Abstract
BackgroundThe role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined.MethodsWithin the phase III study AIO-PK0104 281 patients with advanced pancreatic cancer received an erlotinib-based 1st-line regimen. Archival tissue from 153 patients was available for central immunohistochemistry staining for pERK, pAKT and p53. Within a subgroup analysis, biomarker data were correlated with efficacy endpoints and skin rash using a Cox regression model.ResultsFifty-five out of 153 patients were classified as pERKlow and 98 patients as pERKhigh; median overall survival (OS) was 6.2 months and 5.7 months, respectively (HR 1.29, p = 0.16). When analysing pERK as continuous variable, the pERK score was significantly associated with OS (HR 1.06, 95% CI 1.0-1.12, p = 0.05). Twenty-one of 35 patients were pAKTlow and 14/35 pAKThigh with a corresponding median OS of 6.4 months and 6.8 months, respectively (HR 1.03, p = 0.93). Four out of 50 patients had a complete loss of p53 expression, 20 patients a regular expression and 26 patients had tumors with p53 overexpression. The p53 status had no impact on OS (p = 0.91); however, a significant improvement in progression-free survival (PFS) (6.0 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 patients with a regular p53 expression compared to patients with a complete loss of p53.ConclusionpERK expression may have an impact on OS in erlotinib-treated patients with advanced pancreatic cancer; p53 should be further investigated for its potential role as a predictive marker for PFS and skin rash.Trial registrationNCT00440167 (registration date: February 22, 2007).Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-624) contains supplementary material, which is available to authorized users.
Highlights
The role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined
Regarding the use of EGFR targeting agents in advanced pancreatic cancer, the tumor KRAS status may play a role as a prognostic or even predictive biomarker: based on previous translational results from AIO-PK0104, a large randomized phase III trial comparing a treatment sequence of gemcitabine + erlotinib followed by capecitabine vs capecitabine + erlotinib followed by gemcitabine in patients with advanced disease, patients with a KRAS wildtype may have a prolonged survival compared to patients with KRAS exon 2 mutations [7]
PERK pERK IHC staining was performed on 153 samples, classifying 55 patients as pERKlow (36%) and 98 patients as pERKhigh (64%), with a median score level of 7. pERK expression showed no correlation with KRAS status (p = 0.32), EGFR protein expression (p = 0.38) or EGFR gene amplification (p = 1.00), respectively
Summary
The role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined. Several large phase III trials investigating targeted agents (in unselected patient populations) have failed with only erlotinib (in addition to standard gemcitabine) achieving a moderate gain in overall survival (OS) [3,4]. Regarding the use of EGFR targeting agents in advanced pancreatic cancer, the tumor KRAS status may play a role as a prognostic or even predictive biomarker: based on previous translational results from AIO-PK0104, a large randomized phase III trial comparing a treatment sequence of gemcitabine + erlotinib followed by capecitabine vs capecitabine + erlotinib followed by gemcitabine in patients with advanced disease, patients with a KRAS wildtype may have a prolonged survival compared to patients with KRAS exon 2 mutations [7]. Based on previous analyses conducted on archival formalin fixed paraffin embedded (FFPE) tissue from AIO-PK014 no other marker besides KRAS showed a correlation with survival endpoints or objective response: data on EGFR protein expression, EGFR gene amplification, PTEN expression and on EGFR intron 1 polymorphism did not show - despite previous pre-clinical evidence - a correlation with efficacy study endpoints [10,11,12]
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