P-ERK, P-AKT and p53 as Tissue Biomarkers in Erlotinib-Treated Patients with Advanced Pancreatic Cancer: a Translational Subgroup Analysis From Aio-PK0104

Abstract

Background: The role of downstream targets of the EGFR pathway and of p53 as biomarker in patients ( pts) with advanced pancreatic cancer (APC) has not yet been defined. Methods: Within the phase III study AIO-PK0104 281 pts with APC were randomized between gemcitabine/erlotinib followed by capecitabine and capecitabine/erlotinib followed by gemcitabine. Archival formalin fixed paraffin embedded tissue was used to conduct central immunohistochemistry (IHC) staining for pERK (n = 153), pAKT (n = 35) and p53 (n = 50) expression. A semi-quantitative IHC scoring system considering the cytoplasmic and nuclear expression (staining intensity & % of positive cells) was developed for pERK (score 0-12) and pAKT (score 0-12). The IHC expression status of the tumor-suppressor gene p53 was assessed as a categorical variable (complete loss, regular expression, and overexpression).Within a retrospective, hypothesis-generating subgroup analysis, biomarker data (either as dichotomous or continuous variable) were correlated with efficacy endpoints and skin rash using a Cox regression model. Results: 98/153 pts were classified as pERK high (score 6-12) and 55/153 pts as pERKlow; median OS was 5.7 months in pERK high pts and 6.2 months in pERK low pts (HR 1.29, 95% CI 0.90-1.83, p = 0.16). When analysing pERK as continuous variable, a significant association between the pERK score and OS was found (HR 1.06, 95% CI 1.0-1.12, p [log rank] = 0.050, p [likelihood ratio] = 0.047), indicating an increase in the hazard for death by a factor of 1.06 for each score level of pERK expression. 14/35 pts were classified as pAKT high (score 5-12) and 21/35 pts as pAKT low; median OS was 6.8 months in pAKT high pts and 6.4 months in pAKT low pts (HR 1.03, 95% CI 0.51-2.11, p = 0.93). Regarding p53, 4/50 pts had a complete loss of p53 expression, 20/50 pts a regular expression and 26/50 pts had tumors with a p53 overexpression, respectively. The p53 status had no impact on OS (global p value = 0.91), however a significant improvement in PFS (6.0 months vs. 1.8 months, HR 0.24, p = 0.02) and a higher rate of skin rash (84% vs. 25%, p = 0.02) was observed for pts with a regular p53 expression compared to pts with a complete loss of p53 in their tumor. Conclusion: pERK expression may have an impact on OS and the p53 status might be correlated with PFS (but not with OS) and the occurrence of skin rash in erlotinib-treated pts with APC. A prospective and external validation of these results is necessary.