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Sep 28Mon
  1. biorxiv.org64

    m6A-Driven Intratumoral Cholesterol Biosynthesis Fuels Castration-Resistant Prostate Cancer Progression

    A METTL3–NUP93 interaction couples m6A-mediated nuclear mRNA export to cholesterol biosynthesis, driving castration-resistant prostate cancer. Overexpression of wild-type METTL3 or NUP93, but not enzymatically dead METTL3 or the METTL3-interaction-deficient NUP93 mutant, raised intracellular androgens, activated AR signaling under castrate conditions, and promoted androgen-independent growth in vitro and in vivo. Pharmacological inhibition of METTL3 or targeted demethylation of mRNAs encoding cholesterol biosynthesis enzymes suppressed CRPC malignancy.

    Why it matters: Identifies a druggable m6A-METTL3-NUP93 axis linking mRNA export to androgen production in CRPC.

  2. biorxiv.org67

    Disruption of the ARID1A-containing SWI/SNF complex reprograms tumor-associated macrophages and enhances immunotherapy response

    Disrupting the SWI/SNF chromatin remodeling complex in tumor-associated macrophages reprograms them and improves checkpoint blockade immunotherapy. Pharmacologic inhibition of SWI/SNF ATPase activity slowed tumor growth, and deleting the SWI/SNF subunit Arid1a in myeloid cells was sufficient to suppress tumor progression and enhance checkpoint blockade response. The reprogramming involved reduced enhancer accessibility at poor-prognosis genes such as Spp1, increased accessibility at interferon-stimulated gene promoters, elevated CD86, and required CD86 costimulation and CD8+ T cells.

    Why it matters: It identifies a druggable epigenetic target in macrophages that improves checkpoint blockade response.

  3. biorxiv.org54

    Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis

    Mosaic structural variants occur in all individuals and germ layers, with long- and short-read WGS of 47 normal tissues (168 samples) showing a median 285.2 kb affected per genome. Most variants were repeat-mediated and 8.3% overlapped functional elements, enriched relative to germline variants. Repeat alterations measured from short reads across 15 cancer types matched normal mosaic variation in scale and enabled tumor tracking in cell-free DNA.

    Why it matters: Quantifies repeat-driven mosaic structural variation in normal tissues and shows repeat changes in cell-free DNA can monitor tumors.

  4. biorxiv.org53

    Mutation Order and Selection Shape Intratumor Heterogeneity in Tumor Evolution

    A multitype branching-process model shows that mutation order shapes intratumor heterogeneity, because a driver's effect depends on when it is acquired. An early strong driver expands the intermediate lineage and increases independent malignant founders, while the same driver at the final transition strengthens early-founded malignant clones. Under additive fitness, these counteracting mechanisms can yield a non-monotone relation between selective advantage and clonal concentration, captured in a closed-form limiting Simpson's index.

  5. biorxiv.org62

    A meiotic B-type cyclin selectively drives mitotic progression and fidelity in cancer cells

    Cyclin B3, previously thought to act only in female meiosis, is expressed in mitotic cells and partners with CDK1 and CDK2 to drive timely mitotic progression through proper chromosome alignment and stable kinetochore-microtubule interactions. Depleting cyclin B3 disrupted mitosis in most cancer cell lines tested, including colorectal, osteosarcoma, and breast cancer models, while non-transformed cells were largely unaffected. Phospho-mass spectrometry identified kinetochore and mitotic spindle components as substrates, pointing to a preferential cancer-cell dependency.

    Why it matters: It identifies cyclin B3-CDK1/2 as a mitotic driver that cancer cells depend on more than non-transformed cells.

  6. biorxiv.org62

    Structural polymorphism and population-variable coding capacity of HERV-K(HML-2) in human pangenomes

    Haplotype-resolved long-read assemblies from 292 donors reveal extensive structural polymorphism in HERV-K(HML-2) proviruses: tandem arrays at 13 loci with up to six copies each, a previously undescribed full-length provirus at 8q11.23, and intact open reading frames in many individuals where reference genomes carry disruptive mutations. Short-read genotyping left 32.5% of donor-variant pairs unresolved at sites tied to viral reading frames. HML-2 expression studies should account for the coding alleles each individual carries.

    Why it matters: Reference-based short-read methods miss HML-2 structural and coding variation that affects interpretation of HERV expression in disease.

  7. biorxiv.org56

    ctDNA Release Heterogeneity in Luminal Breast Cancer Revealed by Single-Cell Multi-Omics Spatial Analysis

    Eight recurrent malignant epithelial states in non-metastatic HR+/HER2- breast cancer show distinct ctDNA release potential, defined by scMASTER, a framework combining single-cell transcriptomes and mutations, spatial transcriptomics and matched tumor and plasma DNA sequencing across ten patients. Antigen-presentation, stress, mitosis and mesenchymal-like states released most ctDNA, as did EMT-enriched regions, intraductal luminal progenitors and avascular hypoxic zones. PIK3CA and ESR1 mutations tied to distinct functional states altered ctDNA detectability, and a stratification model from these features identified high-risk, immunosuppressed patients with poor prognosis in external cohorts.

    Why it matters: It explains cellular and spatial sources of tissue-plasma discordance that limit liquid biopsy in HR+/HER2- breast cancer.

  8. biorxiv.org54

    Integrated immunopeptidomics and transcriptomics reveal a cancer-restricted non-canonical HLA class I ligandome in medulloblastoma

    Non-canonical HLA class I peptides could widen the target pool for T-cell immunotherapy in medulloblastoma, a tumor with low mutational burden. Integrated immunopeptidomics and transcriptomics across 21 samples covering the four molecular subgroups identified 2,298 non-canonical HLA-I peptides, 598 of them cancer-restricted, derived mainly from retained introns, out-of-frame open reading frames, and long non-coding RNAs. More than 70% were predicted to bind a patient-matched HLA allotype and about 87% to be immunogenic.

    Why it matters: It expands the antigen repertoire available for T-cell therapy in a low-mutational-burden childhood brain tumor.

  9. biorxiv.org52

    Palmitate-activated IRE1-XBP1 signaling limits DNA damage and is associated with H2A.X-linked DNA damage response transcripts in triple-negative breast cancer cells

    Palmitate-activated IRE1-XBP1 signaling protects triple-negative breast cancer cells from DNA damage during genotoxic stress. In MDA-MB-231 cells exposed to palmitate and etoposide, XBP1 depletion increased DNA damage in IRE1 wild-type cells, IRE1 re-expression reduced it, and pharmacologic IRE1 RNase inhibition increased etoposide-associated damage. H2A.X and the damage-response transcripts HUWE1 and BRCA2 associated with IRE1 immunoprecipitates under combined stress, defining an IRE1-linked DNA-damage-response network.

  10. biorxiv.org57

    RNA isoform-resolved multiplexed sequencing with bioorthogonal barcoding

    Bobcodes, bioorthogonal barcodes attached at multiple internal positions along cellular RNAs via acylation and click chemistries, enable multiplexed sequencing that preserves splice junction information. Template switching onto tethered bobcodes during cDNA synthesis occurs with greater than 99% accuracy in species mixing experiments, and priming choice selects between 3'-end counting and full-length isoform capture. A BOB-seq v0.1 drug screen detects transcriptome-wide on- and off-target RNA splicing effects and outperforms existing multiplexing RNA sequencing methods in workflow simplicity, sample-to-sample variability, and barcoding accuracy.

    Why it matters: It adds isoform resolution to scalable multiplexed RNA sequencing, enabling transcriptome-wide splicing drug screens.

  11. biorxiv.org62

    BLTP3A dysfunction unleashes lysosomal stress-induced antitumor immunity through STING

    A common germline missense variant in BLTP3A, M1098T, impairs lysosomal stress resolution in high-grade serous ovarian cancer, prolonging STING activity and tumor-derived IFN-λ. Patients carrying M1098T had longer overall survival and tumors enriched for cytotoxic T cell-myeloid neighborhoods. In syngeneic tumors, Bltp3a loss or the orthologous variant delayed progression and generated Cxcl9+ antigen-presenting macrophage niches, with tumor-cell STING and IFN-λ required for immune remodeling and tumor control.

    Why it matters: Links a germline variant to antitumor immunity and survival via lysosomal stress and STING.

  12. biorxiv.org69

    Pathway-wide base editing charts chemical-genetic interactions in MAPK signaling

    Base editor scanning across 22 MAPK genes, performed under pathway hyperactivation or inhibition at various nodes, produced a chemical-genetic interaction map of the RAS-RAF-MEK-ERK cascade. Drug resistance mutations often arose in proteins other than the direct drug target, catalytically impaired CRAF mutants gave bidirectional resistance and sensitization to structurally similar MEK inhibitors, and an allosteric site was found in the KRAS N-terminus. The work establishes BE scanning as a scalable method for network-level chemical-genetic mapping in a major oncogenic pathway.

    Why it matters: It charts chemical-genetic interactions across an oncogenic pathway and finds resistance mutations away from the drug target.

  13. biorxiv.org61

    A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity

    Suppressive neutrophils (PMN-MDSCs) depend on mSWI/SNF chromatin remodeling to maintain their identity, and two orally bioavailable mSWI/SNF ATPase antagonists, a degrader and a catalytic inhibitor, produced immune-dependent tumor control in syngeneic models, including tumors resistant to PD-1 blockade. Treatment depleted intratumoral PMN-MDSCs, restored functional CD8+ T cells, enhanced checkpoint therapy without overt toxicity, and blocked PMN-MDSC expansion in mouse and human cells. Mechanistically, antagonism collapsed chromatin accessibility and PU.1/C/EBPβ occupancy at regulatory elements sustaining PMN-MDSC identity.

    Why it matters: It identifies a druggable chromatin dependency of PMN-MDSCs and shows it can restore antitumor immunity and checkpoint response.

  14. biorxiv.org58

    Deciphering the association of spatial landscapes of DCIS with recurrence as invasive breast cancer

    Spatial transcriptomics of 49 primary DCIS specimens shows stromal cell gradients, with TREM2+ macrophages and myofibroblastic cancer-associated fibroblasts enriched in tumor-proximal niches. TREM2+ macrophage abundance near tumor nests is associated with recurrence as invasive breast cancer, and ligand-receptor analysis implicates GRN-SORT1, SPP1-CD44, and LGALS9-CD44 signaling between these macrophages and epithelial cells. Findings were validated by multiplex immunostaining.

    Why it matters: Identifies a spatially defined stromal biomarker for progression from DCIS to invasive breast cancer.

  15. biorxiv.org51

    A plasma metabolomics workflow for breast cancer detection using quantitative GC/MS and machine learning

    A standardized plasma GC/MS metabolomics workflow with machine learning distinguished breast cancer patients from healthy controls in 360 prospectively collected samples (180 per group). Forty-five candidate metabolite biomarkers were identified; Lasso logistic regression, random forest, and SVM models reached AUCs of 0.910, 0.893, and 0.843, and a bagging ensemble improved stability to an AUC of 0.911 with fewer false positives in an independent 15-person control cohort. The work addresses reproducibility and overfitting barriers to clinical use of blood-based breast cancer detection.

  16. biorxiv.org60

    Systemic tumor-cell reprogramming converts solid tumors into in situ biofactories for immunotherapy

    LENTRA, an antigen-targeted lentiviral platform, genetically reprograms tumor cells in vivo to produce therapeutic proteins directly within the tumor after intravenous administration. In multiple murine solid tumor models, tumor-restricted expression of anti-CTLA-4 or IL-12 triggered potent antitumor responses without systemic toxicities, while sialidase secretion drove dendritic cell and T cell infiltration, macrophage reprogramming, tumor regression and durable immune memory. LENTRA also mediated efficient transduction, immune remodeling and reduced tumor viability in patient-derived tumor explants.

    Why it matters: It turns tumors into their own drug-producing biofactories, addressing toxicity of systemic delivery.

  17. biorxiv.org61

    Glutamine and GLS1 are key metabolic checkpoints that Limit T cell Infiltration and Function in HNSCC

    Glutaminase-1 acts as a metabolic checkpoint limiting T cell infiltration and function in head and neck squamous cell carcinoma (HNSCC). Pharmacologic inhibition or genetic deletion of glutaminase-1 increased tumor susceptibility to immune cell-mediated cytotoxicity and sensitized patient-derived tumor fragments to immune checkpoint blockade, via disruption of glutathione-dependent ROS defense, impaired tumor proliferation, and increased MHC expression. Breast cancer fragments, which show low glutaminase-1 expression, were not responsive, supporting patient stratification for metabolism-targeted immunotherapy.

    Why it matters: Identifies a targetable metabolic mechanism of immune checkpoint blockade resistance in HNSCC.

  18. nature.com49

    Old hearts age backwards: transplanted organs adjust to host’s biological age

    Transplanted hearts take on the biological age of their recipients, according to DNA-methylation analysis in mice and in 11 human transplants with donor-recipient age gaps of 8 to 50 years. Young hearts grafted into older animals showed accelerated ageing, while old hearts were rejuvenated in younger hosts. Post-transplant measures such as heart rate, posterior wall thickness and exercise capacity tracked the recipient's age rather than the donor's.

Sep 27Sun
  1. biorxiv.org42

    Integrative Nanopore and Illumina sequencing reveals age-associated tRNA modification and CCA-tail dynamics in yeast

    Nanopore direct RNA sequencing (RNA004 chemistry) with Illumina validation profiles the Saccharomyces cerevisiae tRNAome during replicative aging at single-molecule resolution. Overall tRNA abundance remains largely stable, but aging brings terminal A cleavage at the 3' CCA tail of mature tRNAs, targeted T-loop and anticodon modification changes, and single-molecule evidence of modification co-occurrence. The work adds a benchmarked resource for studying tRNA regulation, translation fidelity, and longevity.

    Why it matters: It links aging to specific tRNA CCA-tail and modification changes at single-molecule resolution.

  2. biorxiv.org54

    Targeted CRISPRi screening reveals unexpected resilience across the RNA polymerase III transcriptome

    An inducible CRISPR interference platform with a custom sgRNA library enabled gene-specific repression of RNA polymerase III-transcribed genes and Pol III machinery. Genome-wide screens in diploid fibroblasts and HEK293T cells uncovered several Pol III dependencies, with multiple initiator methionine tRNA genes among the strongest fitness dependencies. Glioblastoma models, however, remained largely insensitive to repression of both individual Pol III genes and core Pol III components despite efficient target knockdown, challenging the assumption that cancer cells uniformly depend on elevated Pol III activity.

    Why it matters: It shows glioblastoma models tolerate Pol III gene repression, contradicting the link between Pol III activity and cancer growth.

  3. biorxiv.org62

    A single-nucleus multi-omic atlas of gene regulation across 21 adult human tissues

    A single-nucleus multi-omic atlas maps gene regulation across 21 adult human tissues from four donors, profiling 459,856 nuclei including 160,688 with paired transcriptome and chromatin accessibility. It resolves 313 subclusters and identifies 1,085,062 candidate cis-regulatory elements, 161,270 of them novel, plus 871,177 cCRE-gene links. Trained sequence-to-function models flag 18,133 high-effect fine-mapped variants, giving a framework for interpreting non-coding risk.

    Why it matters: It links regulatory DNA to cell-type-specific expression across 21 tissues and prioritizes fine-mapped non-coding variants.

Sep 26Sat
  1. biorxiv.org54

    Discrepancies between ChIP-seq and CUT&Tag histone mark profiles are explained by GC content and chromatin accessibility

    Systematic comparison of ChIP-seq and CUT&Tag histone mark profiles in K562 and MCF-7 cells shows that many disagreements between the assays track GC content and chromatin accessibility. CUT&Tag loses H3K36me3 signal in GC-poor active gene bodies and H3K27me3 signal in GC-poor Polycomb-repressed domains, and promoters with discrepant H3K4me3 and H3K27ac signal differ systematically in GC content and DNase-seq and ATAC-seq signal. Studies profiling histone modification intensity and structure should account for these biases.

    Why it matters: Explains assay-dependent biases that affect interpretation of histone mark profiling comparing ChIP-seq and CUT&Tag.

Sep 25Fri
  1. medrxiv.org56

    Tumour extrinsic neutrophil regulation in mesothelioma correlates with responsiveness to AXL and PD1 inhibition in MIST3, a phase IIA clinical trial

    AXL and PD1 inhibition with bemcentinib plus pembrolizumab met its primary endpoint in the phase IIA MIST3 trial in ICB naïve-relapsed mesothelioma, with a 12-week disease control rate of 46.2% (90% CI 29.2-63.8%); grade 3 or greater adverse events occurred in 53.9% of patients. Multiomic analyses linked response to NF2 loss, immune response signalling, epithelial mesenchymal transition, and neutrophil-related transcriptional programmes including SPI1, ETS2 and FLI1 activation. Gut microbiota composition differed between responders and non-responders and correlated with neutrophil-associated transcription programmes, IRF3 and TLR2.

    Why it matters: Phase IIA evidence that neutrophil and gut microbiota features track response to AXL-PD1 inhibition in mesothelioma.

  2. biorxiv.org51

    A single-nuclei multiomics resource across four brain regions prioritises human neural cell types influencing brain-related traits

    Single-nuclei multiomic profiling of gene expression and chromatin accessibility across ~140,000 nuclei from 40 post-mortem adult brain samples (11 donors, four regions: amygdala, hippocampus, hypothalamus, prefrontal cortex) pinpoints neural cell populations underlying brain-related traits. Integration with GWAS statistics prioritised similar neuronal populations for BMI, schizophrenia, bipolar disorder and age at menarche, and supported enhancer-gene relationships relevant to Alzheimer's disease. The resource nominates effector transcripts and cellular pathways for trait-associated variants.

    Why it matters: It maps non-coding risk variants to specific neural cell types and enhancer-gene pairs across four human brain regions.

Sep 24Thu
  1. medrxiv.org52

    Advancing sarcoma diagnostics with expanded DNA methylation-based classification

    An expanded DNA methylation-based sarcoma classifier (v13.1) was trained on 4377 methylation profiles covering 116 tumor sub-classes, 4 control groups and 93 distinct methylation classes, and validated in 1547 mesenchymal tumors from four independent cohorts. Five-fold nested cross-validation yielded 98% class-level accuracy with a Brier score of 0.017. Predictions were obtained in 73% of validation cases, 91% matched the histopathology diagnosis, and 6% of inconclusive or ambiguous cases gained a definitive molecular diagnosis or reclassification.

    Why it matters: A larger, validated methylation classifier broadens molecular diagnosis options for diagnostically difficult mesenchymal tumors.

Sep 23Wed
  1. medrxiv.org55

    Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer

    Type 2 deiodinase (DIO2), the enzyme converting T4 to T3, is a conserved marker of cancer-associated fibroblasts (CAF) across thyroid cancer and six additional solid tumor types, and is enriched in myofibroblastic CAF. Elevated DIO2 expression correlated with worse overall survival in pancreatic and bladder cancers, while thyroid cancer showed an inverse association linked to loss of epithelial DIO2 during dedifferentiation. In a TPO-CreERT2/BrafV600E/Trp53-deficient mouse model, Dio2 loss in the tumor microenvironment significantly reduced tumor growth, and D2 activity was suppressed by cefuroxime and lenvatinib.

    Why it matters: Identifies DIO2 as a CAF-restricted, druggable target conserved across solid tumors, with preclinical evidence of tumor suppression.

  2. medrxiv.org52

    Potential five-year life years associated with stage IV reductions in NHS Galleri Trial

    A modeling analysis of the NHS-Galleri trial projects that the reduction in stage IV diagnoses seen after two annual multi-cancer early detection screening rounds could yield 66.3 potential five-year life-years in the trial intervention cohort, or 466 per million people screened annually (95% interval 190-743). Intervention and control arms recorded 180 versus 239 stage IV diagnoses across ten evaluable cancers, with colorectal, lung and esophageal cancers accounting for 79% of the net projection. The authors stress this conditional estimate is not evidence of mortality reduction, and longer follow-up is needed.

    Why it matters: Translates NHS-Galleri's stage IV shift into projected life-years per million screened, clarifying what the screening signal may or may not mean.

Sep 22Tue
  1. medrxiv.org54

    Genomic foundation models extend clinicopathologic and transcriptomic prognostication in soft tissue sarcoma

    Evo2, a genomic foundation model, was used to embed short variants, fusions and rearrangements from 102 patients with soft tissue sarcoma and 129 TCGA-SARC cases into patient-level genomic representations for Cox survival modelling. Adding Evo2 to SARCULATOR raised the OS C-index from 0.620 to 0.770 in the study cohort and from 0.595 to 0.716 in TCGA-SARC; in TCGA-SARC it also improved CINSARC-based OS prediction from 0.476 to 0.653. These descriptive point estimates support altered tumor sequence context as an independent prognostic layer for sarcoma risk stratification.

    Why it matters: It shows genomic foundation model features improve established sarcoma prognostication across cohorts and survival endpoints.

  2. medrxiv.org59

    Targeting Polθ Helicase with RP-3467: Preclinical Validation and Clinical Response in a gBRCA1 ovarian cancer patient with an acquired PARPi resistance mutation in TP53BP1

    RP-3467, a selective small-molecule inhibitor of DNA polymerase theta, suppresses Polθ enzymatic activity, abrogates microhomology-mediated end joining, and induces synthetic lethality in homologous recombination-deficient models. Combined with PARP inhibitors olaparib or rucaparib, it produced sustained tumor regression across multiple xenograft and patient-derived xenograft models without added systemic toxicity. In a phase 1 trial (NCT06560632), a heavily pretreated germline BRCA1-mutant ovarian cancer patient with a TP53BP1 loss-of-function mutation achieved a confirmed partial response to RP-3467 plus olaparib by RECIST v1.1.

    Why it matters: First clinical response to a Polθ inhibitor in a PARPi-resistant HRD ovarian cancer patient with mechanistic preclinical support.

Sep 21Mon
  1. medrxiv.org54

    A Causal Multi-modal AI Model Stratifies Residual Risk and Identifies Candidates for Treatment Escalation in Node-Positive HR+/HER2- Early Breast Cancer

    Ataraxis Breast CTX, a causal multi-modal AI model combining clinical variables with H&E histopathology, stratified residual recurrence risk in 556 node-positive HR+/HER2- breast cancer patients from the UNIRAD trial. Five-year disease-free survival was 93% in the low-risk group versus 80% in the high-risk group, and CTX-benefit predicted everolimus benefit in an exploratory multivariable analysis (interaction p = 0.01). The model may inform selection of patients for adjuvant treatment escalation.

    Why it matters: An AI model identifies which high-risk HR+/HER2- breast cancer patients can avoid escalation and who may benefit from everolimus.

  2. medrxiv.org43

    Weighing the Odds: Body Mass Index and Recurrence-Free Survival in Early-Onset Colorectal Cancer

    BMI at diagnosis shows a U-shaped association with recurrence-free survival in early-onset colorectal cancer, with the lowest hazard at BMI 27 and the highest at BMI below 20 or above 30 (LRT p=0.02). In 1,459 curative-intent surgery patients, no such association appeared in average-onset colorectal cancer (LRT p=0.15), and the cohorts differed significantly (LRT p=0.046). The findings suggest the obesity paradox may be specific to EOCRC.

    Why it matters: It suggests the obesity paradox in colorectal cancer may be specific to early-onset disease, where BMI is rising sharply.

  3. medrxiv.org54

    Decidual-Like Natural Killer Cells Are Enriched in Melanomas and Acquire CD9 Through Melanoma Cell Contact

    Melanomas harbor decidual-like NK cells with a CD56 Bright CD16 - CD49a + CD9 + phenotype, a population rare or absent in peripheral blood from patients with melanoma and healthy donors. The cells appear in tumors across sex, melanoma subtype, and disease site, and tumor CD9 expression correlated with intratumoral dl-NK frequency (Pearson rho = 0.40, p = 0.056). Co-culture showed direct contact with CD9-expressing melanoma cells induces CD9 acquisition by NK cells, suggesting an immunologic parallel between melanoma and the maternal-fetal interface.

    Why it matters: It identifies a decidual-like NK cell population in melanoma and a contact-dependent mechanism for its induction.

Sep 20Sun
  1. medrxiv.org57

    Methylation-Based ctDNA for Post-Treatment Surveillance of Non-Viral Head and Neck Cancer

    A methylation-based ctDNA assay (Guardant360) detected recurrence in non-virally associated head and neck squamous cell carcinoma with 76.9% sensitivity and 94.6% specificity (AUC 0.858) in a 50-patient post-treatment cohort. Positive ctDNA preceded clinical detection in 6 of 10 recurrences by a median of 131 days and tracked with worse survival: 1-year progression-free survival was 25.0% versus 96.4%. The findings support adding methylation-based ctDNA to surveillance for this population, pending prospective validation.

    Why it matters: It extends ctDNA surveillance evidence to non-viral HNSCC, where recurrence detection currently relies on exam and imaging.

  2. medrxiv.org66

    An AI Model Identifies Chemotherapy Benefit in Node-Negative HR+/HER2- Breast Cancer Patients from TAILORx, a Phase 3 Randomized Clinical Trial

    An AI model integrating H&E pathology image features with clinical variables (Ataraxis Breast CTX) identified which intermediate-RS node-negative HR+/HER2- breast cancer patients benefit from adjuvant chemotherapy in a prespecified analysis of 6735 TAILORx patients. CTX-benefit showed a significant treatment-by-biomarker interaction (p = 0.016), with high-benefit patients gaining 5.6% in 5-year disease-free interval from chemotherapy while low-benefit patients showed none; stratifying by RS alone at a matching threshold was not significant (p = 0.20). CTX-prognostic also predicted DFI independent of RS (C-index 0.736 with endocrine therapy alone).

    Why it matters: It offers a way to find chemotherapy benefit in intermediate-RS patients whom the 21-gene assay alone cannot stratify.

Sep 17Thu
  1. medrxiv.org61

    Population-Scale Precision Safety in Oncology Reveals Clinical and Genetic Determinants of Systemic Therapy Toxicity

    A large language model-based resource, MSK-Tox, captured the incidence, timing, and grade of anti-cancer therapy toxicity across more than 50,000 patients. Analysis of six representative adverse events showed toxicity risk varies by cancer type, regimen, and clinical context, is predictable from pretreatment clinical features, and has two germline modes: an organ-intrinsic mode, exemplified by a regulatory variant near FOXE1 linked to hypothyroidism, and an immune-mediated mode in which HLA-DRB1*15 drives adrenal insufficiency after immune checkpoint inhibition. The work supports pretreatment risk assessment for harm on the same principles used to predict benefit.

    Why it matters: It shows germline and clinical predictors can identify who will be harmed by cancer therapy before treatment starts.

Sep 16Wed
  1. medrxiv.org56

    Cancer type-specific profiling of chromatin regulator mutations identifies recurrent and co-occurring gene sets associated with improved survival following immune checkpoint therapy

    Distinct sets of chromatin regulator (CR) gene mutations predict improved survival after immune checkpoint inhibitor (ICI) treatment in each of ten cancer types, with some CRs recurrently favorable across cancers. Co-occurrence of mutations in two or more CRs further improved survival, and CR-altered tumors consistently showed higher tumor mutational burden than CR-unaltered tumors. Transcriptomic deconvolution linked CR mutations to cancer-type-specific differences in the tumor microenvironment.

    Why it matters: It maps CR mutations as cancer-type-specific and recurrent predictors of ICI survival across ten cancer types.

Sep 15Tue
  1. medrxiv.org49

    Beyond tumor volume: connectomic measures of tumor burden provide superior prognostic information across tumor compartments in glioblastoma

    A tractography-derived measure of brain-wide tumor involvement, the lesion–tract density index (L-TDI), outperformed conventional tumor volume for predicting overall survival in 999 patients with newly diagnosed glioblastoma across multiple institutions. Tumor volume's prognostic value depended strongly on analytical design and was largely confined to the contrast-enhancing compartment, whereas L-TDI showed robust associations with overall survival across thresholds and tumor compartments and retained its value after adjustment for established clinical variables. The findings support assessing glioblastoma prognosis as a brain-wide disease rather than by local tumor extent.

    Why it matters: It shows a connectomic tumor-burden measure beats conventional volume for glioblastoma survival prediction in 999 patients.

  2. medrxiv.org52

    Distinct Anaerobic Microbial Signature Differentiates Anal Squamous Cell Carcinoma From High-Grade Squamous Intraepithelial Lesions: A Prospective Metagenomic Study

    Anal squamous cell carcinoma (ASCC) carries a distinct anaerobic microbial signature that separates it from high-grade squamous intraepithelial lesions (HSIL). In shotgun metagenomic sequencing of anal swabs from 121 adults (102 HSIL, 19 treatment-naive nonmetastatic ASCC), six anaerobic species, including Fusobacterium nucleatum and Parvimonas micra, were enriched in ASCC, persisted across longitudinal sampling, and declined after treatment initiation. The finding points to microbial features that may help distinguish invasive anal cancer from precursor lesions.

    Why it matters: It identifies a reproducible microbiome signature that could mark progression from HSIL to invasive anal cancer.

  3. medrxiv.org43

    Cross-Source Progression Assessment in Advanced Pancreatic Cancer: An Opportunity-Adjusted Six-State Analysis

    Cross-source progression assessment in advanced pancreatic cancer frequently failed to yield immediate confirmation of progression. Among 645 patients in the primary estimand, only 25 (3.88%) showed same-day concordance, 219 (33.95%) confirmation, 108 (16.74%) explicit nonprogression, and 166 (25.74%) were indeterminate. Among classifiable first opportunities, 33.03% documented explicit nonprogression, supporting an opportunity-adjusted six-state framework over binary discordance estimates.

    Why it matters: Quantifies how often oncology and radiology sources disagree on progression, affecting how progression endpoints are interpreted.

Sep 14Mon
  1. medrxiv.org45

    Matched marrow and blood profiling reveals compartment- and feature-specific liquid-biopsy signals in multiple myeloma

    Peripheral-blood cfDNA matched or exceeded marrow-plasma cfDNA as a liquid biopsy for multiple myeloma, despite the tumor's marrow confinement. In 74 patients profiled across 372 cfDNA time points, blood cfDNA recovered marrow-defined CNAs and mutations at 77.4% vs 72.0% and 69.2% vs 65.4%, and at high tumor fraction adverse-lesion sensitivity reached 100% in both compartments. Marrow cfDNA did show distinct, handling-sensitive fragmentomic architecture (LOOCV AUC=0.910), so compartment, biomarker class, tumor fraction and processing all shape liquid-biopsy performance.

    Why it matters: It shows a simpler blood draw is not inferior to marrow-derived cfDNA for myeloma genomic profiling, with practical processing caveats.

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