The transformation of EGFR-mutated lung adenocarcinoma to small cell lung cancer (SCLC) is one of the significant mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). This phenomenon is observed in about 5–15% of patients treated with different generations of EGFR inhibitors and associated with a poor prognosis. This paper presents two cases of patients harboring advanced EGFR-positive lung adenocarcinoma who underwent histological transformation to small cell carcinoma during initially effective osimertinib therapy. In both cases, the disease progressed rapidly, and we observed a short-lived response to platinum-based and etoposide-based chemotherapy. The time from the start of TKI therapy to transformation was 9 and 18 months, respectively, and the overall survival from the diagnosis of transformation was 2 and 7 months. A review of the literature indicates that the loss of function of the TP53 and RB1 tumor suppressor genes, as well as disturbances in the PI3K/AKT/mTOR pathways and the activation of neuroendocrine factors, play a key role in the transformation process. Histological transformation leads to a loss of sensitivity to TKIs and limits the effectiveness of immunotherapy. For this reason, rebiopsy at the time of clinical progression is essential to determine the mechanism of resistance and select the appropriate second-line treatment. The presented cases confirm the aggressive course of the disease after transformation and emphasize the need for further research into new therapeutic strategies in this particular group of patients.
Siembida et al. (Sun,) studied this question.