Association Between TP53 Mutations and Platinum Resistance in a Cohort of High-Grade Serous Ovarian Cancer Patients: Novel Implications for Personalized Therapeutics

Madeddu, Clelia;Lai, Eleonora;Neri, Manuela;Sanna, Elisabetta;Gramignano, Giulia;Nemolato, Sonia;Scartozzi, Mario;Giglio, Sabrina;Maccio, Antonio

2025-01-01

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Abstract

The integrity of p53 machinery is crucial for platinum activity, while p53 mutation is frequent in high-grade serous ovarian cancer (HGS-OC). This study aimed to evaluate the link between p53 mutations, platinum sensitivity (PS), and the platinum-free interval (PFI) in patients with HGS-OC. We prospectively analyzed 159 consecutive women with ovarian cancer who underwent surgery. The somatic mutational status of BRCA, HRD, and TP53 (according to structural, hotspot, and functional classification) was evaluated. Among enrolled patients, 82.4% of cases were TP53-mutated (MT), and 27.8% were BRCA-MT. The distribution of TP53 mutation categories did not differ significantly between the BRCA-MT and wild-type (WT) cases. In the entire population, the proportion of PS patients was significantly lower in TP53-MT compared to TP53-WT (p = 0.0208), in nonsense/frameshift/splicing compared to missense (p = 0.0319), and in loss-of-function (LOF) compared to GOF (p = 0.0048) MT cases. For the BRCA-MT patients, structural and functional TP53 mutations were not significantly different between the PS and PR patients. Conversely, for the BRCA WT patients, the distribution of structural and functional TP53 mutations significantly differed between PS and PR patients. In a multivariate regression analysis, LOF mutations were found to be independent negative predictors of PS (HR: 0.1717; 95% CI: 0.0661–0.4461; p-value: 0.0003). Kaplan–Meier curves showed a significantly lower PFI in cases with LOF mutations in the overall population (log-rank p = 0.0020) and in BRCA-WT patients (log-rank p = 0.0140). Via multivariate COX testing, it was found that LOF mutations were independently associated with a decreased PFI (p = 0.0036). In conclusion, our data show that HGS-OC harboring p53 LOF mutations is the poorest prognostic subgroup regarding PS and the PFI. Further studies are needed to confirm our findings.