TP53 co-mutations in EGFR mutated patients in NSCLC stage IV: A strong predictive factor of ORR, PFS and OS in EGFR mt+ NSCLC

// Julia Roeper 1 , 3 , 6 , Markus Falk 2 , 6 , Athena Chalaris-Rismann 2 , 6 , Anne C. Lueers 1 , 3 , Hayat Ramdani 1 , 3 , 6 , Katrin Wedeken 4 , Ursula Stropiep 3 , 6 , Linda Diehl 7 , Markus Tiemann 2 , 6 , Lukas C. Heukamp 2 , 6 , Fabian Otto-Sobotka 5 and Frank Griesinger 1 , 3 , 6 1 Department of Internal Medicine-Oncology, Carl v. Ossietzky University of Oldenburg, Oldenburg, Germany 2 Institute of Hematopathology Hamburg, Hamburg, Germany 3 Department of Hematology and Oncology, Pius-Hospital, Oldenburg, Germany 4 Department of Tumor Documentation, Cancer Center Oldenburg, Pius Hospital Oldenburg, Oldenburg, Germany 5 Division of Epidemiology and Biometry, Carl v. Ossietzky University of Oldenburg, Oldenburg, Germany 6 Lung Cancer Network NOWEL.org, Oldenburg, Germany 7 Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Correspondence to: Julia Roeper, email: Julia.roeper@uol.de Keywords: NSCLC; EGFR; TP53 mutation; TKI Received: August 19, 2019     Accepted: December 16, 2019     Published: January 21, 2020 ABSTRACT Introduction: The impact of TP53 co-mutations in EGFR mutated patients on PFS and OS is controversial. Different classifications of TP53 mutations with respect to functional and potential clinical impact have been published. Therefore, we retrospectively analyzed the impact of TP53 co-mutations on ORR, PFS and OS in a cohort of EGFR mutated NSCLC IV patients (UICC 7) using different classifications of TP53 mutations. Methods: 75 EGFR mutated NSCLC IV patients homogeneously treated with 1st line EGFR TKI were analyzed for TP53 co-mutations. TP53 mutations were classified according to three different types of classifications. The endpoints ORR, PFS and OS were investigated. Results: TP53 co-mutations were found in 29/59 patients (49.2%). TP53 co-mutations were a statistically significant independent negative predictive factor for ORR, PFS and OS. TP53 co-mutations were associated with inferior mPFS and mOS: mPFS/mOS 12 vs. 18/24 vs. 42 months for non-disruptive/disruptive mutations vs. WT ( p < 0.004)/( p < 0.009), 11 vs. 17/23 vs. 42 months for pathogenic vs. non-pathogenic/WT ( p < 0.001)/( p < 0.001), and 7 vs. 12 vs. 18/12 vs. 28 vs. 42 months for exon 8 vs. non-exon 8 vs. WT ( p < 0.001)/( p < 0.002). Conclusions: TP53 co-mutations are frequent in EGFR mt+ NSCLC and have a strong negative impact on all clinical endpoints of TKI therapy.