Kevin Jao1, Pascale Tomasini2, Suzanne Kamel-Reid3, Gregorz J Korpanty4, Céline Mascaux2, Shingo Sakashita5, Catherine Labbé4, Natasha B Leighl4, Geoffrey Liu4, Ronald Feld4, Penelope A Bradbury4, David M Hwang6, Melania Pintilie7, Ming-Sound Tsao6, Frances A Shepherd4. 1. Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Ontario, Canada. Electronic address: kevin.jao@mail.mcgill.ca. 2. Aix Marseille University, Assistance Publique Hôpitaux de Marseille. Multidisciplinary Oncology and Therapeutic Innovations department, Marseille, 13015, France. 3. Laboratory Genetics, University Health Network, Toronto, Ontario, Canada. 4. Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Ontario, Canada. 5. Department of Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibraraki, Japan. 6. Laboratory Medicine and Pathobiology, University Health Network, Toronto, Ontario, Canada. 7. Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Abstract
INTRODUCTION: Somatic mutations are becoming increasingly important biomarkers for treatment selection and outcome in patients with non-small-cell lung cancer (NSCLC). The role of multiple somatic mutations in early-stage NSCLC is unclear. METHODS: Tissue from 214 patients with resected NSCLC at the Princess Margaret Cancer Centre was analyzed by next-generation sequencing by Mi-SEQ or Sequenom multiplex platforms. Associations between mutation status, baseline patient characteristics and outcomes (disease-free survival (DFS) after surgical resection and overall survival (OS)) were investigated. RESULTS: Somatic mutations were identified in 184 patients with resected stage I-III NSCLC: None (n = 30), single (n = 101) and multiple (≥2, n = 83). Multiple mutations were significantly associated with younger age (p = 0.0006), female sex (p = 0.012), smoking status (p = 0.002) and adenocarcinoma histology (p = 0.0001).TP53, KRAS and EGFR were the most common mutations. TP53 mutation was the most frequent co-mutation occurring in 72% of patients with multiple mutations. In resected stage I-III patients, multiple mutations were significantly associated with worse DFS (HR = 2.56, p = 0.003) but not OS on univariate analysis. Patients with KRAS and EGFR mutations were also associated with shorter DFS (HR = 2.52, p = 0.016 and HR = 4.37, p = 0.001 respectively) but no OS difference. TP53 mutation was associated with both shorter DFS (HR = 2.21, p = 0.02) and OS (HR = 3.08, p = 0.02). In subgroup univariate analysis, poorer DFS was associated with multiple mutations (p = 0.0015), EGFR (HR = 3.14, p = 0.006), and TP53 (HR = 2.46, p = 0.018) in patients with stage I disease. CONCLUSION: The presence of known somatic mutations is associated with worse DFS in resected NSCLC. The differences are both statistically significant and clinically relevant. The presence of EGFR, KRAS and TP53 mutations was also associated with adverse outcomes. Larger datasets are required to validate whether mutational status is an independent prognostic factor in early stage NSCLC. Crown
INTRODUCTION: Somatic mutations are becoming increasingly important biomarkers for treatment selection and outcome in patients with non-small-cell lung cancer (NSCLC). The role of multiple somatic mutations in early-stage NSCLC is unclear. METHODS: Tissue from 214 patients with resected NSCLC at the Princess Margaret Cancer Centre was analyzed by next-generation sequencing by Mi-SEQ or Sequenom multiplex platforms. Associations between mutation status, baseline patient characteristics and outcomes (disease-free survival (DFS) after surgical resection and overall survival (OS)) were investigated. RESULTS: Somatic mutations were identified in 184 patients with resected stage I-III NSCLC: None (n = 30), single (n = 101) and multiple (≥2, n = 83). Multiple mutations were significantly associated with younger age (p = 0.0006), female sex (p = 0.012), smoking status (p = 0.002) and adenocarcinoma histology (p = 0.0001).TP53, KRAS and EGFR were the most common mutations. TP53 mutation was the most frequent co-mutation occurring in 72% of patients with multiple mutations. In resected stage I-III patients, multiple mutations were significantly associated with worse DFS (HR = 2.56, p = 0.003) but not OS on univariate analysis. Patients with KRAS and EGFR mutations were also associated with shorter DFS (HR = 2.52, p = 0.016 and HR = 4.37, p = 0.001 respectively) but no OS difference. TP53 mutation was associated with both shorter DFS (HR = 2.21, p = 0.02) and OS (HR = 3.08, p = 0.02). In subgroup univariate analysis, poorer DFS was associated with multiple mutations (p = 0.0015), EGFR (HR = 3.14, p = 0.006), and TP53 (HR = 2.46, p = 0.018) in patients with stage I disease. CONCLUSION: The presence of known somatic mutations is associated with worse DFS in resected NSCLC. The differences are both statistically significant and clinically relevant. The presence of EGFR, KRAS and TP53 mutations was also associated with adverse outcomes. Larger datasets are required to validate whether mutational status is an independent prognostic factor in early stage NSCLC. Crown
Authors: Relinde I Y Lieverse; Evert J Van Limbergen; Cary J G Oberije; Esther G C Troost; Sine R Hadrup; Anne-Marie C Dingemans; Lizza E L Hendriks; Franziska Eckert; Crispin Hiley; Christophe Dooms; Yolande Lievens; Monique C de Jong; Johan Bussink; Xavier Geets; Vincenzo Valentini; Giuliano Elia; Dario Neri; Charlotte Billiet; Amir Abdollahi; David Pasquier; Pierre Boisselier; Ala Yaromina; Dirk De Ruysscher; Ludwig J Dubois; Philippe Lambin Journal: BMC Cancer Date: 2020-06-15 Impact factor: 4.430