Intrapatient Molecular and Histologic Heterogeneity After First-generation or Second-generation TKI Therapy of NSCLC Patients

Abstract

Objectives: The discovery of tyrosine kinase inhibitors (TKI) has remarkably improved the clinical course of patients with non–small cell lung cancer driven by Epidermal Growth Factor Receptor (EGFR) mutations. However, virtually in all cases, the disease resurfaces in a TKI-resistant form that is mainly linked to an acquired EGFR-T790M mutation, a MET amplification, or small cell lung cancer (SCLC) transformation. Third-generation TKIs are able to block tumor growth through an irreversible binding to the T790M-mutated receptor. Such new treatments require the diagnostic analysis of new pathologic tissue or a liquid biopsy to detect the presence of the T790M mutation. Materials and Methods: Pre-TKI and post-TKI biopsies from 27 patients with an activating EGFR mutation were collected and analyzed for EGFR-T790M mutation, MET amplification, and SCLC transformation. Results: The T790M mutation was found in 16 patients (59%) whereas MET gene amplification was found in 2 (10.5%) of 19 evaluated cases. The histologic transformation from adenocarcinoma (ADC) to SCLC was identified in 3 patients (11%). In one of them reversal from SCLC back to adenocarcinoma was observed. One patient had the T790M mutation concordantly detected in 2 synchronous lesions whereas another patient showed T790M positivity only in one of 2 specimens. In 4 patients longitudinal biopsies revealed T790M gains and losses not always according to biological expectations. Conclusions: Intrapatient molecular or histologic heterogeneity may be frequently found during routine treatment of non–small cell lung cancer patients. This biological aspect may have profound repercussions on subsequent therapeutic decisions, and therefore requires in-depth investigation.

The Role of the Liquid Biopsy in Decision-Making for Patients with Non-Small Cell Lung Cancer

“…Unlike tissue-based tumor molecular analysis, liquid biopsy allows minimally invasive genomic profiling and, if performed serially, may provide a more comprehensive information regarding global tumor evolution occurring at different metastatic sites throughout the course of disease. Additionally, liquid biopsy can be a useful tool for detection of emerging resistant tumor subclones [64,78,79].…”

Small cell lung cancer transformation during antitumor therapies: A systematic review

“…A 76-year-old female patient with EGFR L858R-mutant adenocarcinoma was diagnosed with SCLC transformation with consistent L858R mutation and received chemotherapy (cisplatin and etoposide) as the subsequent treatment for 5 months, after which she underwent both chemotherapy and immunotherapy (amrubicin, nivolumab, and irinotecan); however, further progression was observed after 6 months, and a second re-biopsy revealed both L858R and T790M mutations, which led to the administration of osimertinib, and a partial response was achieved and lasted for 3 months [ 45 ]. In addition, some of the SCLC-transformed patients experienced further gene mutations and histologic changes, and it was reported that NSCLC could be dominant again during treatment [ 46 , 47 , 48 , 49 ]. Therefore, treatment strategies should be selected according to the individual characteristics of patients.…”