so known for anti EGFR and anti VEGF drugs. Therefore, it is also unlikely that the combination of trastuzumab and cetuximab will show synergistic effects in human Nelarabine pancreatic cancer as suggested by a xenograft mouse model. There may be downstream signalling events involved in non responsiveness to trastuzumab such as RAF, PI3K including the presence of k ras mutations, which can be found in 60 70% of pancreatic cancer patients. In addition, IGF and or TGFb signalling may overcome the effect of HER2 targeting. Additional, tumour associated fibroblasts and stromal development may counteract the effect of chemotherapy including targeted therapy. The heterogeneous and complex biology of pancreatic cancer or some specific tumour stroma interaction, in a cancer with a strong desmoplastic environment, might are some reasons why many chemotherapy regimens containing an anti growth factor inhibitor failed to significantly improve OS.
According Raf Inhibitors to recent reports one promising way to overcome chemotherapy resistance in pancreatic cancer is to focus on the tumour environment and tumour stem cells. There are limitations of this study. First, we miscalculated the needed study sites for rapid patient recruitment as shown by Bang et al for gastric cancer. Therefore, the study had to be closed prematurely. Second, erroneous we did not perform FISH for IHC þ3 HER2 expressing tumours prospectively. Relying on the data found for breast, colon and biliary cancer we assumed HER2 amplification in þ3 HER2 expressing tumours.
Third, there was no control group comparing anti HER2 treatment with conventional chemotherapy because the study gsk3b inhibitor was designed as a two step phase II study. This way testing chemotherapy regiments with only a few study sites does not fit for biomarker guided trials studying targeted therapy applicable to 10 20% of patients. Despite these limitations, we can conclude that IHC þ2 and þ3 HER2 expression is present in about 25% but HER2 gene amplification in only 4% of patients with pancreatic cancer. Even in patients with HER2 amplifying tumours, the combination chemotherapy with trastuzumab and capecitabine does not result in improved PFS and OS compared with historical gemcitabine or capecitabine alone. According to these results we do not recommend further evaluation of anti HER2 treatment in patients with metastatic pancreatic cancer.
The oral fluoropyrimidine capecitabine is an established therapy in metastatic breast cancer, either alone or in combination with chemotherapeutic or biological agents. Capecitabine was initially evaluated as monotherapy in pretreated MBC, buy Nepafenac showing consistent activity in phase II and III trials.1 7 Increasingly, capecitabine is used in the first line setting,8 where it has demonstrated good efficacy and tolerability.9,10 In this review article, introspection we will focus on data for capecitabine in combination with the anti angiogenic agent bevacizumab.Until recently, bevacizumab was approved in Europe as first line therapy for HER2 negative MBC in combination with either paclitaxel or docetaxel, but in March 2011 it was announced that the indication in combination with docetaxel has been withdrawn by the European Commission.14 In a third phase III trial, Regimens In Bevacizumab for Breast .