Catherine Labbé1, Michael Cabanero2, Grzegorz J Korpanty3, Pascale Tomasini4, Mark K Doherty5, Céline Mascaux6, Kevin Jao7, Bethany Pitcher8, Rick Wang9, Melania Pintilie10, Natasha B Leighl11, Ronald Feld12, Geoffrey Liu13, Penelope Ann Bradbury14, Suzanne Kamel-Reid15, Ming-Sound Tsao16, Frances A Shepherd17. 1. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada; Division of Respirology and Thoracic Surgery, Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC, G1V 4G5, Canada. Electronic address: catherine.labbe@criucpq.ulaval.ca. 2. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. 3. Canadian Cancer Trials Group, Queen's University, 10 Stuard Street, Kingston, ON, K7L 3N6, Canada. Electronic address: greg.korpanty@gmail.com. 4. Aix-Marseille University, Public Assistance, Marseille Hospitals, 80 Rue Brochier, 13005 Marseille, France. Electronic address: pascaletomasini@yahoo.fr. 5. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. Electronic address: mark.doherty@sunnybrook.ca. 6. Aix-Marseille University, Public Assistance, Marseille Hospitals, 80 Rue Brochier, 13005 Marseille, France. Electronic address: celinejmmascaux@gmail.com. 7. Division of Medical Oncology and Hematology, Hôpital du Sacré-Coeur de Montréal, 5400 Boulevard Gouin Ouest, Montreal, QC, H4J 1C5, Canada. Electronic address: kevin.jao@mail.mcgill.ca. 8. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. Electronic address: bethany.r.gill@gmail.com. 9. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. Electronic address: rick.wang@uhnresearch.ca. 10. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. Electronic address: pintilie@uhnresearch.ca. 11. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. Electronic address: natasha.leighl@uhn.ca. 12. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. Electronic address: ronald.feld@uhn.ca. 13. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. Electronic address: geoffrey.liu@uhn.ca. 14. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. Electronic address: penelope.bradbury@uhn.ca. 15. Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada. Electronic address: suzanne.kamel-reid@uhn.ca. 16. Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada. Electronic address: ming.tsao@uhn.ca. 17. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. Electronic address: frances.shepherd@uhn.ca.
Abstract
INTRODUCTION: TP53 mutations are common in non-small cell lung cancer (NSCLC) and have been reported as prognostic of poor outcome. The impact of TP53 co-mutations in epidermal growth factor receptor (EGFR)-mutated NSCLC is unclear. MATERIALS AND METHODS: Tissue from 105 patients with EGFR-mutated NSCLC at Princess Margaret Cancer Centre was analyzed by next-generation or Sanger sequencing to determine TP53 mutational status. Associations between TP53 status and baseline patient and tumor characteristics, treatments and outcomes (relapse-free survival [RFS] after surgical resection, overall survival [OS], overall response rate [ORR] and progression-free survival [PFS] on EGFR tyrosine kinase inhibitors [TKIs]), were investigated. RESULTS: Dual TP53/EGFR mutations were found in 43/105 patients (41%). Among 76 patients who underwent surgical resection, neither RFS (HR 0.99, CI 0.56-1.75, p=0.96) nor OS (HR 1.39, CI 0.70-2.77; p=0.35) was associated with TP53 status. Sixty patients (24 TP53 MUT; 36 TP53 WT) received first-generation EGFR TKIs for advanced disease. ORR was not significantly different (TP53 MUT 54%, WT 66%, p=0.42). There was a non-significant trend towards shorter PFS on EGFR TKIs with TP53 mutation (HR 1.74, CI 0.98-3.10, p=0.06). When limited to TP53 missense mutations (n=17), PFS was significantly shorter (HR 1.91, CI 1.01-3.60, p=0.04). Among 11 evaluable patients treated with T790M inhibitors, ORR was not significantly different (TP53 MUT 3/3 [100%], WT 7/8 [88%]). CONCLUSIONS: Patients with dual TP53/EGFR mutations, especially missense mutations, had marginally lower response rates and shorter PFS when treated with EGFR TKI therapy. Larger datasets are required to validate these observations.
INTRODUCTION:TP53 mutations are common in non-small cell lung cancer (NSCLC) and have been reported as prognostic of poor outcome. The impact of TP53 co-mutations in epidermal growth factor receptor (EGFR)-mutated NSCLC is unclear. MATERIALS AND METHODS: Tissue from 105 patients with EGFR-mutated NSCLC at Princess Margaret Cancer Centre was analyzed by next-generation or Sanger sequencing to determine TP53 mutational status. Associations between TP53 status and baseline patient and tumor characteristics, treatments and outcomes (relapse-free survival [RFS] after surgical resection, overall survival [OS], overall response rate [ORR] and progression-free survival [PFS] on EGFR tyrosine kinase inhibitors [TKIs]), were investigated. RESULTS: Dual TP53/EGFR mutations were found in 43/105 patients (41%). Among 76 patients who underwent surgical resection, neither RFS (HR 0.99, CI 0.56-1.75, p=0.96) nor OS (HR 1.39, CI 0.70-2.77; p=0.35) was associated with TP53 status. Sixty patients (24 TP53 MUT; 36 TP53 WT) received first-generation EGFR TKIs for advanced disease. ORR was not significantly different (TP53 MUT 54%, WT 66%, p=0.42). There was a non-significant trend towards shorter PFS on EGFR TKIs with TP53 mutation (HR 1.74, CI 0.98-3.10, p=0.06). When limited to TP53 missense mutations (n=17), PFS was significantly shorter (HR 1.91, CI 1.01-3.60, p=0.04). Among 11 evaluable patients treated with T790M inhibitors, ORR was not significantly different (TP53 MUT 3/3 [100%], WT 7/8 [88%]). CONCLUSIONS:Patients with dual TP53/EGFR mutations, especially missense mutations, had marginally lower response rates and shorter PFS when treated with EGFR TKI therapy. Larger datasets are required to validate these observations.
Authors: Charu Aggarwal; Christiana W Davis; Rosemarie Mick; Jeffrey C Thompson; Saman Ahmed; Seth Jeffries; Stephen Bagley; Peter Gabriel; Tracey L Evans; Joshua M Bauml; Christine Ciunci; Evan Alley; Jennifer J D Morrissette; Roger B Cohen; Erica L Carpenter; Corey J Langer Journal: JCO Precis Oncol Date: 2018-08-31
Authors: B Melosky; N Blais; P Cheema; C Couture; R Juergens; S Kamel-Reid; M-S Tsao; P Wheatley-Price; Z Xu; D N Ionescu Journal: Curr Oncol Date: 2018-02-28 Impact factor: 3.677