Week 2026-W23

This study optimized a hybridization-based enrichment protocol for DNA derived from FFPE samples, a critical component in precision oncology. By systematically varying hybridization conditions, researchers maximized enrichment efficiency and coverage uniformity. The optimized protocol, using two rounds of short hybridization, demonstrated approximately sixfold higher enrichment than comparable commercial kits. It ensures adequate target coverage and high variant recall, even with increased duplicate rates. This protocol offers flexibility for scaling from small panels to whole-exome sequencing, making it suitable for precision oncology applications with challenging FFPE samples.

This single-center retrospective study assessed the clinical utility of comprehensive genomic profiling (CGP) in 108 patients with advanced or recurrent non-small cell lung cancer (NSCLC) after standard treatments. CGP detected druggable genetic aberrations in 37% of patients, with EGFR mutations being the most common. Resistance mechanisms were identified in nearly half of patients re-biopsied after targeted therapy. Although CGP-guided therapy was recommended for 35.2% of patients, only 16.6% received it, showing a trend towards prolonged overall survival for this subgroup. The study concludes that CGP can identify actionable mutations missed by conventional diagnostics, thus providing additional therapeutic opportunities in NSCLC.

This prospective study evaluated gene expression profiling of seven genes (EGFR, FGFR2, PIK3CA, PTEN, SMAD4, STK11, TP53) in cell-free RNA (cfRNA) from exhaled breath condensate (EBC) in patients with advanced lung adenocarcinoma. Results indicated that PIK3CA showed the best diagnostic performance in distinguishing patients from healthy controls. High expression of FGFR2 and PIK3CA was associated with significantly shorter overall survival, highlighting their prognostic relevance. EGFR expression demonstrated a strong correlation between EBC and plasma, and low EGFR expression was linked to longer survival in patients receiving chemotherapy alone. This non-invasive EBC-based approach offers potential for molecular characterization and patient stratification.

This large genomic analysis of 2901 endometrial carcinomas refines molecular classification by addressing several clinical questions. The study confirms that all four mismatch repair genes (MLH1, MSH2, MSH6, PMS2) confer an equivalently favorable prognosis, validating dMMR status as a class-level prognostic designation. It demonstrates that the exceptional survival benefit associated with POLE-ultramutated tumors is confined to canonical exonuclease-domain hotspot mutations, excluding variants of uncertain significance. Finally, patients with TP53 mutations and high copy-number instability (CNH) are identified as having the most urgent unmet therapeutic need.

An open-label, phase 3 trial evaluated zanidatamab, a HER2-targeted bispecific antibody, with or without tislelizumab (anti-PD-1), combined with chemotherapy, as first-line treatment for HER2-positive advanced gastroesophageal adenocarcinoma. Patients were randomized to receive zanidatamab-tislelizumab-chemotherapy, zanidatamab-chemotherapy, or trastuzumab-chemotherapy. Both zanidatamab-tislelizumab-chemotherapy and zanidatamab-chemotherapy arms demonstrated significantly longer progression-free survival (median 12.4 months for both) compared to trastuzumab-chemotherapy (8.1 months). Overall survival was also longer with zanidatamab-tislelizumab-chemotherapy (26.4 months) than with trastuzumab-chemotherapy (19.2 months). Diarrhea was the most common grade 3 or higher adverse event.

This retrospective observational study, conducted using the Italian ATLAS Registry, evaluated the efficacy and safety of amivantamab in 119 patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations. Most patients had previously received platinum-based chemotherapy, with or without immunotherapy. Amivantamab, administered as a single agent in subsequent lines, demonstrated an objective response rate of 37.5%, a median progression-free survival of 9.6 months, and a median overall survival of 16.9 months. The safety profile was manageable, with grade 3-4 treatment-related adverse events reported in 10.9% of patients, confirming data from the CHRYSALIS trial in a heavily pretreated real-world population.

This retrospective study analyzed 120 cases of lung adenocarcinoma (LUAD) with malignant serous effusions (MSE) to characterize their clinicopathologic, molecular, and prognostic features. Pleural effusions were most common, but pericardial involvement was associated with the shortest overall survival. Molecular profiling revealed TP53 mutations and actionable alterations in genes such as EGFR, KRAS, BRAF, ALK, and ROS1. NKX2-1 (TTF-1) negativity and the absence of actionable alterations were independent adverse prognostic factors, with dual NKX2-1/CD274 (PD-L1) negativity defining the poorest prognosis subgroup. Immunotherapy-based regimens and tyrosine kinase inhibitors showed varying survival benefits.

This study developed a novel immune classification for colorectal cancer (CRC) through integrative multi-omics analysis. By utilizing gene expression, mutation, and methylation profiles from two large CRC cohorts, three distinct clusters (MotifCC) were identified, each with unique molecular and immune characteristics. Cluster1, featuring high WNT pathway activation, exhibited the worst prognosis and a tumor-promoting microenvironment, suggesting benefit from a combination of immunotherapy and WNT-targeted treatment. Cluster2, with low immune infiltration and high glycolysis intensity, might respond to metabolism inhibitors, while Cluster3, characterized by high gene methylation, high tumor mutation burden, and microsatellite instability, showed a better response to immunotherapy. This classification provides valuable insights for understanding CRC heterogeneity and tailoring immunotherapy strategies.

The Oncogenicity Variant Interpreter (OncoVI) is an open-source, Python-based tool developed to harmonize and automate the oncogenicity classification of somatic variants in precision oncology. It implements guidelines from the Clinical Genome Resource/Cancer Genomics Consortium/Variant Interpretation for Cancer Consortium, performing functional annotation and evidence collection from public resources. OncoVI achieved 80% accuracy on a gold standard set of 93 somatic variants and showed 79% concordance with Molecular Tumor Board assessments on 7802 real-world variants. This tool aims to support reproducible and standardized somatic variant interpretation across institutions.

Lancet2 is an open-source somatic variant caller designed to enhance the detection of small variants in short-read sequencing data. It introduces significant improvements, including better variant discovery and genotyping through partial order multiple sequence alignment and read re-alignment. The tool also optimizes somatic variant scoring with explainable machine learning models and provides enhanced variant visualization. Benchmarking showed that Lancet2 outperformed other leading tools in variant calling performance, especially for InDels, while also demonstrating substantial speed improvements and reduced memory usage.

This study performed whole genome and transcriptome sequencing on 50 tumor samples from 37 patients with locally advanced or metastatic breast cancer. It uncovered extensive genomic complexity, with triple-negative breast cancer (TNBC) showing the highest tumor mutational burden. Homologous recombination deficiency (HRD) was found in 27% of patients, frequently in BRCA1/2 wild-type cases due to deleterious structural variants in other repair genes. Therapeutically actionable alterations were identified in 84% of patients, including a novel ESR1::EP300 fusion potentially linked to endocrine resistance. These findings underscore the utility of whole-genome sequencing for characterizing metastatic disease and guiding therapies.

Somatic mutations in GC-rich promoter regions are significant drivers of cancer, yet their detection is challenging due to poor sequencing coverage in these areas. This study introduces a hybrid capture assay optimized for over 3000 cancer gene promoters, enabling deep sequencing of these complex regions. This method facilitates the discovery of reliable point mutations, short insertions/deletions, copy number variants, and mutational signatures. The assay nominated candidate noncoding driver mutations in CDK4, SMAD3, and GATA3 in breast cancer, paving the way for future functional follow-up.

This review examines established and emerging biomarkers for stratifying patients with early-stage breast cancer to optimize adjuvant systemic therapy. It highlights that while clinicopathological factors remain fundamental, decision-making is increasingly driven by precise biological markers. ER and HER2 status are crucial, and multigene assays refine recurrence risk and chemotherapy benefit in hormone receptor-positive cancers. Immune and DNA-repair biomarkers inform targeted therapies in HER2-positive and triple-negative subtypes, while mutation profiling of genes like ESR1, PIK3CA, AKT, MTOR, and PTEN guides targeted treatments. Emerging approaches, including liquid biopsy and artificial intelligence, offer dynamic insights but require prospective validation.

This study investigated the prevalence and characteristics of germline mutations in 1094 Chinese colorectal cancer (CRC) patients using a 53-gene hereditary cancer panel. Pathogenic/likely pathogenic (P/LP) germline mutations were identified in 9.3% of patients, with mismatch repair (MMR) genes being the most frequently affected. Chinese patients showed lower frequencies of MUTYH and APC mutations but higher rates of MMR mutations compared to Western populations. Patients harboring germline P/LP mutations had significantly better progression-free survival, and a notable proportion of carriers lacked family history or were diagnosed after age 65. These findings highlight the need for population-specific genetic testing and screening strategies tailored for Asian populations.

This study investigated oncogenic fusions in 11 unclassified pulmonary spindle cell tumors, aggressive neoplasms with limited treatment options. Using anchored multiplex PCR-based targeted RNA sequencing, researchers identified ALK gene fusions in two patients (18.2%), specifically PPFIBP1::ALK and SYCL3::ALK. Both tumors also exhibited positive ALK immunohistochemical staining, despite showing morphological heterogeneity. These findings expand the molecular spectrum of these rare tumors and highlight the importance of detecting ALK fusions, including those with uncommon partners.

This meta-analysis assessed the performance of breast cancer risk prediction models in women with a family history of the disease. The Gail (BCRAT) and BOADICEA models demonstrated good calibration, while Tyrer-Cuzick overpredicted and BRCAPRO underpredicted risk. Regarding discriminatory accuracy, no single model was clearly superior, with Tyrer-Cuzick version 8, BOADICEA, and BRCAPRO showing similar modest discrimination. The authors suggest that BOADICEA may be useful for patient management in familial breast cancer risk settings, despite limitations such as high risk of bias and study heterogeneity.

This study analyzed the genomic profile of 480 patients with metastatic adenocarcinoma of unknown primary (ACUP) using the FoundationOne CDx platform. The most frequent mutations included TP53, KRAS, and CDKN2A. Results showed that GNAS and PIK3CA mutations were associated with better overall survival. Conversely, ARID1A and NOTCH1 alterations were linked to a worse prognosis. These findings highlight the significance of specific genomic alterations as prognostic markers in ACUP.

This prospective study investigated the prevalence of non-BRCA germline pathogenic variants (PVs) and their impact on response to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). Among 184 patients, 36% harbored PVs in pan-cancer susceptibility genes, including variants in 31 genes not previously found in other US cohorts. Patients received NAT with doxorubicin, cyclophosphamide, paclitaxel, and carboplatin, with or without immunotherapy or targeted therapy. Despite this high prevalence, the presence of these non-BRCA germline PVs was not associated with a significant difference in pathologic complete response (pCR) or radiologic response. The findings suggest the utility of multigene panels for screening but indicate that these variants are not predictive of NAT response in TNBC.

This paper introduces TF-DWGNet, a novel Graph Neural Network framework developed for multi-omics cancer subtype classification. The model features two key innovations: a supervised tree-based strategy for constructing directed weighted graphs tailored to each omics modality, and a tensor fusion mechanism to efficiently capture unimodal, bimodal, and trimodal interactions. Experiments on three real-world cancer datasets demonstrate that TF-DWGNet consistently outperforms state-of-the-art baselines. Furthermore, it provides valuable interpretable insights through modality-level contribution scores and ranked feature importance.