Abstract / Summary
Abstract Objective Anaplastic thyroid cancer (ATC) is an extremely aggressive tumour, with high mortality rates. Dabrafenib plus Trametinib (DT) has significantly impacted the survival of patients with BRAF p.V600E ATC, with noticeable variations in survival between patients. TP53 is frequently mutated in ATC, but its impact on DT response is still unclear. We aimed to investigate the association between TP53 mutational status and clinical outcomes in ATC patients treated with DT. Methods BRAF positive ATC patients (n=25) treated with DT between 2018 and 2026 were included. Response was assessed by RECIST 1.1. TP53 association with clinicopathological features was evaluated. Four BRAF-mutant cell lines were used: two TP53 mutant (T235, T238) and two TP53 wild-type (OCUT1, IHH4). Results TP53 mutations, detected in ATC from 10 patients, were associated with a significantly lower overall survival (6.5 vs 21 months; p<0.01), and a trend towards shorter progression-free survival (7 vs 19 months; p=0.09), and duration of response (5.5 vs 9 months; p=0.09). No significant associations were found between TP53 mutations and sex, primary tumour size, N and M stage, or PI3K pathway alterations. Complementary in vitro experiments across multiple BRAF p.V600E cell lines provided mechanistic support for these clinical observations, demonstrating that TP53-mutant cells consistently exhibited reduced sensitivity to combined DT therapy. Conclusions This study suggested that TP53 mutations represent a prognostic factor, associated with worse survival in patients with BRAF p.V600E ATC undergoing DT treatment, highlighting the potential clinical value of incorporating TP53 profiling into patient management.