ABSTRACT
INTRODUCTION: Current research in EGFR-mutated NSCLC focuses on the management of drug resistance and uncommon mutations, as well as on the opportunity to extend targeted therapies' field of action to earlier stages of disease. AREAS COVERED: We conducted a review analyzing literature from the PubMed database with the aim to describe the current state of art in the management of EGFR-mutated NSCLC, but also to explore new strategies under investigation. To this purpose, we collected recruiting phase II-III trials registered on Clinicaltrials.govand conducted on EGFR-mutated NSCLC both in early and advanced stage. EXPERT OPINION: With this review, we want to provide an exhaustive overview of current and new potential treatments in EGFR-mutated NSCLC, with emphasis on the most promising newly investigated strategies, such as association therapies in the first-line setting involving EGFR-TKIs and chemotherapy (FLAURA2) or drugs targeting different driver pathways (MARIPOSA). We also aimed at unearthing challenges to achieve in this field, specifically the need to fully exploit already available compounds while developing new ones, the management of new emerging toxicities and the necessity to improve our biological understanding of the disease to design trials with a solid scientific rationale and to allow treatment personalization such in case of uncommon mutations.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Drug Resistance, Neoplasm , ErbB Receptors , Lung Neoplasms , Molecular Targeted Therapy , Protein Kinase Inhibitors , Animals , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/genetics , Drug Development , ErbB Receptors/genetics , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/genetics , Mutation , Neoplasm Staging , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/administration & dosageABSTRACT
BACKGROUND: Universal screening of colorectal cancer (CRC) patients for Lynch syndrome (LS) through MisMatch Repair (MMR) testing is recommended. BRAF V600E mutation and/or MLH1 promoter methylation (Reflex Testing, RefT)generally rule out LS in MLH1-deficient (dMLH1) patients. We estimated the impact of RefTon genetic counseling (GC) and on the diagnostic yield of genetic testing (GT). METHODS: Overall, 3199 CRC patients were referred to our center between 2011 and 2021. Patients referred until January 2019 (n=2536) underwent universal MMR testing and were termed 'Cohort A'; among patients after February 2019 (n=663), 'Cohort B', RefT was also performed in dMLH1 patients. RESULTS: Overall, 401/3199 patients (12.5%) were MMR-deficient (dMMR); 312 (77.8%) in cohort A and 89 (22.2%) inB; 346/401 were dMLH1 (86.3%), 262/312 (83.9%) in cohort A and 84/89 (94.3%) in B. In Cohort A, 91/312 (29.1%) dMMR patients were referred to GC, 69/91 (75.8%) were in the dMLH1 group; 57/69 (82.6%) dMLH1 patients underwent GT and 1/57 (1.7%) had LS. In Cohort B, 3/84 dMLH1 patients did not undergo BRAF testing. Three BRAF wt and not hypermethylated of the remaining 81 dMLH1 patients were referred to GC and GT, and one had LS. This diagnostic pathway reduced GC referrals by 96% (78/81) in Cohort B and increased the diagnostic yield of GT by about 20 times. CONCLUSION: Our findings support RefT in dMLH1 CRC patients within the LS diagnostic pathway, as it reduces the number of GC sessions needed and increases the diagnostic yield of GT.