WCLC 2025 - Posters & ePosters-P3.12.30 Histological Transformation as Resistance Mechanism in NSCLC: A Multicenter Study Exploring Clinico-Pathological and Molecular Features

P3.12.30 Histological Transformation as Resistance Mechanism in NSCLC: A Multicenter Study Exploring Clinico-Pathological and Molecular Features

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This international, multicenter retrospective study across 15 European hospitals represents the largest cohort investigating histological transformation (HT) as a resistance mechanism in non-small cell lung cancer (NSCLC), beyond the well-known EGFR-mutated and small cell lung cancer (SCLC) transformations. HT—where tumor histology changes during therapy—is recognized as a mechanism by which NSCLC evades treatment, but its clinico-pathological and molecular drivers remain poorly understood.<br /><br />The study analyzed clinical, pathological, treatment response, and molecular data from 75 patients undergoing HT. The cohort was predominantly female (69.3%) and never-smokers (54.7%), with 82.7% having stage IV disease at diagnosis and a high incidence of brain metastases (34.7%). Before HT, most patients (73.3%) received targeted therapies, primarily for tumors harboring driver mutations; notably, 70.7% had EGFR mutations, 9.3% ALK rearrangements, and smaller subsets had RET/ROS1, BRAF, or KRAS mutations. Histological subtypes post-HT included SCLC (62.7%), squamous (16%), and neuroendocrine variants.<br /><br />Molecular profiling before and after HT showed that tumors retained their original driver mutations despite transformation. The median time to HT was approximately 31 months. Median overall survival was 35.5 months from diagnosis and only 10.7 months following HT, underscoring the aggressive nature of transformed disease. Treatment responses post-transformation were heterogeneous, with a subset achieving partial or complete responses.<br /><br />This study highlights HT as an underexplored and possibly more common resistance phenomenon with heterogeneous histologic changes. Given the retention of driver mutations, further molecular analyses are imperative to identify biomarkers predicting HT onset and to optimize therapeutic strategies. Understanding HT’s mechanisms may improve management and outcomes for NSCLC patients experiencing resistance through histologic shifts.

Asset Subtitle

Laura Masfarré

Meta Tag

Speaker Laura Masfarré

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

histological transformation

non-small cell lung cancer

NSCLC resistance

EGFR mutations

small cell lung cancer

SCLC transformation

molecular profiling

driver mutations

brain metastases

targeted therapies