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Introduction: Small cell lung cancer (SCLC) transformation represents a mechanism of resistance to osimertinib in EGFR-mutated lung adenocarcinoma, which dramatically impacts patients' prognosis due to high refractoriness to conventional treatments.Case Description: We present the case of a patient who developed a SCLC phenotypic transformation as resistance mechanism to second-line osimertinib for T790M-positive EGFR-mutated NSCLC. Our patient received platinum–etoposide doublet following SCLC switch and achieved a modest clinical benefit which lasted 4 months. NGS and IHC analyses for p53 and Rb were performed on subsequent liver biopsies, revealing baseline TP53 mutation and complete absence of p53 and Rb expression. Primary cell cultures were established following a liver biopsy at the time of SCLC transformation, and drug sensitivity assays showed meaningful cell growth inhibition when osimertinib was added to platinum–etoposide compared with control (p < 0.05). A review of the current literature regarding SCLC transformation after failure of osimertinib was performed.Conclusions: Based on retrospective data available to date, platinum–etoposide chemotherapy is the preferred treatment choice in the occurrence of SCLC transformation after osimertinib failure. The extension of osimertinib in combination with chemotherapy in the occurrence of SCLC transformation as resistance mechanism to osimertinib is a matter of debate. The combination of osimertinib and platinum–etoposide was effective in inhibiting cell growth in our primary cell cultures. Clinical studies are needed to further explore this combination in the occurrence of SCLC transformation as a resistance mechanism to osimertinib.

Background: Operable stage I-III non-small cell lung cancer (NSCLC) has a high risk of recurrence, mainly due to remnant clones of the disease defined as minimal residual disease (MRD). Adjuvant chemotherapy has a limited efficacy in reducing the risk of relapse, and prognostic as well as predictive biomarkers in this context are currently missing.Methods: We performed a systematic review to evaluate the state of the art about the role of circulating tumor DNA detection through liquid biopsy for the assessment of MRD in resected early-stage NSCLC patients.Results: Among the 650 studies identified, 13 were eligible and included. Although highly heterogeneous, all the studies demonstrated a poor prognosis in patients with post-operative MRD, with a detection rate ranging from 6% to 45%. MRD detection preceded radiographic/clinical recurrence by a mean of 5.5 months. MRD positive patients were most likely to benefit from adjuvant treatment in terms of recurrence-free survival (RFS). Consistently, adjuvant therapy did not minimize the risk of relapse in the MRD negative group.Conclusions: Liquid biopsy has a relevant role in assessing post-surgical MRD in resected NSCLC. Since currently there are no criteria other than stage and risk factors for the choice of adjuvant treatment in this setting, post-operative assessment of MRD through liquid biopsy might be a promising approach to guide the decision.

Background: Resistance to EGFR-TKIs constitutes a major challenge for the management of EGFR-mutated NSCLC, and recent evidence suggests that deregulation of specific microRNAs (miRNAs) may influence resistance to targeted agents. In this retrospective study, we explored the role of specific plasmatic miRNAs (miR-21, miR-27a and miR-181a) as a surrogate for predicting EGFR-TKI performance in EGFR-mutated NSCLC patients. Methods: Plasma samples of 39 advanced EGFR-mutated NSCLC patients treated with EGFR-TKIs were collected at different points in time and miRNA levels were assessed by RT-PCR. Results: Higher basal values of miR-21 were reported in patients who achieved a partial/complete response (PR/CR) compared to those with stability/progression of disease (SD/PD) (p = 0.011). Along the same line, patients who experienced a clinical benefit lasting at least six months displayed higher basal levels of circulating miR-21 (p = 0.039). However, dynamic evaluation of miRNA values after two months from the start of EGFR-TKI treatment showed that patients who experienced SD had an increase in miR-21 levels (Fold Change [FC] = 2.6) compared to patients achieving PR/CR (p = 0.029). The same tendency was observed for miR-27a (FC = 3.1) and miR-181a (FC = 2.0), although without reaching statistical significance. Remarkably, preclinical studies showed an increase in miR-21 levels in NSCLC cells that became resistant after exposure to EGFR-TKIs. Conclusions: Our study provides interesting insights on the role of circulating miRNAs, in particular miR-21, and their dynamic change over time in predicting EGFR-TKI response in EGFR-mutated NSCLC.