Maxime Borgeaud

Homozygous deletion of methylthioadenosine phosphorylase (MTAP), one of the most frequent somatic copy-number alterations in cancer, creates a context of synthetic lethal vulnerability. MTAP loss leads to the accumulation of 5'-methylthioadenosine (MTA), which partly inhibits protein arginine methyltransferase 5 (PRMT5), and induces a dependency on residual PRMT5 activity; a dependency that can be pharmacologically exploited. This review describes the MTAP-PRMT5 synthetic lethal axis from molecular biology to clinical translation. First-generation nonselective PRMT5 inhibitors were limited by hematological toxicity and reduced potency in MTA-rich environments. Second-generation MTA-cooperative inhibitors, which overcome these constraints by selectively stabilizing the inactive PRMT5-MTA complex, are characterized by tumor selectivity. Early-phase clinical data for MTA cooperative PRMT5 inhibitors showed encouraging signals of efficacy with manageable safety profiles in early-phase trials, establishing clinical proof of concept. Various agents have now entered the next steps of clinical development either alone or in combination. In this review we also discuss the biomarker challenges, essential to patient selection, including the limitations of different methods, as well as emerging resistance mechanisms to PRMT5 inhibitors. Molecular testing standardization, pharmacodynamic endpoint integration, and prospective resistance characterization are identified as priorities for next phases of development of PRMT5 inhibition.

The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene has revolutionized the management of lung cancer, enabling the development of targeted tyrosine kinase inhibitors (TKIs). These therapies offer improved survival and reduced side effects compared with conventional treatments. Recent advancements have significantly reshaped the treatment paradigm for EGFR‐mutant non‐small cell lung cancer. TKIs are now incorporated into the management of early stage and locally advanced disease, and phase 3 trials have explored combination strategies in metastatic settings. Although these intensified approaches improve progression‐free survival, they come with increased toxicity and higher costs, underscoring the need for precise patient selection to maximize benefit. Emerging data on biomarkers, such as co‐mutations and circulating tumor DNA, show promise for refining treatment decisions. In addition, significant progress in understanding resistance mechanisms to EGFR TKIs has broadened therapeutic options. This review provides a comprehensive overview of the current landscape of EGFR‐mutant nonsmall cell lung cancer, highlighting recent breakthroughs and discussing strategies to optimize treatment based on the latest evidence.

Tumor dormancy plays a pivotal role in cancer relapse. Dormant tumor cells have been identified in distant sites, even in early-stage tumors, and are associated with worse outcomes. This review explores the current understanding of the molecular and cellular mechanisms behind tumor dormancy, including the role of the immune system and the microenvironment. Targeting dormant tumor cells could be a therapeutic strategy to offer long-term remission and potentially cure cancer. Unfortunately, the translation of this knowledge in clinical practice is lacking. We assess the feasibility of detecting and measuring dormant tumor cells in clinical practice, and give an overview of potential therapeutic targets, both in terms of maintaining tumor cells in a dormant state, and in terms of eradicating this tumor population.

Aim: Characterize febrile neutropenia in the real-world and explore potentially modifiable risk factors. Patients & methods: Characteristics of patient presenting with febrile neutropenia after systemic cancer treatment were investigated, with a thorough evaluation of potential risk factors. Results: The rate of febrile neutropenia requiring hospitalization was comparable with clinical trials (mean absolute difference 2%, 95% CI: -1-4%; p = 0.29). The in-hospital mortality rate was 6%. Most cases resulted from low-risk regimens (50%) and 18.2% presented no apparent risk factors. 42.4% of patients presented modifiable factors potentially involved in the occurrence of febrile neutropenia. Conclusion: Febrile neutropenia rate in contemporary real-world evidence is comparable with clinical trials. Appropriate G-CSF administration and avoidance of potentially harmful drug-interactions represent potential areas for improvement.

Lung cancer remains the most common cause of cancer death across the world. Non-small-cell lung cancer (NSCLC) represents the most frequent type of lung cancer and is frequently diagnosed at an advanced stage. Stage III NSCLC, which encompasses 30% of cases, refers to a state between localized and metastatic disease, and is associated with poor prognosis. As highlighted in this review, stage III represents a heterogenous group, whose complex management includes multimodal treatment, discussed below, and requires discussion in multidisciplinary teams. The goal of this approach is a maximalist attitude in these patients with locally advanced and non-metastatic disease. However, many issues remain under debate including the optimal sequences of treatment between different treatment modalities, patient selection particularly for surgery, the duration of perioperative treatments and the identification of biomarkers to determine which patients might benefit of specific treatment like immunotherapy and targeted therapies. This review describes the current landscape of management of stage III NSCLC, discussing the critical issue of resectability, and highlighting the recent advancements in the field, particularly the incorporation of immune-checkpoint inhibitors (ICIs) and targeted therapies in this setting.