Detection of TP53 Mutations in Tissue or Liquid Rebiopsies at Progression Identifies ALK+ Lung Cancer Patients with Poor Survival

• Main Authors: Petros Christopoulos, Steffen Dietz, Martina Kirchner, Anna-Lena Volckmar, Volker Endris, Olaf Neumann, Simon Ogrodnik, Claus-Peter Heussel, Felix J. Herth, Martin Eichhorn, Michael Meister, Jan Budczies, Michael Allgäuer, Jonas Leichsenring, Tomasz Zemojtel, Helge Bischoff, Peter Schirmacher, Michael Thomas, Holger Sültmann, Albrecht Stenzinger
• Format: Article
• Language: English
• Published: MDPI AG 2019-01-01
• Series: Cancers
• Subjects: anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC); tumor protein p53 gene (TP53) mutation; tyrosine kinase inhibitor; progression-free survival; overall survival
• Online Access: https://www.mdpi.com/2072-6694/11/1/124

Anaplastic lymphoma kinase (ALK) sequencing can identify resistance mechanisms and guide next-line therapy in ALK+ non-small-cell lung cancer (NSCLC), but the clinical significance of other rebiopsy findings remains unclear. We analysed all stage-IV ALK+ NSCLC patients with longitudinally assessable TP53 status treated in our institutions (n = 62). Patients with TP53 mutations at baseline (TP53mutbas, n = 23) had worse overall survival (OS) than patients with initially wild-type tumours (TP53wtbas, n = 39, 44 vs. 62 months in median, p = 0.018). Within the generally favourable TP53wtbas group, detection of TP53 mutations at progression defined a “converted” subgroup (TP53mutconv, n = 9) with inferior OS, similar to that of TP53mutbas and shorter than that of patients remaining TP53 wild-type (TP53wtprogr, 45 vs. 94 months, p = 0.043). Progression-free survival (PFS) under treatment with tyrosine kinase inhibitors (TKI) for TP53mutconv was comparable to that of TP53mutbas and also shorter than that of TP53wtprogr cases (5 and 8 vs. 13 months, p = 0.0039). Fewer TP53wtprogr than TP53mutbas or TP53mutconv cases presented with metastatic disease at diagnosis (67% vs. 91% or 100%, p < 0.05). Thus, acquisition of TP53 mutations at progression is associated with more aggressive disease, shorter TKI responses and inferior OS in ALK+ NSCLC, comparable to primary TP53 mutated cases.