NPJ Precision Oncology最新文献

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide, highlighting the urgent need for non-invasive strategies for early detection. Here, we present a machine learning-assisted metabolomics approach for the early detection of LUAD. Untargeted metabolomic profiling was performed on 199 serum samples from healthy individuals, patients with lung precancerous lesions, and those with stage I LUAD. An ensemble machine learning workflow was developed to identify metabolite panels capable of discriminating clinical status with high accuracy. We observed progressive metabolic alterations in bile acid, lipid, amino acid, and purine metabolism during LUAD initiation and stepwise progression. Notably, ensemble learning identified a six-metabolite panel, including 12-hydroxydodecanoic acid, hypoxanthine, xanthosine, cholic acid, agmatine, and paraxanthine, for accurate detection of early-stage LUAD, and a distinct four-metabolite panel, comprising 7-α,27-dihydroxycholesterol, 11-undecanedicarboxylic acid, biliverdin, and Prolyl-Valine, for precise differentiation between pre-invasive and invasive lesions. Both panels demonstrated promising diagnostic potential, with performance metrices comparing favorably to established methodologies within the current study cohort. This study delineates the evolutionary trajectory of the serum metabolome associated with early LUAD pathogenesis and provides promising biomarkers for non-invasive early detection.

The treatment principle for locally advanced cervical cancer is concurrent chemoradiotherapy (CCRT). However, local recurrence or distant metastasis may still occur after the completion of CCRT. Currently, there is no effective method to monitor the efficacy of CCRT and predict prognosis. This study aims to predict the therapeutic efficacy and prognosis by dynamically monitoring human papillomavirus (HPV) circulating tumor DNA (HPV ctDNA) levels. We enrolled 31 patients with locally advanced cervical cancer and used the HPV-Seq (14 subtypes) to quantify HPV genotype-specific DNA in plasma and tissues before and during CCRT, and in the post-treatment plasma. Regular imaging was performed to evaluate tumor regression. HPV reads in plasma and tissues decreased significantly during treatment (p < 0.05). Higher HPV ctDNA levels were associated with poorer treatment outcomes (p < 0.05). In univariate and multivariate analyzes, dynamic changes in plasma HPV ctDNA were an independent factor for predicting early treatment outcome. These findings indicate that longitudinal HPV ctDNA monitoring reflects the efficacy of CCRT in locally advanced cervical cancer and provides a basis for earlier identification of candidates for post-CCRT treatment intensive and prognostic stratification.

Prostate cancer (PCa) is a heterogeneous disease, impeding early detection and risk stratification. Liquid biopsies (LBx) enable minimally invasive tumor profiling, but circulating tumor-derived DNA (ctDNA) detection remains difficult, particularly in early-stage PCa. We developed a multimodal LBx approach combining genomic and epigenomic cell-free DNA (cfDNA) features in plasma and urine from newly diagnosed PCa patients to improve early characterization of PCa and risk stratification of aggressive disease. Plasma and urine samples from 55 localized PCa (lPCa) patients, 18 advanced PCa (aPCa) patients, and 36 cancer-free controls were subjected to low-coverage whole-genome sequencing and methylated DNA immunoprecipitation sequencing to assess fragmentation, chromosomal instability, and methylation in cfDNA. This complementary approach yielded a 45% ctDNA detection rate in newly diagnosed PCa. Major differences were observed between aPCa and controls, reflecting increasing signals with tumor progression. Epigenomic cfDNA features differentiated lPCa from aPCa, and ctDNA was detected in 46% of PCa patients with prostate-specific antigen <10 ng/mL, suggesting potential for risk stratification. This study highlights the value of multimodal LBx approaches for early characterization of primary PCa and identification of aggressive disease at initial diagnosis. Integration into clinical workflows could complement diagnostics and support personalized decision-making tailored to patients' PCa risk profiles.

While homologous recombination deficiency (HRD) presents therapeutic opportunities in endometrial cancer (EC), its molecular determinants and clinical implications remain poorly characterized. Through genomic analysis of 688 cancer-related genes combined with genomic scar assessment, we investigated HRD molecular features and clinical relevance of HRD across three cohorts: an EC cohort from Sun Yat-sen University Cancer Center (SYSUCC, n = 114), the Cancer Genome Atlas EC cohort (n = 500), and a high-grade serous ovarian cancer (HGSOC) cohort (n = 118). HRD was identified in 23.7% of SYSUCC EC cases, and HRD tumors paradoxically had fewer short-nucleotide variations in HRR genes than proficient (HRP) tumors (18.52% vs. 48.28%, P = 0.007). Mechanistic analysis revealed large-scale transition (LST) losses as the potential predominant HRD driver in EC, occurring significantly more frequently in HRD versus HRP tumors (74.1% vs 5.7%; P < 0.001). Comparative genomics demonstrated enrichment of HRR gene LST losses was EC-specific, contrasting with HGSOC where LST distribution was HRD-independent. Clinically, elevated HRD scores predicted reduced progression-free survival (HR 1.74, 95% CI 1.03-2.94; P = 0.04) yet enhanced platinum sensitivity (HR 0.41, 95% CI 0.18-0.94; P = 0.034). Our findings indicate that the HRD phenotype in EC, driven primarily by LST losses rather than short-nucleotide variations, serves as both a prognostic and predictive biomarker.

BBP-398 is a selective allosteric SHP2 inhibitor designed to inhibit mitogen-activated protein kinase (MAPK) pathway-driven tumors. We performed the first-in-human phase 1 trial described herein to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of BBP-398 in patients with advanced solid tumors harboring MAPK pathway mutations. Once-daily BBP-398 was administered at 350-550 mg in the dose-escalation phase (1a; n = 35) followed by a dose-expansion phase (1b; n = 37). The study endpoints were dose-limiting toxicities, treatment-emergent adverse events, pharmacokinetics, target engagement, disease control rate, progression-free survival, and overall survival. In phase 1a, 26% of the 23 evaluable patients had stable disease, with a median progression-free survival duration of 1.8 months (range, 1.7-4.1 months). In phase 1b, 30% of the 27 evaluable patients had stable disease (31% at 350 mg, 27% at 450 mg), with median progression-free survival of 2.2 months and 1.9 months at 350 mg and 450 mg, respectively. We halted dose escalation at 550 mg owing to an increased rate of thrombocytopenia and edema. At daily doses of up to 450 mg, BBP-398 exhibited an acceptable safety profile and produced disease stabilization in nearly 30% of heavily pretreated patients.

We report a single-arm phase 2 trial of pembrolizumab in advanced malignant peripheral nerve sheath tumors at Oslo University Hospital. Long-lasting response in 1 of 8 patients was associated with high tumor density of PD-1⁺CD8⁺ T cells. Mixed response in another patient was associated with PD-L1 expression, and PD-L1 was mostly not co-expressed on CD68⁺ macrophages or CD8⁺ cells. The study was prematurely closed due to a slow accrual rate.

We report a child with an antenatally detected brain tumor that progressed over three years' time despite surgery, chemo- and proton therapy. Retrospective whole-genome and transcriptome sequencing with methylation analysis of primary tumor tissue led to the molecular diagnosis infant-type hemispheric glioma, and identified a novel SNRNP70::ALK fusion, providing a therapeutic target for compassionate-use precision treatment with the ALK tyrosine kinase inhibitor lorlatinib. Functional studies confirmed the fusion protein to be expressed and active in the patient's tumor. After two years of therapy, the child has sustained partial tumor regression on MRI and no new neurological symptoms. We conclude that comprehensive multi-omics analyses are required for correct molecular diagnosis in childhood CNS tumors and can radically impact patient outcome by identifying molecular targets for precision treatment.

Unique disease characteristics of younger patients warrants investigation of tumor genomics in young-onset metastatic breast cancer (MBC). Targeted DNA sequencing was completed for tumors of MBC patients diagnosed between 2009-2020. Multivariable logistic regression tested associations between single nucleotide variants (SNVs) and copy number variants and age at MBC diagnosis. Multivariable Cox regression estimated hazard ratios for overall survival (OS) by somatic alterations. Among 2,357 MBC patients, tumors of those ≤40 years at diagnosis (vs. >55) were more likely to harbor amplifications in ERBB2 and MYC (p < 0.01) and mutations in TP53 (odds ratio [OR] = 1.83, p < 0.001), and less likely to harbor mutations in CDH1 and PIK3CA (p < 0.001). OS was shorter among younger recurrent MBC patients [median: 2.8 (≤ 40) vs. 3.6 years ( > 55), p = 0.04], with SNVs in TP53 and PTEN associated with shorter OS. Distinct tumor genomics of young-onset MBC patients suggest differences in tumor biology that should guide investigation of targetable pathways.

Acute myeloid leukemia (AML) is sustained by oncogenic signaling and stress-adaptive networks that enable proliferative sustenance and therapeutic resistance. Transcriptomic profiling of AML blasts revealed upregulation of FLT3, SYK, HOXA9/10, and CTNNB1 with elevated oxidative phosphorylation (OXPHOS). Proteasome inhibition induced phosphorylation-dependent ubiquitination and nuclear export of β-catenin, triggering stress signaling (p62/SQSTM1/c-JUN/NRF2) and apoptosis in FLT3^ITD mutant AML blasts. Dual targeting of FLT3/SYK (TAK-659) and the proteasome (Ixazomib) showed strong synergy across genetically defined AML subsets, irrespective of FLT3 mutant status. In Tet2^-/-;Flt3^ITD AML-transplanted mice models, combination therapy markedly reduced leukemic burden, restored CD45.1⁺ normal hematopoiesis, corrected disease-associated cytopenias, and normalized hematopoietic stem and progenitor composition. In our phase I/II clinical trial, this combination therapy induced rapid leukemic clearance, early transcriptional silencing of HOXA/FLT3/NRF2 programs, and durable hematologic responses in refractory AML patients. These findings define a therapeutically targetable axis linking FLT3/SYK/β-catenin signaling to stress adaptation, provide a mechanistic basis for combinatorial targeting in high-risk AML. Trial registration: NCT04079738, Date of registration 03 September 2019.

Class II and III BRAF mutations are uncommon events, with limited data on their clinical and biological characteristics. We investigated clinical and molecular features of BRAF mutation classes in a total of 24,402 patients with mismatch repair proficient CRC (MMRp). Samples collected between 2006 and 2023 were profiled using next-generation sequencing and whole-transcriptome sequencing. We identified 1268 (5.2%), 132 (0.54%), and 323 (1.3%) patients with class I, II, and III BRAF-mutated CRC. Patients with class III mutations had significantly better median overall survival (OS) than those with class I mutations (23.6 vs 17.4 months; HR = 1.26, CI: 1.08-1.47, p = 0.004). Transcriptomic analyses revealed that the MAPK pathway score was significantly lower for class II and III BRAF mutations without concurrent RAS mutations than for those with RAS co-mutations. The cetuximab score, an RNA expression-based predictor of EGFR therapy response, was significantly better for class II and III BRAF mutations than for class I. The cetuximab score significantly improved for only class III BRAF mutations when those with concurrent RAS mutations were excluded. The results of this large multi-institutional analysis of BRAF mutation classes reveal the prognostic value of class II and III BRAF mutations, and their distinct clinical and molecular features.