Histologic Transformation from Adenocarcinoma to Squamous Cell Carcinoma as a Mechanism of Resistance to EGFR Inhibition

Transformation of lung adenocarcinoma to small cell lung carcinoma in the setting of tyrosine kinase inhibitor therapy: Cytological approach of a clinically challenging phenomenon

“…23 In addition, MET and HER2 amplification and over-expression (which create resistance by bypassing the EGFR signaling pathway) were seen in 15% to 20% of cases of resistance in one series, 9,12 another series reported resistance due to MET amplification in 3% of the cases, and due to HER2 amplification in 13% of the cases. [26][27][28][29][30][31][32][33] These cases were observed to retain their original EGFR mutation, three cases developed an addition mutation in Thr790Met of EGFR Exon 20, 30,31 whereas two cases harbored an addition PIK3CA mutation. Immunocytochemistry stains for Synaptophysin (d) and CD56 (e) were positive, supporting the diagnosis of small cell carcinoma [Color figure can be viewed at wileyonlinelibrary.com] carcinoma transformation, 5,12,13,[16][17][18] or squamous cell transformation.…”

“…Molecular testing of the case discussed in this review and of the core biopsy cases reported in literature, performed at the time of TKI resistance acquisition, revealed retention of the same type of EGFR mutation detected in the initial diagnostic biopsies. [26][27][28][29][30][31][32][33] EMT manifests on the ultrastructural level by acquiring mesenchymal markers such as Vimentin and Fibronectin, and downregulating the expression of cellular junction proteins, such as Ecadherin and Gamma Catenin. 12 One year after TKI resistance acquisition, a third FNA was performed to monitor patient's disease progression.…”

Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors by Transformation to Small Cell Lung Cancer in an EGFR-mutant Patient

“…According to the relevant literature, the criteria to expect a probable secondary TKI resistance are single-agent treatment with EGFR-TKI for EGFR mutations and related drug sensitivity, systemic progression under TKI treatment, and other systemic chemotherapies after cessation of TKIs (12). However most often, the responsibility for TKI resistance lies in particular mutations, overexpression of growth factors, amplification of some oncogenes, histopathological transformation to SCLC, and squamous cell cancer and NSCLC with neuroendocrine morphology (13,14,15). SCLC transformation is relatively rare.…”

Overcoming T790M mutant small cell lung cancer with the third‐generation EGFR‐TKI osimertinib

“…EGFR‐TKIs have revolutionized the therapeutic field by inhibiting the EGFR ‐induced downstream signaling pathway in non‐small cell lung cancer (NSCLC). However, most patients ultimately experience drug resistance and progression within two years, and several acquired resistance mechanisms have been identified, including EGFR T790M mutation, MET or HER2 amplification, phosphoinositide 3‐kinase pathway activation, and rare transformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) . If an NSCLC patient has acquired a T790M mutation, the third‐generation EGFR‐tyrosine kinase inhibitor (TKI) osimertinib is recommended …”