P53 mutations in advanced cancers: Clinical characteristics and outcomes in a phase I setting.

Abstract

10607 Background: p53 mutation is one of the most common mutations in human tumors and plays an important role in apoptosis, genomic stability and inhibition of angiogenesis. Methods: We retrospectively reviewed 121 consecutive patients (pts) with solid tumors referred to the Clinical Center for Targeted Therapy (Phase I program) who were tested for p53 mutation, and compared clinical characteristics and outcomes in p53 positive vs. wild-type (wt) pts. Results: Of the 121 tested pts, 65 (53.7%) were p53 mutation-positive. The presence of p53 mutation was not associated with sex and race. Tumors with p53 mutation metastasized more often to the liver (44 pts (67.7%) with mutated p53 vs. 26 pts (46.4%) with wt p53, p=0.0264); there was no difference in metastasis to the bones, lungs, brain, soft tissues and adrenals. p53 mutation also showed a trend toward an association with PTEN-loss (13 out of 43 (30%) with p53 mutated vs. 4 out of 37 (11%) with wt p53, p=0.053). Among pts with the p53 mutation, the best median progression-free survival (PFS) prior to phase I trial entry was 10.97 months (range 0.85–29.04 months) when the treatment regimen included bevacizumab and 4.37 months (range 0.92–14.98 months) when the treatment did not include bevacizumab (P=0.0046). Among patients with wt p53, there was no significant difference in PFS between bavacizumab-containing regimens and regimens without bevacizumab. The median OS from diagnosis was 7.7 years (95% CI 6.32–9.84 years) vs. 11.8 years (95% CI 10.37 years, not attained) for p53 mutant vs. wild-type disease (p = 0.03). Univariate analysis for OS from diagnosis showed that mutated p53, Hispanic race (vs. Caucasians) and the shorter time from diagnosis to metastasis were associated with a worse prognosis. Conclusions: Tumors with p53 mutation have a more aggressive clinical behavior, metastasize more to the liver and may have a higher rate of PTEN loss compared to tumors with wt p53; In addition, anti-angiogenic agents may be of therapeutic value in p53-mutated pts.