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Fredensborg, Denmark

Jorgensen J.T.,Dx Rx Institute
Oncology | Year: 2010

Amplification of the HER2 gene and over-expression of the HER2 protein in gastric cancer have been shown in a large number of studies. HER2 positivity can be detected in approximately 20% of patients, which is a characteristic associated with poor prognosis. Preclinical in vitro and in vivo studies have demonstrated that both trastuzumab and lapatinib are effective in different gastric cancer models and have thus lead to the initiation of clinical studies. In the first phase III study, the ToGA trial, HER2-positive patients with advanced gastroesophageal and gastric adenocarcinoma were randomized to receive 5-fluorouracil/capecitabine and cisplatin either alone or in combination with trastuzumab. A statically significant gain in overall survival was seen in the patients who received the combined treatment of trastuzumab and chemotherapy. It is expected that the encouraging results from the ToGA trial will have an immediate impact on the management of patients and that routine HER2 testing of patients with advanced gastric cancer will be initiated within a relatively short period of time. Copyright © 2010 S. Karger AG.

Jorgensen J.T.,Dx Rx Institute
Expert Review of Molecular Diagnostics | Year: 2016

The immune checkpoint inhibitors pembrolizumab and nivolumab together with their diagnostic assays have recently been granted market authorization for treatment of advanced non-small-cell lung cancer in the USA. The two assays, PD-L1 IHC 22C3 pharmDx and PD-L1 IHC 28-8 pharmDx (both by Dako, Glostrup, Denmark), are the first PD-L1 IHC assays to obtain regulatory approval through the Premarket Approval process. This approval is supported by recent clinical studies that have shown a positive correlation between PD-L1 expression and the outcome following treatment with different PD-1/PD-L1 checkpoint inhibitors. These diagnostic assays are able to identify the group of non-small-cell lung cancer patients who will benefit most from treatment with the immune checkpoint inhibitors. However, so far, it is only the PD-L1 IHC 22C3 pharmDx assay, which is linked to the use of pembrolizumab, that has obtained regulatory status as a companion diagnostic. © 2015 Taylor & Francis.

Jorgensen J.T.,Dx Rx Institute
World Journal of Gastroenterology | Year: 2014

Amplification of the human epid ermal growth factor receptor 2 (HER2) gene and overexpression of the HER2 protein is found in 15%-20% of patients with gastric and gastroesophageal junction cancer. The degree of HER2 overexpression and amplification varies with the location of the carcinoma, with higher expression in the gastroesophageal and proximal parts compared to the distal parts of the stomach. Further, HER2 overexpression and amplification also seems to be related to the Lauren histological classification, with higher levels found in the intestinal phenotype compared to the diffuse and mixed types. The prognostic properties of HER2 overexpression and amplification are still under debate, but a large number of studies seem to indicate that HER2 is a negative prognostic factor. The usefulness of HER2 targeted therapy in gastric cancer was demonstrated in the ToGA trial, where HER2-positive patients with advanced gastric and gastroesophageal junction adenocarcinoma were randomized to receive 5-FU/capecitabine and cisplatin, either alone or in combination with trastuzumab. A statically significant gain in overall survival was seen in patients who received the combined treatment of trastuzumab and chemotherapy. Patients with a strong overexpression of the HER2 protein (IHC3+) specifically benefited from the treatment, with a median overall survival of 17.9 mo. As a consequence of the positive results of the ToGA trial, patients with advanced gastric or gastroesophageal junction adenocarcinoma are now routinely tested for HER2. The ToGA trial must be characterized as a landmark in the treatment of gastric cancer and it has paved the way for a number of new HER2 targeted compounds such as pertuzumab, ado-trastuzumab emtansine, lapatinib, afatinib, and dacomitinib, which are currently undergoing phase and clinical testing. Overall, this review will discuss the current status of HER2 in gastric and gastroesophageal junction cancer and the future direction in relation to HER2 target therapy. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

Winther H.,Dako Denmark | Jorgensen J.T.,Dx Rx Institute
Pharmaceutical Medicine | Year: 2010

Within oncology, companion diagnostics are considered to be of important value as the efficacy rates of anticancer pharmacotherapy in many cases remain low. Both the costs and the consequences of treatment failure are significant. Drug-diagnostic combinations have been known for several decades within oncology and the preselection of patients based on the differences in their biology was practiced as early as the 1970s. In relation to the development of the first companion diagnostic (for the selective estrogen receptor modulator, tamoxifen), an increased efficacy rate was shown in patients identified as expressing high levels of the targeted estrogen receptor. Another drug-diagnostic combination within oncology the humanized monoclonal antibody trastuzumab targeting the human epidermal growth factor receptor 2 (HER2) and the immunohistochemical HER2 assay has become a model for the co-development of a drug and companion diagnostic. In this co-development process, the companion diagnostic development stages closely align to the drug development phases, passing through a Prototype Assay stage, an Analytically Validated Assay stage and ending up as a Clinically Validated Assay. The obvious outcomes of drug-diagnostic co-developments are more effective drugs and hopefully also reduced numbers of patients in the controlled clinical trials. Typically, at least two independent, randomized, phase III trials, both displaying positive results over the current standard treatment, have been applied as a standard for regulatory approval. However, by incorporating companion diagnostics in the clinical trial designs, the numbers of patients in these studies will decrease. The variability in the pathophysiology of the patients will be reflected, and this information is used to identify those patients that are likely to respond to the targeted drug and thereby validate the clinical utility of the companion diagnostic. Studies designed to assess both a diagnostic and a drug can be based on both prospective and retrospective designs. The targeted clinical trial design allows for an increased success rate in the individual drug-diagnostic co-developments by reducing the failure rate, which in turn will reduce development costs and time, and hence increase the probability of therapeutic and registration success. Drug approval authorities such as the US FDA, European Medicines Agency and the State Food and Drug Administration in Japan, are also encouraging greater use of companion diagnostics for drug development. The drug-diagnostic co-development model will be the preferred future way to develop new targeted anticancer drugs, which will be to great benefit for the cancer patients. © 2010 Adis Data Information BV. All rights reserved.

Jorgensen J.T.,Dx Rx Institute | Hersom M.,Copenhagen University
Journal of Cancer | Year: 2012

Through the recent conduct of the ToGA trial, HER2 has shown to be predictive for the treatment with trastuzumab in advanced gastric and gastro-oesophageal cancer. When it comes to the prognostic properties the situation is different. Despite the fact that it is more than 20 years ago since the first studies demonstrating an association between a positive HER2 status and poor prognosis were published the issue is still controversial. In this current systematic review a large number of studies on HER2 and gastric cancer have been reviewed. The studies included in this review should fulfill the following two criteria. First criterion: The number of patients in each study should be ≥ 100, and the HER2 status should have been determined either by immunohistochemistry (IHC) or in situ hybridization (ISH). Second criterion: The selected articles should include an analysis of the association between the HER2 status and survival or relevant clinicopathological characteristics. Forty-two publications with a total of 12,749 patients fulfilled the two criteria and were reviewed in detail. The majority of the publications (71%) showed that a HER2-postive status measured either by IHC or ISH was associated with poor survival and/or clinicopathological characteristics, such as serosal invasion, lymph node metastases, disease stage, or distant metastases. Based on the current analysis a clear trend towards a potential role for HER2 as a negative prognostics factor in gastric cancer was shown, suggesting that HER2 overexpression and/or amplification is a molecular abnormality that might be linked to the development of gastric cancer. © Ivyspring International Publisher.

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