Week 2026-W24

This prospective observational study assessed the utility of circulating tumor DNA (ctDNA) for mutational profiling and dynamic monitoring in 33 patients with metastatic colorectal cancer receiving palliative chemotherapy. ctDNA was detected in most patients at baseline, revealing frequent mutations in APC, TP53, KRAS, and PIK3CA. Good concordance was observed between plasma ctDNA profiles and tissue data. Longitudinal analysis showed the emergence of acquired mutations, particularly RAS mutations under anti-EGFR therapy, and correlated high ctDNA levels with shorter overall survival. These findings highlight ctDNA's potential to guide personalized treatment strategies and monitor resistance.

The phase III COSMIC-313 study investigated the addition of cabozantinib to nivolumab and ipilimumab in previously untreated patients with advanced renal cell carcinoma. Final results confirmed a significant progression-free survival (PFS) benefit for the triplet regimen (16.6 months vs 11.2 months for the doublet). However, no significant improvement in overall survival (OS) was observed. Exploratory biomarker analyses suggest that patients with higher levels of M2-like macrophages might experience improved PFS and OS with the triplet therapy.

The phase II ORCHARD study investigated the efficacy and safety of combining osimertinib with datopotamab deruxtecan (Dato-DXd) in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who had progressed on first-line osimertinib. Two Dato-DXd doses (4 mg/kg and 6 mg/kg) were evaluated. Both cohorts demonstrated clinical benefit, with objective response rates (ORR) of 43% and 36% respectively. Median progression-free survival (PFS) was 9.5 months for the 4 mg/kg dose and 11.7 months for 6 mg/kg, while median overall survival (OS) reached 19.8 months and 26.2 months. Although the 6 mg/kg dose was associated with higher toxicity, it was manageable, and this dose is suggested as the preferred starting dose given the overall benefit-risk profile.

The prospective, multicenter ELIOS study characterized acquired resistance mechanisms to first-line osimertinib in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). By analyzing paired tumor biopsies taken pre-treatment and post-progression, the study identified frequent alterations including MET amplification, CDKN2A/CDKN2B and MTAP deletions, and the EGFR C797S mutation. Proteogenomic analysis also revealed high TROP2 expression, irrespective of genetic alterations. The findings highlight the heterogeneous nature of resistance and the complementary utility of tissue and liquid biopsies for alteration detection. This study emphasizes the need for therapeutic strategies targeting multiple resistance pathways.

A novel study developed and validated a blood-based DNA methylation marker model (BBDMM) for predicting lung cancer risk. This model utilizes informative CpG sites identified through epigenome-wide association studies (EWAS). It was developed and internally validated in a German cohort of over 2,400 participants, then externally validated in Norwegian cohorts. The BBDMM demonstrated excellent discriminatory capacity, with AUCs of 0.84 and 0.85, and predictive stability over periods up to 18 years before diagnosis. These findings suggest significant potential for improving lung cancer screening.

This retrospective study investigated eight cases of multifocal micronodular pneumocyte hyperplasia (MMPH) associated with tuberous sclerosis complex (TSC), a rare benign pulmonary lesion. Patients typically presented with multiple ground-glass nodules in the lungs on CT scans and various clinical manifestations of TSC. A significant diagnostic challenge was highlighted, as intraoperative frozen sections were often misdiagnosed as early-stage lung adenocarcinoma. Next-generation sequencing revealed TSC1 or TSC2 gene mutations in most patients, confirming the association with TSC. All followed-up patients showed a favorable overall survival.

This study investigated the utility of urinary extracellular vesicles (EVs) as a liquid biopsy source for colorectal cancer (CRC). Urinary EVs demonstrated superior purity and DNA quality compared to plasma and urinary cell-free samples. Detecting RAS/BRAF mutations in urinary EV-DNA after curative surgery allowed for minimal residual disease (MRD) identification. MRD positivity was strongly associated with an increased risk of recurrence and inferior overall survival. These findings suggest that urinary EV-DNA is a promising tool for postoperative monitoring and risk stratification in CRC patients.

This study investigated the impact of next-generation sequencing (NGS) panel size on therapeutic recommendations in precision oncology. Comparing a 430-gene panel to a smaller 185-gene panel in 281 patients, researchers found molecular alterations in nearly all tumors. While most stratified therapy recommendations were achievable with the smaller panel, the expanded panel enabled additional recommendations for 8.8% of patients and identified actionable variants in five extra genes. The study emphasizes the necessity of sufficient genomic coverage for reliable tumor mutational burden (TMB) calculation, thereby establishing a minimal standard for genomic cancer care.

This retrospective study utilized targeted next-generation sequencing to identify genetic variants with prognostic value in uveal melanoma. Mutations in BAP1, CHEK2, and DICER1 were independently associated with a poorer prognosis and increased metastatic risk. Furthermore, BAP1 and LRP1B mutations were linked to epithelioid/mixed histology, while SF3B1 mutation was associated with spindle cell morphology. These findings suggest that mutational profiling could improve risk stratification and patient follow-up.

This retrospective study investigated the frequency and molecular profiles of PAX8-positive conventional urothelial carcinomas (UCs) of the urinary bladder. Out of 101 cases, 10% were found to be PAX8-positive by immunohistochemistry. Next-generation sequencing (NGS) was performed on 20 cases, including all PAX8-positive UCs. The findings revealed that PAX8-positive UCs frequently harbored TERT promoter mutations, TSC1 alterations, NOTCH1 loss, and WT1 loss, while notably lacking RB1 loss, distinguishing them from PAX8-negative UCs. These results indicate a distinct molecular signature for PAX8-positive UCs, emphasizing the need for careful diagnostic interpretation of PAX8.

This study characterizes Epstein-Barr virus (EBV)-positive small cell neuroendocrine carcinoma of the nasopharynx (SCNEC-nasopharynx), a rare and aggressive entity. By analyzing 15 cases, it described their distinct clinicopathological and molecular features. Patients typically presented with advanced-stage disease and had a median overall survival of 33 months following multimodal therapy. Molecular profiling revealed a higher mutational burden and unique alterations in cell cycle and DNA damage pathways compared to non-keratinizing carcinomas. These findings provide an essential foundation for precise diagnosis and the future development of targeted therapies.

Clear cell adenocarcinoma of the urinary tract (CCA-UT) is a rare and aggressive tumor with limited understanding of its clinicopathologic and molecular features. This multi-institutional study characterized 35 cases, showing a female predominance and advanced stage at presentation. Genomic alterations were found in 91% of cases, frequently involving chromatin modifiers such as ATRX, KMT2C, ARID1A, and ARID1B. The heterogeneous molecular profile of these tumors highlights the critical role of molecular analysis in identifying potential therapeutic targets.

This study investigates the impact of next-generation sequencing (NGS) on the diagnosis of BAP1 inactivated melanocytic tumors (BIMTs), which often exhibit significant morphological atypia, complicating their classification. A survey among dermatopathologists revealed that incorporating NGS results significantly improved diagnostic accuracy and interobserver agreement. Specific genomic aberrations, including pathogenic variants in TERT-p, CDKN2A, PTEN, and MYC amplification, were found exclusively in malignant cases. These findings suggest that NGS could refine melanoma diagnosis, which is critical for guiding access to effective therapies.

This study compared the efficiency of bisulfite and enzymatic DNA methylation conversion methods for analyzing colorectal cancer (CRC) biomarkers. Researchers quantified methylation levels of BCAT1, IKZF1, and SEPTIN9 in paired tumor and normal tissues from 24 CRC patients. Results indicated that bisulfite conversion led to significantly higher methylation levels for IKZF1 and SEPTIN9 in tumor tissues compared to enzymatic conversion. This potential overestimation by the bisulfite method could impact the specificity of methylation biomarkers.

This study re-evaluates the clinicopathological and molecular features of nonampullary duodenal neoplasms with gastric phenotype, proposing a novel classification. Analyzing 105 lesions, researchers observed a predominance of low-grade tumors and frequent heterogeneity. Next-generation sequencing revealed recurrent mutations in GNAS, KRAS, and APC. MDM2 gene amplification was identified as a potential marker for histological progression in high-grade tumors. Despite morphological diversity, the prognosis was extremely favorable, with no metastases, supporting the reclassification as "gastric-type adenomas."

This study identified invasion/metastasis-related differentially methylated genes (DMGs) with prognostic relevance in diffuse gliomas. A risk model was constructed using two marker genes, ERRFI1 and MYO1G, demonstrating robust predictive performance in both training and independent validation cohorts. Patients classified as high-risk exhibited worse overall survival and altered immune infiltration. In vitro functional validation showed that knockdown of ERRFI1 or MYO1G inhibited glioma cell proliferation, invasion, and migration, with potential involvement of the EGFR/MAPK/ERK pathway.

This retrospective study investigated the incidence of MYCN amplification in unilateral retinoblastoma and its association with RB1 inactivation and clinical features. Out of 139 analyzed cases, 7.2% exhibited MYCN amplification, and all these cases also showed RB1 inactivation. Researchers found that MYCN amplification was significantly associated with more advanced disease and aggressive histopathological features, including secondary glaucoma and massive choroidal or scleral invasion. These findings suggest that MYCN amplification could identify a more aggressive subgroup of retinoblastomas.

Lung cancer is a lethal malignancy urgently requiring effective early detection strategies, as current cfDNA-based approaches often lack sensitivity in early stages. This study developed a novel computational feature, First-Order Transition Probability (FOTP), to capture nucleotide sequential dependencies within cfDNA fragments. Using low-pass whole-genome sequencing data, an SVM model trained with FOTP achieved 73.9% sensitivity for stage I and 81.8% for stage II lung cancer at 95% specificity. This method, which significantly outperforms existing fragmentomic features, is biologically interpretable and offers a scalable strategy for early cancer screening.

This study identified three distinct molecular phenotypes of small cell lung cancer (SCLC): proliferative, iNotch, and infiltrated, characterized by high proliferation, inhibitory Notch signaling, and immune-rich microenvironments, respectively. These phenotypes were reproducible across multiple independent cohorts. Further analysis revealed that a subset of patients within the infiltrated phenotype, exhibiting high ANXA1 expression, resisted immune checkpoint inhibitors (ICIs) due to M2 macrophage polarization and CD8+ T cell suppression. Only ANXA1Low infiltrated patients derived significant benefit from chemotherapy combined with ICIs. These findings offer new strategies to enhance immunotherapy efficacy in SCLC.

This study conducted a detailed micro-costing analysis of implementing whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) in routine clinical care for cancer patients. The primary goal was to identify the key cost drivers hindering the widespread adoption of these comprehensive diagnostic technologies. Researchers developed a multidimensional costing model, which revealed that consumables, particularly flow cells, represent the main expenditure. While personnel and equipment costs decreased with increasing sample volumes, consumable and data processing/storage costs remained largely unchanged. The conclusion emphasizes that falling consumable prices are crucial for broader integration of WGS/WTS as a clinical-grade test.

This study modeled the cost-effectiveness of various genomic testing strategies for patients with advanced non-small-cell lung cancer (NSCLC) in Australia. It compared combinations of sampling methods (tissue biopsy, liquid biopsy) and molecular tests (single-gene, small, or large panels). Results indicated that large genomic panel strategies, while more expensive, yielded the highest gains in quality-adjusted life years (QALYs). The analysis concluded that these comprehensive genomic testing approaches are potentially cost-effective, despite a notable budget impact on the healthcare system.

Lung cancer biopsies often yield limited material, complicating predictive molecular testing and sometimes necessitating re-biopsy. This study investigated the feasibility of repurposing routine diagnostic slides, specifically H&E-stained and immunostained sections, for molecular analysis. From 40 lung biopsy specimens, DNA extraction and targeted next-generation sequencing were successfully performed for 33 cases. The results demonstrated high concordance of detected variants, suggesting this approach is a viable alternative for molecular testing.