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World J Clin Oncol. Apr 24, 2022; 13(4): 276-286
Published online Apr 24, 2022. doi: 10.5306/wjco.v13.i4.276
New horizons for uncommon mutations in non-small cell lung cancer: BRAF, KRAS, RET, MET, NTRK, HER2
Maria Eugenia Olmedo, Raquel Cervera, Luis Cabezon-Gutierrez, Yolanda Lage, Elena Corral de la Fuente, Ana Gómez Rueda, Xabier Mielgo-Rubio, Juan Carlos Trujillo, Felipe Couñago
Maria Eugenia Olmedo, Yolanda Lage, Ana Gómez Rueda, Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid 28034, Spain
Raquel Cervera, Department of Medical Oncology, Del Henares University Hospital, Coslada 28822, Madrid, Spain
Luis Cabezon-Gutierrez, Medical Oncology, Hospital Universitario de Torrejón, Torrejón de Ardoz 28850, Madrid, Spain
Elena Corral de la Fuente, Medical Oncology Department, Hospital Universitario Ramon y Cajal, Madrid 28034, Spain
Xabier Mielgo-Rubio, Department of Medical Oncology, Foundation Alcorcón University Hospital, Alcorcón 28922, Madrid, Spain
Juan Carlos Trujillo, Department Thoracic Surgery, Hospital de la Santa Creu I Sant Pau, Barcelona 08029, Catalonia, Spain
Juan Carlos Trujillo, Department of Surgery, Universitat Autonoma de Barcelona, Barcelona 08029, Catalonia, Spain
Felipe Couñago, Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Pozuelo 28223, Madrid, Spain
Felipe Couñago, Department of Radiation Oncology, Hospital La Luz, Madrid 28003, Spain
Felipe Couñago, Medicine Department, School of Biomedical Sciences, Universidad Europea de Madrid, Madrid 28670, Spain
Author contributions: Olmedo ME, Cervera R, Cabezón L, Lage Y, Corral de la Fuente E, Gómez Rueda A performed research and wrote the paper; Couñago F, Trujillo JC, Mielgo-Rubio X contributed a critical review of the manuscript for important intellectual content; Mielgo-Rubio X contributed to management of the manuscript and submission.
Conflict-of-interest statement: Xabier Mielgo-Rubio declares the following conflicts of interest: Advisory role; Boehringer-Ingelheim, AstraZeneca, Bristol Myers Squibb. Speakers’ bureau; Roche, AstraZeneca, Bristol Myers Squibb, MSD, Abbott. Research funding; Bristol Myers Squibb. Luis Cabezón-Gutiérrez received speaker or consulting fees from Angelini, Grunenthal, Kyowa Kirin, Mundipharma, Pfizer, Roche, Rovi, Leo Pharma, Merck Serono, Ipsen Pharma, Lilly, Amgen, Boehringer Ingelheim, and AstraZeneca; The remaining authors declare no conflicts of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Maria Eugenia Olmedo, MD, PhD, Consultant Physician-Scientist, Department of Medical Oncology, Ramón y Cajal University Hospital, M-607, km. 9, 100, Madrid 28034, Spain. maruolmedogarcia@hotmail.com
Received: April 19, 2021
Peer-review started: April 19, 2021
First decision: July 6, 2021
Revised: September 5, 2021
Accepted: April 3, 2022
Article in press: April 3, 2022
Published online: April 24, 2022
Processing time: 367 Days and 17.9 Hours
Abstract

The 2004 discovery of EGFR mutations, followed by ALK rearrangements, ushered in a targeted therapy era for advanced non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors targeting gene alterations have substantially improved survival and quality of life for patients with NSCLC. In the last decade, rearrangements of the ROS1 oncogene have been incorporated into healthcare practice that are applicable to another small subgroup of patients who benefit from similar targeted strategies. Recent genome studies of lung adenocarcinoma have identified other possible therapeutic targets, including RET, NTRK fusions, c-MET alterations, and activating mutations in KRAS, BRAF, and HER2, all with frequencies greater than 1%. Lung cancers harbouring these genome changes can potentially be treated with agents approved for other indications or under clinical development. This review updates the therapeutic arsenal that especially targets those genes.

Keywords: BRAF; NTRK; KRAS; MET; RET; HER2; Non-small cell lung cancer; Targeted therapy; Uncommon mutations

Core Tip: Compared to other types of cancer, non-small cell lung cancer (NSCLC) is highly genetically altered. Outside of EGFR, ALK, and ROS1, reflecting 15%-20% of clinical practice, other molecular alterations with important recent advances in their therapeutic arsenal and already in phase II/III trials are BRAF, KRAS, RET, MET, NTRK, and HER2. The goal is to achieve, compared to conventional treatments such as chemotherapy, better symptom control, better response rates, and improved progression-free survival and overall survival in patients with NSCLC.