Sai F Yeung1, Joanna H M Tong1, Peggy P W Law1, Lau Y Chung1, Raymond W M Lung1, Carol Y K Tong1, Chit Chow1, Anthony W H Chan1, Innes Y P Wan2, Tony S K Mok3, Ka F To4. 1. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong; Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong. 2. Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong. 3. Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong; Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong. 4. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong; Li Ka-Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: kfto@cuhk.edu.hk.
Abstract
INTRODUCTION: Oncogenic driver mutations activating receptor tyrosine kinase pathways are promising predictive markers for targeted treatment. We investigated the mutation profile of an updated driver events list on receptor tyrosine kinase/RAS/PI3K axis and the clinicopathologic implications in a cohort of never-smoker predominated Chinese lung adenocarcinoma. METHODS: We tested 154 lung adenocarcinomas and adenosquamous carcinomas for EGFR, KRAS, HER2, BRAF, PIK3CA, MET, NRAS, MAP2K1, and RIT1 mutations by polymerase chain reaction-direct sequencing. MET amplification and ALK and ROS1 translocations were assessed by fluorescent in situ hybridizations. MET and thyroid transcription factor-1 protein expressions were investigated by immunohistochemistry. RESULTS: Seventy percent of lung adenocarcinomas carried actionable driver events. Alterations on EGFR (43%), KRAS (11.4%), ALK (6%), and MET (5.4%) were frequently found. ROS1 translocation and mutations involving BRAF, HER2, NRAS, and PIK3CA were also detected. No mutation was observed in RIT1 and MAP2K1. Patients with EGFR mutations had a favorable prognosis, whereas those with MET mutations had poorer overall survival. Multivariate analysis further demonstrated that MET mutation was an independent prognostic factor. Although MET protein expression was detected in 65% of lung adenocarcinoma, only 10% of the MET-immunohistochemistry positive tumors harbor MET DNA alterations that drove protein overexpression. Appropriate predictive biomarker is essential for selecting patients who might benefit from specific targeted therapy. CONCLUSION: Actionable driver events can be detected in two thirds of lung adenocarcinoma. MET DNA alterations define a subset of patients with aggressive diseases that might potentially benefit from anti-MET targeted therapy. High negative predictive values of thyroid transcription factor-1 and MET expression suggest potential roles as surrogate markers for EGFR and/or MET mutations.
INTRODUCTION: Oncogenic driver mutations activating receptor tyrosine kinase pathways are promising predictive markers for targeted treatment. We investigated the mutation profile of an updated driver events list on receptor tyrosine kinase/RAS/PI3K axis and the clinicopathologic implications in a cohort of never-smoker predominated Chinese lung adenocarcinoma. METHODS: We tested 154 lung adenocarcinomas and adenosquamous carcinomas for EGFR, KRAS, HER2, BRAF, PIK3CA, MET, NRAS, MAP2K1, and RIT1 mutations by polymerase chain reaction-direct sequencing. MET amplification and ALK and ROS1 translocations were assessed by fluorescent in situ hybridizations. MET and thyroid transcription factor-1 protein expressions were investigated by immunohistochemistry. RESULTS: Seventy percent of lung adenocarcinomas carried actionable driver events. Alterations on EGFR (43%), KRAS (11.4%), ALK (6%), and MET (5.4%) were frequently found. ROS1 translocation and mutations involving BRAF, HER2, NRAS, and PIK3CA were also detected. No mutation was observed in RIT1 and MAP2K1. Patients with EGFR mutations had a favorable prognosis, whereas those with MET mutations had poorer overall survival. Multivariate analysis further demonstrated that MET mutation was an independent prognostic factor. Although MET protein expression was detected in 65% of lung adenocarcinoma, only 10% of the MET-immunohistochemistry positive tumors harbor MET DNA alterations that drove protein overexpression. Appropriate predictive biomarker is essential for selecting patients who might benefit from specific targeted therapy. CONCLUSION: Actionable driver events can be detected in two thirds of lung adenocarcinoma. MET DNA alterations define a subset of patients with aggressive diseases that might potentially benefit from anti-MET targeted therapy. High negative predictive values of thyroid transcription factor-1 and MET expression suggest potential roles as surrogate markers for EGFR and/or MET mutations.
Authors: Tobias Raphael Overbeck; Dana Alina Cron; Katja Schmitz; Achim Rittmeyer; Wolfgang Körber; Sara Hugo; Juliane Schnalke; Laura Lukat; Tabea Hugo; Marc Hinterthaner; Kirsten Reuter-Jessen; Tessa Rosenthal; Joachim Moecks; Annalen Bleckmann; Hans-Ulrich Schildhaus Journal: Transl Lung Cancer Res Date: 2020-06
Authors: Richard E Kast; Nicolas Skuli; Samuel Cos; Georg Karpel-Massler; Yusuke Shiozawa; Ran Goshen; Marc-Eric Halatsch Journal: Breast Cancer (Dove Med Press) Date: 2017-07-11