Jana Kaethe Striefler

SPARC expression in resected pancreatic cancer patients treated with gemcitabine: results from the CONKO-001 study

BACKGROUND Previous investigations in pancreatic cancer suggested a prognostic role for secreted protein acidic and rich in cysteine (SPARC) expression in the peritumoral stroma but not for cytoplasmic SPARC expression. The aim of this study was to evaluate the impact of SPARC expression in pancreatic cancer patients treated with gemcitabine compared with untreated patients. PATIENTS AND METHODS CONKO-001 was a prospective randomized phase III study investigating the role of adjuvant gemcitabine when compared with observation. Tissue samples of 160 patients were available for SPARC immunohistochemistry on tissue microarrays to evaluate its impact on patient outcome. RESULTS Strong stromal SPARC expression was associated with worse disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P = 0.005, OS: P = 0.033). Its negative prognostic impact was restricted to patients treated with gemcitabine (DFS: P = 0.007, OS: P = 0.006). High cytoplasmic SPARC expression also was associated with worse patient outcome (DFS: P = 0.041, OS: P = 0.011). Again the effect was restricted to patients treated with gemcitabine (DFS: P = 0.002, OS: P = 0.003). In multivariable analysis, SPARC expression was independently predictive of patient outcome. CONCLUSIONS Our data confirm the prognostic significance of SPARC expression after curatively intended resection. The negative prognostic impact was restricted to patients who received adjuvant treatment with gemcitabine, suggesting SPARC as a predictive marker for response to gemcitabine.

Does long‐term survival in patients with pancreatic cancer really exist?—Results from the CONKO‐001 study

Long‐term survival (LTS) in patients (pts) with pancreatic cancer is still uncommon, little data is available to identify long‐term survivors. The CONKO‐001 study, which established gemcitabine after resection as adjuvant therapy, may provide data to answer this question.

α-Smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001 study

Background:Previous investigations in pancreatic cancer suggest a prognostic role for α-smooth muscle actin (α-SMA) expression and stromal density in the peritumoural stroma. The aim of this study was to further validate the impact of α-SMA expression and stromal density in resectable pancreatic cancer patients treated with adjuvant gemcitabine compared with untreated patients.Methods:CONKO-001 was a prospective randomised phase III study investigating the role of adjuvant gemcitabine as compared with observation. Tissue samples of 162 patients were available for immunohistochemistry on tissue microarrays to evaluate the impact of α-SMA expression and stromal density impact on patient outcome.Results:High α-SMA expression in tumour stroma was associated with worse patient outcome (DFS: P=0.05, OS: P=0.047). A dense stroma reaction was associated with improved disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P=0.001, OS: P=0.001). This positive prognostic impact was restricted to patients with no adjuvant treatment (DFS: P<0.001, OS: P<0.001). In multivariable analysis, α-SMA and stromal density expression were independently predictive factors for survival.Conclusions:Our data confirm the negative prognostic impact of high α-SMA expression in pancreatic cancer patients after curatively intended resection. In contrast to former investigations, we found a positive prognostic impact for a dense stroma. This significant influence was restricted to patients who received no adjuvant therapy.

Human equilibrative nucleoside transporter 1 expression analysed by the clone SP 120 rabbit antibody is not predictive in patients with pancreatic cancer treated with adjuvant gemcitabine - Results from the CONKO-001 trial

BACKGROUND High expression of human equilibrative nucleoside transporter 1 (hENT1) is considered to predict survival in patients treated with adjuvant gemcitabine for pancreatic cancer. A standard evaluation system for immunohistochemical analysis (antibody, scoring system) has not yet been established. METHODS CONKO-001, a prospective randomised phase III study investigated the role of adjuvant gemcitabine (gem) as compared to observation (obs). Tumour samples of 156 patients were analysed by immunohistochemistry with the rabbit monoclonal antibody SP120 (Ventana Medical Systems) for expression of hENT1. Kaplan-Meier analyses for median disease-free survival (DFS) and overall survival (OS) were performed in dependence of hENT1 expression measured analogously to Farrell et al. 2009 and Poplin et al. 2013. RESULTS For the 88 gem and 68 obs patients, median DFS/OS was 12.9/22.7 months and 6.2/19.1 months. High hENT1 expression was not associated with improved median DFS (Farrell: no hENT1 22.2 months, low hENT1 13.7 months, high hENT1 12.1 months, p=0.248; Poplin: low hENT1 13.2 months versus high hENT1 11.5 months, p=0.5) or median OS (Farrell: no hENT1 21.7 months, low hENT1 24.7 months, high hENT1 19.5, p=0.571; Poplin: low hENT1 24.4 months versus high hENT1 19.7 months, p=0.92;) in the gem group or in the obs group (median DFS Farrell: no hENT1 5.1 months, low hENT1 6.2 months, high hENT1 7.5 months, p=0.375; Poplin: low hENT1 6.2 months versus high hENT1 5.9 months, p=0.83; median OS Farrell: no hENT1 20.2months, low hENT1 17.7 months, high HENT1 19.1 months, p=0.738; Poplin: low hENT1 17.7 months versus high hENT1 20.4 months, p=0.65) measured by the Farrell or Poplin Score. CONCLUSIONS We cannot confirm a predictive role of hENT1 measured by the clone SP120 rabbit antibody in our study population. Reproducible standard procedures are urgently needed prior to the implementation or exclusion of hENT1 as a predictive biomarker in the treatment of pancreatic cancer. TRIAL REGISTRATION ISRCTN34802808.

KRAS mutations in codon 12 or 13 are associated with worse prognosis in pancreatic ductal adenocarcinoma

Objective Mutations in the KRAS and P53 genes belong to the most frequently observed genetic alterations in pancreatic ductal adenocarcinoma. The aim of this study was to examine the frequency and prognostic impact of KRAS mutations. In addition, we attempted to define molecular subgroups with distinct biologic behavior by combination of KRAS sequencing data with p53 protein expression data. Methods KRAS mutational analyses were performed in a study group of 153 patients by Sanger sequencing. Immunohistochemistry for p53 was performed on tissue microarrays. Results KRAS mutations in codon 12 or 13 were found in 68% of cases. Nuclear staining for p53 was detectable in 110 (68%) of 162 evaluable cases. We found no correlation between KRAS mutational status and p53 expression. KRAS mutational status but not p53 immunohistochemistry was an independent prognostic factor in the study group (P = 0.02). In a stratified analysis according to KRAS mutational status, p53 expression failed to define prognostic groups beyond the impact of KRAS mutational status. Conclusions Our results support the crucial role of KRAS mutational status in pancreatic cancer biology. KRAS mutational status may serve as a prognostic marker. However, its predictive role for targeted therapies remains to be evaluated.

High nuclear poly-(ADP-ribose)-polymerase expression is prognostic of improved survival in pancreatic cancer.

Klauschen F, von Winterfeld M, Stenzinger A, Sinn B V, Budczies J, Kamphues C, Bahra M, Wittschieber D, Weichert W, Striefler J, Riess H, Dietel M & Denkert C 
(2012) Histopathology 61, 409–416

CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial.

Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m2 days 1, 8, 15, every 4 weeks plus erlotinib 100 mg once per day (GemErlo) or gemcitabine (Gem) alone for six cycles. The primary end point of the study was to improve disease-free survival (DFS) from 14 to 18 months by adding erlotinib to gemcitabine. Results In all, 436 patients were randomly assigned at 57 study centers between April 2008 and July 2013. A total of 361 instances (83%) of disease recurrence were observed after a median follow-up of 54 months. Median treatment duration was 22 weeks in both arms. There was no difference in median DFS (GemErlo 11.4 months; Gem 11.4 months) or median overall survival (GemErlo 24.5 months; Gem 26.5 months). There was a trend toward long-term survival in favor of GemErlo (estimated survival after 1, 2, and 5 years for GemErlo was 77%, 53%, and 25% v 79%, 54%, and 20% for Gem, respectively). The occurrence or the grade of rash was not associated with a better survival in the GemErlo arm. Conclusion To the best of our knowledge, CONKO-005 is the first study to investigate the combination of chemotherapy and a targeted therapy in the adjuvant treatment of PDAC. GemErlo for 24 weeks did not improve DFS or overall survival over Gem.

P53 overexpression and Ki67-index are associated with outcome in ductal pancreatic adenocarcinoma with adjuvant gemcitabine treatment

In pancreatic cancer there is a need for prognostic risk stratification and subsequent therapy strategies. Molecular analysis has shown in different cancers that variation in clinical behavior can be associated with specific alterations. The cell cycle regulators p16 and p53 belong to the most often alterated genes in pancreatic ductal adenocarcinoma (PDAC). We analyzed protein expression of p16, p53 and Ki67 by immunohistochemistry in 162 tumours of the CONKO-001 trial that investigated the role of adjuvant gemcitabine in pancreatic cancer patients. We could show that high proliferation of tumours and strong and consistent nuclear p53 expression by tumour cells is associated with a worse disease-free survival and overall survival in the overall study population. However, stratified analysis according to treatment arm revealed that the effect of deregulated p53 expression and high Ki67 expression was restricted to the disease free survival of patients treated with adjuvant gemcitabine. In multivariable survival analysis, p53 did not retain its prognostic status. Our study supports the important role of p53 and Ki67 expression in PDAC. They provide prognostic information in patients with adjuvant gemcitabine treatment and may contribute to treatment decision. However, these results should be validated in further studies.

Early and Late Posttransplant Lymphoproliferative Disorder After Lung Transplantation-34 Cases From the European PTLD Network

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Prognostic significance of DNA cytometry for adjuvant therapy response in pancreatic cancer.

The continuous progress in treatment options for pancreatic adenocarcinoma has lead to a re‐evaluation of prognostic markers. In this study the prognostic relevance of DNA Index and classical histopathological parameters with regard to disease‐free (DFS) and overall survival (OS) was analyzed within the CONKO‐001 patient population.