Endocrine Abstracts

Background: Poorly differentiated (PDTCs), anaplastic (ATCs) thyroid cancers and few well differentiated thyroid cancers (WDTC) are particularly aggressive and refractory to all treatments, including tyrosine kinase inhibitors (TKIs). Since in other tumors, TP53 mutations are related to a poorer response to TKIs treatment, we aimed to investigate the impact of TP53 mutations on thyroid cancer response to Lenvatinib (LEN) treatment.

Methods: We investigated the molecular profile (including TP53 mutations) of 30 tumor tissues (23 WDTCs and 7 PDTCs/ATCs) obtained at surgery from patients subsequently treated with LEN (initial median dose of 20±6.8 mg/day) for a mean time of 31 months (range 6-84). Moreover, we evaluated by statistical analyses the association between TP53 mutations, clinico-pathological features, and tumor response rate to LEN defined as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD), according to revised Response Evaluation Criteria in Solid Tumors (RECIST) criteria guidelines version 1.1.

Results: Among the 30 tumor tissues, 8 (4 WDTCs and 4 PDTCs/ATCs) harbored TP53 mutations within exons 5-8 encoding the DNA binding domain of the protein. Univariate analysis, according to LEN response, revealed TP53 mutations as a significant predictor of poor response to this TKI. Indeed, all the 8 patients with TP53 mutations developed PD during LEN (P = 0.005). Considering the best morphological response (BMR), 6 patients achieved a temporary SD, while the other 2 showed a PD. Kaplan–Meier curve demonstrated that patients harbouring TP53 mutations has a shorter Overall Survival (OS) rate than wild type tumors (P= 0.0007). This difference remained significant also considering only patients affected with DTC (P = 0.0453) or with PDTC/ATC (P = 0.049). In addition, patients harboring TP53 mutations showed a shorter progression-free survival (PFS) rate than those TP53 wild type (P = 0.0005). This difference remained significant also considering only patients affected with DTC (P = 0.026) or with PDTC/ATC (P = 0.049). Similarly, considering PFS rate associated to BMR, patients harbouring TP53 mutations showed a shorter PFS rate than the wild type ones (P = 0.016).

Conclusions: We demonstrated for the first time in advanced thyroid cancer that the presence of inactivating mutations in TP53 is associated to worse OS and PFS rates during Lenvatinib treatment. Thus, the evaluation of the tumor molecular profile and particularly of TP53 mutations is crucial for the selection of the best therapeutic option for patients with progressive thyroid cancer.