Fabrice André

Tumor phenotype and therapeutic vulnerability are shaped by dynamic transcriptional states that are not captured by genetic profiling alone and are difficult to monitor longitudinally. Existing plasma-based approaches have largely been developed using samples with high circulating tumor DNA fractions, evaluated across expression quantiles rather than individual genes, and rarely benchmarked head-to-head. Using timepoint-matched plasma epigenomes and tumor transcriptomes, we identify biologically grounded relationships between circulating chromatin, fragmentation, and transcription. H3K4me3 and H3K36me3 encode distinct positional information reflecting promoter activity and transcriptional elongation, while gene-body fragment periodicity predicts expression. We integrate these relationships into APEX, a machine-learning framework for genome-wide single-gene expression inference. Across 559 plasma samples spanning 24 cancer types and clinically relevant tumor fractions, APEX outperforms existing approaches for individual-gene inference, resolves pancreatic cancer transcriptional subtypes, tracks therapeutic targets in small-cell lung cancer, and identifies NECTIN4 expression as a biomarker of response to enfortumab vedotin in urothelial cancer.

The growing administrative burden associated with clinical research has become a major challenge for investigators and research teams, contributing to increased costs, delays in trial implementation, and reduced research efficiency. In response, the European Society for Medical Oncology (ESMO) and ASCO have led multiple initiatives aimed at streamlining clinical research, identifying unnecessary bureaucracy, and promoting more pragmatic, patient-focused approaches. In line with these initiatives from ESMO, ASCO, and other stakeholders, the recent ICH Good Clinical Practice (GCP) guideline E6(R3) has incorporated numerous changes to rationalize the administrative procedures in clinical research. The revised guideline places substantially greater emphasis on applying proportionality between processes and risks, the relevance of the data, and the reliability of results; avoiding unnecessary complexity and burden in clinical research; and incorporating input from investigators and patients into trial design and conduct. The guideline also clarifies several aspects of clinical trial operations, including informed consent procedures, reconsenting requirements, source documentation, and delegation practices, providing opportunities to reduce administrative burden without compromising participant safety or data integrity. Together, the initiatives led by ESMO, ASCO, and other stakeholders, alongside the principles embedded within GCP E6(R3), reflect the shared recognition that clinical research processes should focus on activities that protect data integrity and the rights and well-being of patients. Effective implementation of these principles will be critical for improving the efficiency, sustainability, and accessibility of clinical research.

The retinoblastoma protein (Rb) is a tumour suppressor best known for repressing E2F transcription factors and halting cell cycle progression ¹ . In hormone receptor-positive (HR ⁺ ) breast cancer, CDK4/6 inhibitors activate Rb by preventing its phosphorylation, forming a key component of current endocrine therapy regimens ² . How pharmacologically activated Rb remodels chromatin and influences transcription beyond cell cycle arrest remains poorly understood. Here we show that CDK4/6 inhibition induces redistribution of hypophosphorylated Rb to promoters and enhancers. Although Rb predictably binds to cell cycle gene promoters to repress transcription, at other sites, it unexpectedly promotes expression of oestrogen-responsive genes by integrating into oestrogen receptor (ER)-rich transcriptional hubs. CDK4/6 inhibition enhances ER target gene expression in breast cancer cells, patient-derived xenografts and clinical HR ⁺ breast cancer samples in an Rb-dependent manner. This reprogramming is mediated in part by KDM5A, whose interaction with Rb contributes to gene regulation at these loci. Critically, components of this Rb-driven ER transcriptional program are pro-proliferative. In endocrine-sensitive tumours, this effect can be neutralized with anti-oestrogen therapy, explaining therapeutic synergy. In endocrine-resistant settings such as ESR1 -mutant breast cancer, the program persists, limiting the therapeutic efficacy of CDK4/6 inhibition. These findings reframe Rb as a dual-function transcriptional regulator that, although enforcing cell cycle arrest, can also activate programs that counteract its tumour suppressor function.

Hallmarks from gene set enrichment analysis (GSEA) of bulk RNA sequencing from tissue biopsies of FGFR inhibitor-naïve patients.

Clinical and molecular characteristics of FGFR inhibitor-naïve patients experiencing acquired resistance to lirafugratinib with off-target alterations only.

Clinical and molecular evolution of patient ST2726.

Primary resistance to lirafugratinib in FGFR inhibitor-naïve patients.

Differential impact on intracellular signaling exerted by lirafugratinib and futibatinib in FGFR2::BICC1 Ba/F3 with a kinase domain with no mutations (wild-type, WT), and with M538I or L618F mutations.

In vivo evaluation of lirafugratinib and futibatinib in ST4193 PDX.

Clinical and molecular evolution of patients pretreated with a FGFR inhibitor before undergoing lirafugratinib.