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. 2018 Oct 1;29(10):2068-2075.
doi: 10.1093/annonc/mdy333.

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer

A Kron  1 , C Alidousty  2 , M Scheffler  1 , S Merkelbach-Bruse  2 , D Seidel  3 , R Riedel  1 , M A Ihle  2 , S Michels  1 , L Nogova  1 , J Fassunke  2 , C Heydt  2 , F Kron  4 , F Ueckeroth  2 , M Serke  5 , S Krüger  6 , C Grohe  7 , D Koschel  8 , J Benedikter  9 , B Kaminsky  10 , B Schaaf  11 , J Braess  12 , M Sebastian  13 , K-O Kambartel  14 , R Thomas  15 , T Zander  4 , A M Schultheis  2 , R Büttner  2 , J Wolf  16
Affiliations

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer

A Kron et al. Ann Oncol. .

Abstract

Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).

Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.

Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4-5.6) versus 10.3 months (95% CI: 8.6-12.0), P < 0.001; OS 15.0 months (95% CI: 5.0-24.9) versus 50.0 months (95% CI: 22.9-77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3-4.1) versus 6.2 months (95% CI: 1.8-10.5), P = 0.021; OS 2.0 months (95% CI: 0.0-4.6) versus 9.0 months (95% CI: 6.1-11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9-7.2) versus 14.0 months (95% CI: 8.0-20.1), P < 0.001; OS 17.0 months (95% CI: 6.7-27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1-10.7) versus 9.9 months (95% CI: 6.4-13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).

Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.

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Figures

Figure 1.
Figure 1.
(A) Flowsheet of molecular diagnostics. NGS, next-generation sequencing; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. (B) Allocation of patients to cohorts for evaluation of treatment-related OS. BSC, best supportive care; PFS, progression-free survival; OS, overall survival.
Figure 2.
Figure 2.
(A) Frequencies of co-occurring genetic aberrations in ALK-positive NSCLC patients. Results of NGS, single gene sequencing and FISH analysis in 197 ALK FISH-positive patients. (B) Correlation between PD-L1 positivity (expression score) and TP53 mutation status in 34 ALK-positive patients.
Figure 3.
Figure 3.
(A) PFS with different systemic treatments dependent on TP53 mutation status. Kaplan–Meier blots for the total cohort (n = 228), for chemotherapy (n = 102), for crizotinib (n = 93) and for next-generation ALK inhibitors (n = 33). (B) OS in the treatment-related cohorts dependent on TP53 mutation status. Kaplan–Meier blots for the total cohort (n = 143), for chemotherapy (n = 22), for crizotinib (n = 63) and for ceritinib (n = 24).
See this image and copyright information in PMC

Comment in

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