Correlation of p 53 Mutations with Resistance to Platinum-based Chemotherapy and Shortened Survival in Ovarian Cancer 1

Purpose: The p53 tumor suppressor gene plays a central role in cell cycle regulation and induction of apoptosis. We analyzed p53 alterations and their impact on response to chemotherapy and clinical outcome in ovarian cancer patients. Experimental Design: One hundred seventy-eight ovarian carcinomas, snap frozen and stored at 80°C, were analyzed for mutations of the p53 gene (exons 2–11) by single-strand conformation polymorphism and DNA sequencing and for p53 overexpression by immunohistochemistry (monoclonal antibody DO7). Results: p53 mutations were found in 56% (99 of 178) of the tumors, and 62% of these were located in evolutionary highly conserved domains of the gene. Time to progression and overall survival were significantly shortened in patients with p53 mutations compared with wild-type p53 (P 0.029 and P 0.014) and patients with mutations in highly conserved domains as opposed to nonconserved domains or wild-type p53 (P 0.010 and P 0.007). p53 protein overexpression (>10% positively stained nuclei) was found in 62% (110 of 178). Time to progression and overall survival were shorter in cases with p53 overexpression (cutpoint, 10%: P 0.071 and P 0.056) but only marginally significant. Resistance to adjuvant cisplatin or carboplatin chemotherapy was significantly more frequent in patients with p53 overexpression (P 0.001) or p53 missense mutations (P 0.008) than patients with normal p53. Conclusions: p53 alterations correlate significantly with resistance to platinum-based chemotherapy, early relapse, and shortened overall survival in ovarian cancer patients in univariate analysis. In multivariable analysis though, p53 was not an independent prognostic factor.