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

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.

SUBMITTER: Roeper J

PROVIDER: S-EPMC6980625 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Roeper Julia J Falk Markus M Chalaris-Rißmann Athena A Lueers Anne C AC Ramdani Hayat H Wedeken Katrin K Stropiep Ursula U Diehl Linda L Tiemann Markus M Heukamp Lukas C LC Otto-Sobotka Fabian F Griesinger Frank F

Oncotarget 20200121 3

<h4>Introduction</h4>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.<h4>Methods</h4>75 EGFR mutated NSCLC IV patients homogeneously treated w ...[more]

PMID: 32076486

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Project description:BackgroundDespite disappointing outcomes from immuno-monotherapy, studies reported that NSCLC patients with EGFR mutation may possibly benefit from combined immunotherapy. Whether the response to prior EGFR-TKI has association with the outcomes of subsequent immunotherapy remains unclear.Patients and methodsAdvanced NSCLC patients with resistance to EGFR-TKIs and received ICI treatment from January 2016 to June 2019 were retrospectively analyzed. Single cell sequencing and flow cytometry were conducted to explore the difference of cell components in tumor microenvironments (TME). A 1:3 matched case-control study was conducted to compare the clinical effects of combined immunotherapy with standard chemotherapy as second-line treatment.ResultsFifty-eight patients treated with anti-PD-1/PD-L1 based immunotherapy behind EGFR-TKI treatment were enrolled. Correlation analysis showed TKI-PFS had a significantly negative association with corresponding IO-PFS (r = -0.35, p = 0.006). TKI-PFS cutoff 10 months had the most significant predictive function for posterior immunotherapy and was validated to be an independent predictor by uni- and multivariate analyses. Kaplan-Meier analysis showed that patients with TKI-PFS less than 10 months had significantly prolonged IO-PFS and higher ORR than those with long (median PFS, 15.1 vs 3.8 months; HR, 0.26, p = 0.0002; ORR, 31.8 versus 10%, p = 0.04). Single cell RNA-seq revealed that the cell components were varied among patients after treatment with EGFR-TKI. Patients with short TKI-PFS demonstrated a relatively higher proportion of CD8 effector cells and lower ratio of M2 like macrophage to M1 like macrophages, which was validated by flow cytometry. Case-control study demonstrated that combined immunotherapy achieved significantly longer PFS (HR, 0.51, 95% CI: 0.31-0.85, p = 0.02), longer OS (HR, 0.48, 95% CI: 0.26-0.89, p = 0.05) and higher ORR (33.3 vs 10.0%, p = 0.02) than traditional chemotherapy for patients with short TKI-PFS.ConclusionPatients with short TKI-PFS conferred better response to immunotherapy than those with long. The status of TME were different among those two populations. Combined ICI treatment could promisingly be a better choice than classical chemotherapy in second-line setting for patients with short TKI-PFS and no T790M mutation. Underlying mechanisms need to be further explored.

Dataset Information

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

Publications

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

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