Overexpression of p53 in Patients with Primary Ovarian Epithelial Cancer

ABSTRACT & COMMENTARY

Synopsis: Overexpression of p53 is not an independent prognostic factor for patients with primary epithelial ovarian cancer.

Source: Eltabbakh GH, et al. Cancer 1997;80:892-898.

The clinical significance of p53 overexpression in patients with ovarian cancer remains uncertain. Eltabbakh and colleagues conducted a study in which the aim was to investigate the independent prognostic significance of p53 overexpression in patients with primary epithelial ovarian cancer. Tumors obtained from 221 patients with primary epithelial ovarian cancers of all stages (I-IV) were studied for p53 overexpression semiquantitatively by immunohistochemical techniques. The median duration of follow-up of surviving patients was seven years.

The presence or absence and degree of p53 overexpression were correlated with the clinicopathologic features of the study population and overall survival. One hundred seven tumors (48.4%) exhibited p53 overexpression. The overexpression was graded as mild in 16.7% of cases, moderate in 5.9%, and strong in 25.8%. Overexpression of p53 was associated with advanced stage (P = 0.04), higher grade (P = 0.0003), serous histology (P = 0.0018), and patient age older than 61 years (P = 0.013). In univariate analysis, p53 overexpression was a significant prognostic factor (P = 0.049 for any degree of overexpression; P = 0.03 for strong overexpression). However, in multivariate analysis, after adjustment for stage and size of residual tumor following cytoreductive surgery, p53 overexpression did not retain statistical significance. Survival curves for patients with different stages and grades of tumor differentiation did not demonstrate a difference in survival among patients with no p53 overexpression compared with those who demonstrated any degree of p53 overexpression or compared with those who demonstrated strong p53 overexpression. Eltabbakh et al conclude that p53 overexpression is not an independent prognostic factor for patients with primary epithelial ovarian cancer.

COMMENT BY DAVID M. GERSHENSON, MD

Over the past decade or so, technological advances in the field of molecular biology and genetics have allowed us to illuminate the cellular and subcellular mechanisms that control tumor growth. For example, in the area of genetic susceptibility testing, the discovery of BRCA1 and BRCA2 has allowed us to begin to focus on so-called "high-risk" families and to provide risk assessment and genetic counseling to female members of those families with regard to their lifetime risk of breast and ovarian cancer. Clinical applications of basic scientific discoveries for patients with ovarian cancer, however, have been slow. The p53 tumor suppressor gene appears to play a major role in human tumorigenesis. Mutations of p53 are found in approximately 50% of all epithelial ovarian cancers.

The significance of this finding continues to elude us. We do know that borderline ovarian tumors have a very low rate of p53 overexpression. And, as demonstrated in this study, for invasive ovarian tumors, the higher the stage, the higher the rate of p53 overexpression. Some studies have reported that p53 mutation or overexpression is a significant prognostic factor, whereas others have not noted such a relationship. As emphasized by Eltabbakh et al, they used the technique most often employed in such reports—immunohistochemistry.

This technique will detect p53 missense mutations because of the presence of a stable mutant protein but may miss other types of mutation (such as deletions or additions), which do not result in a stable protein. Therefore, larger studies using both DNA sequencing and immunohistochemistry may reveal different results than this study has. Nevertheless, for the time being, p53 status is of negligible assistance in treatment planning for patients with epithelial ovarian cancer. Hopefully, future studies will allow us to use molecular markers such as p53 for prognostic purposes. In addition, such markers will eventually allow segregation of patients for different treatment strategies. Despite the disparity in study findings, p53 is already being studied in clinical trials as a target for gene therapy.