Profilage épigénomique de l'ADN Circulant Libre (cfDNA) Pour caractériser l'évolution Dynamique Des Sous-types moléculaires du Cancer du Poumon à Petites Cellules à un Stade étendu au Cours de la chimiothérapie-immunothérapie de première Ligne

Lung cancer is the leading cause of cancer-related deaths in France and worldwide. It is divided into two main types: non-small cell lung cancer (NSCLC), which makes up about 85% of cases, and small cell lung cancer (SCLC), which accounts for the remaining 15%. Treatment options for SCLC have changed very little over the past 40 years. The recent addition of immunotherapy to standard platinum-based chemotherapy for extensive-stage SCLC has improved overall survival by only 2-3 months. As a result, the prognosis remains extremely poor, with a median survival of about 12 months.

A new molecular classification of SCLC has emerged based on gene-expression profiling. It identifies four subgroups: SCLC-A, SCLC-N, SCLC-P, and SCLC-I. The first three groups are defined by the high activity of a specific transcription factor (ASCL1, NEUROD1, or POU2F3). The SCLC-I group is characterized by low activity of these transcription factors and high expression of inflammation-related genes, and may respond better to immunotherapy. Pre-clinical studies also suggest that each subgroup has specific sensitivities to different chemotherapies and to certain targeted drugs such as PARP or AURKA inhibitors.

SCLC also shows strong heterogeneity within individual tumors, with cancer cells able to shift from one transcriptional state to another over time. This plasticity suggests that the dominant molecular subtype at diagnosis may change during disease progression or in response to treatment. However, how these subtypes evolve during chemo-immunotherapy has never been studied directly in patients, mainly because new tumor biopsies are rarely performed after the initial diagnosis.

Recent work has shown that circulating cell-free DNA (cfDNA) methylation profiling can distinguish SCLC molecular subtypes from a blood sample. In addition, new epigenomic approaches based on cfDNA fragmentation patterns derived from low-pass whole-genome sequencing (lpWGS) can provide information about gene regulation and transcription factor activity using plasma samples. These techniques make it possible to capture both gene-level signals and broader epigenomic patterns, potentially overcoming the lack of tumor tissue available for analysis.

Hypothesis: We hypothesize that changes in SCLC molecular subtypes during first-line chemoimmunotherapy contribute to treatment resistance and progression, and can be identified by cfDNA epigenomic profiling. These changes may also limit the predictive utility of molecular characterization performed at diagnosis for guiding second-line therapeutic strategies.