MESH: A Non-Randomised Phase II Trial of Methotrexate in Metastatic Colorectal Cancer with MSH2 Deficiency
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ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Metastatic Colorectal Cancer Resistanct To Standard Chemotherapy With Evidence Of Deficiency Of The Mismatch Repair Gene Msh2, Either On Immunohistochemistry Of Tumour Histology Or On Testing Of Peripheral Blood For A Germline Mutation In Msh2
PROVIDER: 2523875 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:To assess the efficacy of methotrexate in a genetically selected population of patients with advanced colorectal cancer, who have loss of a particular gene, MSH2. The efficacy of methotrexate will be evaluated by the proportion of cases that have a significant response to treatment (objective response rate).
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Project description:We hypothesised that in esophagogastric junction adenocarcinomas combining molecular predictive biomarkers with FDG-PET would optimise response prediction. Changes in FDG uptake in tumours meaured by PET scans after 14 days of chemotherapy define metabolic responders and non-responders. However while <5% of metabolic non-responders will go onto have a response to the full 9-12 week chemotherapy protocol providing a high negative predictive value for FDG-PET, the positive predictive value of metabolic response is more limited. Only 50% of those patients that have a metabolic response determined by FDG PET at day 14 will go on to subsequently have a response to the full 9-12 week chemotherapy protocol . We used global gene expression profiling to identify molecular biomarkers that when combined with FDG-PET would improve predictive accuracy, in particular we aimed to identify molecular biomarkers that could sub-classify FDG PET defined metabolic responders into those that did and did not subsequently go on to have a radiological response and hence clinical benefit from the full chemotherapy protocol. Patients with stage IB-IV esophagogastric junction adenocarcinomas(n=28) received platinum combination chemotherapy .FDG-PET CT scans were performed at baseline and day 14 and expression profiling (Affymetrix ST1.0 Exon Genechips) on baseline tumour biopsies. 14 patients were classified as FDG-PET metabolic responders and gene expression was analysed in these tumour specimens to determine differences between those that did subsequently go on to have a radiological response (n=10) or did not have a radiological response (n=4) to the full 9-12 week chemotherapy protocol. A tissue microarray(n=154 esophagogastric adenocarcinomas who underwent surgery+/-neoadjuvant chemotherapy)was used with immunohistochemistry for qualification of gene expression profiling results. Radiological response was assessed after 3or4 cycles of chemotherapy by RECISTv1.1.
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Project description:We report the results of a molecular study in thirty-seven cases of gliomatosis cerebri, correlating these results with prognosis. The well-known prognostic factors of gliomas, i.e., age, KPS, histology (Grade 2 vs. 3), or contrast enhancement, was predictive of response or outcome only in a percentage of patients but not in all patients. We identified an 8 miRNA signature able to predict patient prognosis with microarray gene expression profiling. The 8 gene features were used to built a prediction method able to distinguish patients with good prognosis (more likely to be responsive to therapy) from patients with a poor prognosis (less likely to be responsive to therapy). Keywords: miRNA expression profile Fifty-nine patients, between 12- and 73-years-old, with clinical signs of increased intracranial pressure were admitted to our institutions between January 2000 to September 2005. Pre-operative neuroradiological studies (CT scan and MRI) showed diffuse infiltrative processes involving more than two different lobes, no identifiable focal mass, and contrast enhancement absent or less than 1 cm in diameter. Written informed consent and tumour DNA were obtained for molecular analysis. Other eligibility criteria included a Karnofsky Performance Scale index (KPS) >50, normal bone marrow function (white blood cell count >3.0X109/l, neutrophil count >1.5X109/l, platelet count >100X109/l, and haemoglobin >10g/dL), normal liver function (aspartate aminotransferase or alanine aminotransferase <2 times the upper limit of laboratory normal, normal bilirubin, and alkaline phosphatase < 2 times the upper limit of normal), and normal renal function (serum creatinine <1.5 mg/dL). The patients received chemotherapy with temozolamide and radiotherapy. The TMZ schedule consisted of 150 to 200 mg/m2 was orally administered once daily on days 1 to 5. Treatment cycles were repeated every 28 days, with a maximum of 24 months. All patients had a monthly neurological and performance status evaluation and a radiological (MRI) evaluation every 2 to 3 months. Responses were evaluated according to previously described criteria (8): a clinical response was defined as an improvement of a neurological deficit or cognitive function evaluated by Mini-Mental Status Examination, an improvement of at least 75% in seizure frequency, or the disappearance of intracranial hypertension. When radiological MRI scans showed a reduction of more than 50% in the hyper intense area it was considered a partial response (PR), and a <50% regression or an objective regression of mass effect, was considered a minor response (MR). Disease was considered as stable when no clinical or radiological changes were seen for at least 6 months, whereas neurological deterioration, a need to increase corticosteroids, or evidence of tumour progression on MRI (an increase in the T2 or the appearance of contrast enhancement) indicated tumour progression.
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