Phospho-ERK (pERK) and Ki67 expression as compared to thickness and mitotic rate (MR) as prognostic factors in patients with stage I/II melanomas

Abstract

9020 Background: Tumor thickness and MR in the vertical growth phase (VGP) are key prognostic factors for melanoma patients. We hypothesized that the expression of two biomarkers associated with proliferation, Ki67, a measure of cell division, and pERK, a consequence of melanoma cells signaling through the MAP kinase pathway, would be associated with poor prognosis and more accurately predict those who would have a metastasis within ten years (MET). Methods: We evaluated Ki67 and pERK expression by immunohistochemistry in a nested cohort study of 50 patients with stage I/II VGP melanomas seen at Penn's Pigmented Lesion Clinic (1972–91). Ki67 expression was determined by the % of melanoma cells positive in VGP hot spots. Nuclear pERK expression by melanoma cells in the tumor's invasive edge (pERK/IE) was quantified using a modified H-score. Cut-points for both were established by maximizing the difference between survival distributions. Fisher's exact test (0.05, one-sided) had 75% power to detect an odds ratio (OR) of 4.3 with 19 and 42 patients with and without MET. Results: The odds of MET were 10.6-fold and 4.3-fold higher in patients having high Ki67 (p=0.013) and high pERK/IE (p<0.01) expression, respectively, compared to those with low expression. Thickness (OR=1.7, p=0.004) and MR (OR=1.3, p=0.002) were also each associated with MET. In the multivariate model the adjusted odds ratios for Ki67 and pERK/IE remained strong [4.0 (p=0.061) and 5.9 (p=0.030)], but thickness and MR were no longer significant. Conclusions: New biomarkers strongly associated with clinical outcome are needed. Both Ki67 and pERK/IE expression were strongly associated with prognosis, were notably more informative than thickness and MR in predicting MET, and are therefore candidates for validation in larger datasets. No significant financial relationships to disclose.