TP53 Alterations Associate with Poor Response to Lenvatinib in Patients with Advanced Thyroid Cancer.

Abstract

Context: No data are available about the possible association of TP53 mutations and the response to multikinase inhibitors (MKIs) in thyroid cancer (TC).

Objective: We evaluated the impact of TP53 mutations on the response to lenvatinib (LEN) in advanced TCs and in in vitro models.

Patients and interventions: We investigated the molecular profile, including TP53 mutations, of 30 tumor tissues from patients treated with LEN, and tested p53 status by immunohistochemistry. These data were compared with clinical-pathological features, and tumor response to LEN. The response to LEN was also evaluated in TP53-defective and TP53-proficient TC cell lines.

Results: TP53 mutations significantly correlated with a poor response to LEN (p=0.005). TP53 mutated patients had a shorter progression-free survival (PFS) (p<0.0001) and overall survival (OS) rates (p=0.0007). Accordingly, patients harbouring altered nuclear p53 protein expression had shorter PFS and OS (p=0.0001 and p=0.0056, respectively). These data were confirmed in a validation cohort. In accordance with clinical data, TC cell lines with p53 alterations had low or null sensitivity, while those TP53 wild type showed different degrees of sensitivity, primarily due to the increased number of tumor cells in G1 phase, consistent with the cytostatic effect of LEN.

Conclusions: We show for the first time in advanced TC that the presence of TP53 alterations is a predictor of poor response to LEN treatment and associates to worse PFS and OS rates. The evaluation of TP53 mutations/p53 expression might be included into the patient/tumor characterization to be done before starting an MKI treatment.