German Clinical Trials Register

Acronym/abbreviation of the study

Opposite II: REDESIGN study

URL of the study

No Entry

Brief summary in lay language

Gastric cancer is the third leading cause of tumor-related deaths worldwide. In Western countries, the majority of diagnoses are made at locally advanced or metastatic tumor stage. Since the publication of the landmark MAGIC study, perioperative chemotherapy has been the standard of care for patients with resectable, locally advanced tumors. Modern combination therapies such as the FLOT regimen have led to further improvement in prognosis. Nevertheless, the majority of patients relapse after initial curative therapy and die of the disease. A clear histologic response after neoadjuvant therapy, defined as <10% vital tumor cells in the primarius, is observed in approximately 30% of patients. Individualization of perioperative therapy based on molecularly defined subgroups has not yet been established.

Brief summary in scientific language

1.1 Therapy of locally advanced, resectable gastric carcinoma Gastric carcinoma is the third leading cause of tumor-related deaths worldwide. In Western countries, the majority of diagnoses are made at locally advanced or metastatic tumor stage. Since the publication of the landmark MAGIC study, perioperative chemotherapy has been the standard of care for patients with resectable, locally advanced tumors. Modern combination therapies such as the FLOT regimen have led to further improvement in prognosis. Nevertheless, the majority of patients relapse after initial curative therapy and die of the disease. A clear histologic response after neoadjuvant therapy, defined as <10% of vital tumor cells in the primarius, is observed in approximately 30% of patients. Individualization of perioperative therapy based on molecularly defined subgroups has not yet been established. After recurrence, only palliative therapy is considered in the vast majority of patients, with median survival of patients with metastatic disease being only about 11-13 months, and about 16 months in patients with HER-2 overexpressing tumors with additional administration of trastuzumab. 1.2 Individualization of gastric cancer therapy With the application of modern taxane-containing chemotherapy regimens, a good response is observed in about 30% of patients receiving neoadjuvant therapy. increase in this rate with cytostatic-only therapy seems unlikely. In addition to the group of HER-2 overexpressing tumors, no molecularly defined subgroups exist to date, for which an approved targeted therapy is available. Numerous targeted agents, such as EGFR antibodies, mTOR inhibitors or cMET antibodies did not provide a survival benefit over standard cytostatic therapy in unselected patient populations in phase III trials. 1.3 Development of resistance during therapy Many targeted therapies, as well as cytotoxic therapies, often lead to a short-lived response followed by relapse, which usually occurs within one year, as the selective pressure of the therapy increases the outgrowth of resistant tumor cells. Two different mechanisms are First, intratumoral heterogeneity (ITH): subpopulations within the tumor exhibit intrinsic within the tumor exhibit intrinsic (=primary) resistance (e.g., specific RAS- mutations that prevent effective anti-EGFR-based therapies). Second, tumor cells develop tumor cells through higher mutagenesis rates or other adaptive mechanisms escape mechanisms to evade the effect of therapy (=secondary resistance). Spatial and longitudinal biopsies of tumor samples are critical to capture the complexity and dynamics of ITH and tumor plasticity under treatment. For colorectal cancer, it has been shown that research on ITH based on patient-derived organoids (PDOs) of colon carcinomas is able to reveal subclone-specific differences in response to treatment. Longitudinal analyses in patients are difficult to obtain due to organizational difficulties and ethical concerns regarding the multiple biopsies required. Here, PDOs can be a valuable tool to capture clonal evolution under therapy and to model treatment-related escape mechanisms. A better understanding of molecular changes in gastric cancer under treatment pressure could possibly predict therapy resistance in an individual patient in the future. This would allow the identification of preventive strategies or the development of adapted, coordinated therapies, to overcome the emerging resistance, ideally while the patient is still receiving an effective therapy. 1.4 Organoids Organoids represent a novel innovative cell culture method that allows the outgrowth of organ-specific stem cells. The method has been further developed and now also allows the outgrowth of cancer stem cells from primary tumors into PDOs. In a next step, PDO biobanks were established, which then allow, among other things, high-throughput drug screenings on PDOs. A PDO biobank of human gastric cancer patients, which reflects the heterogeneity of the disease and allows screening of therapeutics, was established by AG Stange at the University Hospital Dresden and other groups (Han et al. established. Preliminary results from the Opposite study (ClinicalTrials.gov Identifier: NCT03429816; EK Dresden #169052018) indicate that gastric cancer PDOs can be used to predict response to FLOT therapy. Thus, this technology also appears to be useful for predicting the development of resistance under FLOT therapy.