Tp53 Mutations In Egfr Mt Plus Nsclc Iv As A Predictive Factor For Orr, Pfs, And Os Irrespective Of T790m.
JOURNAL OF CLINICAL ONCOLOGY(2019)
摘要
e20679 Background: The impact of TP53 mutations in EGFR mt+ pts on PFS and OS is controversial, and different classifications of TP53 mt+ with respect to functional and potential predictive impact have been published. Therefore, we retrospectively analyzed the impact of TP53 aberrations on ORR, PFS and OS in a cohort of EGFR mt+ NSCLC IV pts (UICC 7) using different classifications of TP53 mutations. Methods: 75 EGFR mt+ NSCLC IV pts were analyzed for TP53 co-mutations. TP53 mt+ were classified according to Poeta et al. into (1) disruptive vs. non-disruptive, according to structural prediction and biophysical characteristics into (2) pathogenic vs. non-pathogenic and finally into (3) exon 8 vs. non-exon 8 mutations according to Crino et al.. The endpoints ORR according to Recist 1.1, PFS and OS were calculated by Kaplan Meier. Results: 69 of the 75 EGFR mt+ pts (92%) had a common mutation in EGFR E19/21. In 59/75 pts (79%) material was sufficient for successful TP53 analysis. TP53 mt+ were found in 29/59 pts (49%), 16/59 (27%) had a TP53 disruptive mt+, 13/59 (22%) a TP53 non-disruptive mt+ and 30/59 a TP53 WT configuration. Using the structural/biophysical classification, 7/59 (12%) had a TP53 non-pathogenic and 22/59 (37%) a TP53 pathogenic mt+. Of the 29 mutated pts, 6 had a TP53 Exon 8 mt+. Median PFS on 1 st line TKI was 12 vs. 18 months for non-disruptive/disruptive mt+ vs. WT (p < 0.004), 11 vs. 17 months for pathogenic vs. non-pathogenic/WT (p < 0.0001), and 7 vs. 12 vs. 18 months for exon 8 vs. non-exon 8 vs. WT (p < 0.006). Median OS was 24 vs. 42 months in non-disruptive/disruptive mt+ vs. WT (p < 0.0009), 23 vs. 42 months in pathogenic vs. non-pathogenic/WT (p < 0.001) and 12 vs. 28 months for TP53 exon 8 vs. non-exon 8 mt+ (p < 0.024). Additionally ORR was significantly impacted by TP53 mt+. In rebiopsy samples on acquired resistance, no new TP53 mutations were observed and there were no correlations of TP53 mutations with clinical factors and the EGFR mt+ type including T790M. Conclusions: TP53 seems to be a frequent co-mutation in EGFR mt+ NSCLC and has a strong impact on all clinical endpoints on TKI therapy. These data might have an impact on the management and follow up of pts with TP53 mt+. Furthermore, there is an urgent need for further therapeutic approaches in this patient group.
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p53
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