Alessandro Leonetti1,2,3, Mjriam Capula3,4,5, Roberta Minari2, Giulia Mazzaschi2, Alessandro Gregori3, Btissame El Hassouni3, Filippo Papini3,4, Paola Bordi2, Michela Verzè2, Amir Avan3,6, Marcello Tiseo1,2, Elisa Giovannetti3,4. 1. Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy. 2. Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy. 3. Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands. 4. Fondazione Pisana per la Scienza, San Giuliano, 56017 Pisa, Italy. 5. Institute of Life Sciences, Sant'Anna School of Advanced Studies, 56100 Pisa, Italy. 6. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, 13131-99137 Mashhad, Iran.
Abstract
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.
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 NSCLCpatients. METHODS: Plasma samples of 39 advanced EGFR-mutated NSCLCpatients 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.
Entities:
Keywords:
EGFR-mutated NSCLC; miRNA; response to EGFR-TKI; targeted therapy