The Journal of clinical endocrinology and metabolism · 2025
TP53 Alterations Are Associated With Poor Response to Lenvatinib in Patients With Advanced Thyroid Cancer.
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Cirello Valentina, Colombo Carla, Tosi Delfina, Manzo Alessandro, Borghi Maria Orietta, Gianelli Umberto, Gazzano Giacomo, Ferrero Stefano, Dionigi Gianlorenzo, Persani Luca, Fugazzola Laura
Аннотация
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 effect of TP53 mutations on the response to lenvatinib (LEN) in advanced TCs and in vitro models.
METHODS: 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 = .005). TP53-mutated patients had a shorter progression-free survival (PFS) (P < .0001) and overall survival (OS) rates (P = .0007). Accordingly, patients harboring altered nuclear p53 protein expression had shorter PFS and OS (P = .0001 and P = .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 with 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.
CONCLUSION: 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 is associated with worse PFS and OS rates. The evaluation of TP53 mutations/p53 expression might be included in the patient/tumor characterization to be performed before starting an MKI treatment.
OBJECTIVE: We evaluated the effect of TP53 mutations on the response to lenvatinib (LEN) in advanced TCs and in vitro models.
METHODS: 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 = .005). TP53-mutated patients had a shorter progression-free survival (PFS) (P < .0001) and overall survival (OS) rates (P = .0007). Accordingly, patients harboring altered nuclear p53 protein expression had shorter PFS and OS (P = .0001 and P = .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 with 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.
CONCLUSION: 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 is associated with worse PFS and OS rates. The evaluation of TP53 mutations/p53 expression might be included in the patient/tumor characterization to be performed before starting an MKI treatment.