Identification of a highly lethal V3⁺TP53⁺ subset in ALK⁺ lung adenocarcinoma

Abstract

Tyrosine kinase inhibitors (TKI) have improved prognosis in metastatic anaplastic lymphoma kinase (ALK)‐driven lung adenocarcinoma, but patient outcomes vary widely. We retrospectively analyzed the clinical course of all cases with assessable baseline TP53 status and/or ALK fusion variant treated at our institutions (n = 102). TP53 mutations were present in 17/87 (20%) and the echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK variant 3 (V3) in 41/92 (45%) patients. The number of metastatic sites at diagnosis was affected more by the presence of V3 than by TP53 mutations, and highest with both factors (mean 5.3, p < 0.001). Under treatment with ALK TKI, progression‐free survival (PFS) was shorter with either TP53 mutations or V3, while double positive cases appeared to have an even higher risk (hazard ratio [HR] = 2.9, p = 0.015). The negative effect of V3 on PFS of TKI‐treated patients was strong already in the first line (HR = 2.5, p = 0.037) and decreased subsequently, whereas a trend for PFS impairment under first‐line TKI by TP53 mutations became stronger and statistically significant only when considering all treatment lines together. Overall survival was impaired more by TP53 mutations (HR = 4.9, p = 0.003) than by V3 (HR = 2.4, p = 0.018), while patients with TP53 mutated V3‐driven tumors carried the highest risk of death (HR = 9.1, p = 0.02). Thus, TP53 mutations and V3 are independently associated with enhanced metastatic spread, shorter TKI responses and inferior overall survival in ALK+ lung adenocarcinoma. Both markers could assist selection of cases for more aggressive management and guide development of novel therapeutic strategies. In combination, they define a patient subset with very poor outcome.

Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases

“…39,42 In particular, V3 + TP53 + patients represent a very unfavorable, highly lethal subset in ALK + NSCLC, the identification of which requires combined RNA-and DNA sequencing, as performed in our study (Fig. 5) did not consider several clinical variables, similar results have also been observed in meticulously controlled retrospective analyses, 39,40,42 which further highlights the potential clinical value of TP53 sequencing, as performed in our study, but will require confirmation in prospective clinical trials. 42 Of note, although the retrospective outcome analyses exemplary performed in our cohort (Fig.…”

“…TP53 mutations for example are associated with a shorter PFS under TKI treatment and with an inferior overall survival in EGFR-driven NSCLC (Fig. 39,42 In particular, V3 + TP53 + patients represent a very unfavorable, highly lethal subset in ALK + NSCLC, the identification of which requires combined RNA-and DNA sequencing, as performed in our study (Fig. 41 Similar effects have been described for NSCLC driven by ALK-and ROS1 fusions.…”

“…41 Similar effects have been described for NSCLC driven by ALK-and ROS1 fusions. 42 Of note, although the retrospective outcome analyses exemplary performed in our cohort (Fig. 5b).…”

“…41 Similar effects have been described for NSCLC driven by ALK-and ROS1 fusions. 39,42 In particular, V3 + TP53 + patients represent a very unfavorable, highly lethal subset in ALK + NSCLC, the identification of which requires combined RNA-and DNA sequencing, as performed in our study (Fig. 5b).…”

Molecular and clinical analysis of Chinese patients with anaplastic lymphoma kinase (ALK)‐rearranged non‐small cell lung cancer

“…The present data provide a novel insight into the differences in prognosis between EML4-ALK variant V1 and variant V3 patients. A number of studies have demonstrated that TP53 mutations predict a poor outcome following systemic therapy for ALK fusion NSCLC, and coalterations between EML4-ALK variant V3 and TP53 mutations define a patient subset with worse prognosis [55][56][57]. The present study demonstrated that the frequency of concurrent TP53 mutations and EML4-ALK variant V3 was markedly higher compared with that of concurrent TP53 mutations and EML4-ALK variant V1, which indicates that TP53 mutation may be one of the critical reasons for the differences in prognosis between patients with EML4-ALK variant V1 and variant V3 NSCLC.…”