Combination of tissue and liquid biopsy molecular profiling to detect transformation to small cell lung carcinoma during osimertinib treatment.

BACKGROUND

Histological transformation of advanced non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is one of the mechanisms of resistance to third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib. This acquired TKI resistance is linked to the high degree of tumor heterogeneity and adaptive cellular signaling pathways, including epidermal growth factor receptor ()-dependent pathways, observed in NSCLC.

METHODS

Here, we investigated a series of paired pre- and post-histological transformation biopsies obtained from three patients initially having a NSCLC with an mutation treated with first-generation TKI, who then received osimertinib as second-line after resistance and, lastly, developed a histological transformation to SCLC. Both tissue and liquid biopsies were analyzed using large panel sequencing approaches at various time points to reconstruct the clonal evolutionary history of the tumor.

RESULTS

Our complementary analysis of tumor tissue and circulating tumor DNA samples allowed us to better characterize the histological and molecular alterations associated with resistance to osimertinib. SCLC transformation was linked to the presence of several concomitant gene alterations, including and , but also to specific signal bypass, such as and amplifications and activation of the PI3K/AKT/mTOR pathway.

CONCLUSION

Our report emphasizes the mutational landscape of SCLC histological transformation and highlights the importance of combining tissue and liquid biopsy profiling before and during osimertinib treatment to predict such histological transformation.