landscape of pediatric pcALCL.

Humans↗

PubMed2026

Testicular aggressive B-cell lymphoma with plasmablastic morphology harboring concurrent IGH::MYC and IGH::BCL2 rearrangements.

BACKGROUND: Aggressive B-cell lymphomas with plasmablastic morphology are uncommon neoplasms that may exhibit overlapping morphologic, immunophenotypic, and genetic features of plasmablastic lymphoma (PBL) and double-hit lymphoma (DHL). Concurrent IGH::MYC and IGH::BCL2 rearrangements are rarely encountered in this setting, particularly in the testis. Here, we describe an unusual case presenting significant diagnostic challenges at the interface between PBL and DHL. CASE PRESENTATION: We report a 66-year-old, immunocompetent man presenting with a 5 cm left testicular mass. Histologic examination revealed diffuse proliferation of large atypical lymphoid cells with plasmablastic morphology. Immunohistochemically, the tumor expressed CD138, CD38, and MUM1, with focal BCL2, c-MYC protein, and CD79a positivity, while CD20, CD19, PAX5, CD10, BCL6, and ALK were negative. EBV-encoded RNA in situ hybridization was negative. Fluorescence in situ hybridization identified IGH::MYC [t(8;14)] rearrangement in 45% and IGH::BCL2 [t(14;18)] rearrangement in 21% of analyzed nuclei. Next-generation sequencing additionally revealed BRAF V600E mutation, CDKN2A deletion, and human leukocyte antigen class I genomic alterations. CONCLUSION: This case highlights a rare testicular aggressive B-cell lymphoma with plasmablastic morphology and concurrent IGH::MYC and IGH::BCL2 rearrangements, representing a diagnostically challenging neoplasm at the interface between PBL and DHL. Our findings underscore the value of integrated morphologic, immunophenotypic, cytogenetic, and molecular analyses in evaluating aggressive B-cell lymphomas with plasmablastic features arising in immune-privileged sites.

Humans↗

PubMed2026

Comprehensive molecular profiling of advanced NSCLC in Greek patients:A prospective HeCOG study.

BACKGROUND: We report for the first time the molecular landscape and outcome associations from the prospective CLIMEDIN trial in Greece. METHODS: Two hundred patients with newly diagnosed advanced NSCLC (March 2022-October 2023) were enrolled and randomized to standard-of-care education versus additional automated, adverse-event-targeted digital interventions. Within this study baseline testing (EGFR, ALK, PD-L1) was performed in all; 165 tumors underwent comprehensive NGS (Oncomine Comprehensive Assay v3). Primary endpoint was improvement in AEs/QoL; secondary endpoints included ORR, PFS and OS. Associations between genomic alterations and outcomes were explored. RESULTS: Median age was 68 years; 75% male; 52% current smokers; adenocarcinoma 68.5%. Most received chemo-immunotherapy (66%). At data cut-off (December 2025; reverse-Kaplan-Meier median follow-up 36.3 months), median PFS was 9.6 months and median OS was 15.2 months. Across 200 tumors, 495 pathogenic variants (PVs) were identified in 83 genes. Exploratory outcome analyses showed longer OS in EGFR-mutant disease (preserved under parsimonious multivariable adjustment) and a formal KRAS × smoking interaction for OS (interaction P = 0.011). CONCLUSIONS: In this cohort, the molecular profile mirrors other Caucasian series, with clinically relevant enrichment patterns for EGFR and KRAS. ECOG performance status and first line treatment were the dominant prognostic factors in this cohort. A novel KRAS and smoking interaction for overall survival warrants prospective validation.

Aged↗

PubMed2026

A comprehensive survey of genetic variants in neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children and is characterized by marked clinical and molecular heterogeneity. Genomic alterations play a critical role in NB pathogenesis; however, population-specific mutational features remain insufficiently characterized, particularly among Chinese patients. METHODS: Whole-exome sequencing (WES) was performed on tumor, para-tumor, and matched peripheral blood samples from nine pathologically confirmed Chinese patients with NB. Somatic variant profiles were compared with four publicly available NB datasets from cBioPortal, published in 2012, 2013, 2015, and 2023. Mutational patterns, recurrently altered genes, and Gene Ontology (GO) enrichment were analyzed using R version 4.3.2 and clusterProfiler version 4.10.0. RESULTS: A total of 77 missense variants were identified in our cohort. Single-nucleotide polymorphisms (SNPs) represented the predominant variant type, and C > T substitutions were the most frequent nucleotide change. MAP1A variants, comprising two missense variants in one patient, and RBM33 variants, comprising two distinct variants in two patients, were detected in our cohort and, to the best of our knowledge, have not been previously reported in NB, although their frequencies were low. No MYCN amplification or variants in ALK, ATRX, or DAXX were detected. Comparative analysis with the cBioPortal datasets revealed no somatic variants universally shared across all cohorts. In addition, high-risk patients exhibited distinct mutational patterns, with enrichment of the Gene Ontology term "collagen-containing extracellular matrix." CONCLUSIONS: These findings highlight the molecular diversity of NB and suggest the presence of potential population-specific genetic features in Chinese patients. The low-frequency MAP1A and RBM33 variants identified in this cohort warrant further validation in larger, independent cohorts. Moreover, the enrichment of extracellular matrix-related pathways in high-risk NB supports further investigation of tumor-microenvironment interactions as potential therapeutic targets.

Extracellular matrix↗