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

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 (TP53mut(bas), n = 23) had worse overall survival (OS) than patients with initially wild-type tumours (TP53wt(bas), n = 39, 44 vs. 62 months in median, p = 0.018). Within the generally favourable TP53wt(bas) group, detection of TP53 mutations at progression defined a “converted” subgroup (TP53mut(conv), n = 9) with inferior OS, similar to that of TP53mut(bas) and shorter than that of patients remaining TP53 wild-type (TP53wt(progr), 45 vs. 94 months, p = 0.043). Progression-free survival (PFS) under treatment with tyrosine kinase inhibitors (TKI) for TP53mut(conv) was comparable to that of TP53mut(bas) and also shorter than that of TP53wt(progr) cases (5 and 8 vs. 13 months, p = 0.0039). Fewer TP53wt(progr) than TP53mut(bas) or TP53mut(conv) 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.