Phase II study of cetuximab plus 5-FU/LV for unresectable colorectal cancer
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ABSTRACT:
DISEASE(S): Unresectable Colorectal Cancer
PROVIDER: 2624880 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:5-Fluorouracil (5-Fu) and leucovorin (LV) are often given in combination to treat colorectal cancer. 5-Fu/LV prevents cell proliferation by inhibiting thymidylate synthase, which catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. While 5-Fu has been shown to cause cognitive impairment, the synergistic effect of 5-Fu with LV has not been fully explored. The present investigation was designed to assess how the combination of 5-Fu and LV affect cognition in a murine model. Six-month-old male mice were used in this study; 15 mice received saline injections and 15 mice received 5-Fu/LV injections. One month after treatment, the elevated plus maze, Y-maze, and Morris water maze behavioral tasks were performed. Brains were then extracted, cryosectioned, and stained for CD68 to assay microglial activation and with tomato lectin to assay the vasculature. All animals were able to locate the visible and hidden platform locations in the water maze. However, a significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden-platform training (first probe trial) in animals that received 5-Fu/LV, but these animals showed spatial memory retention by day 5. There were no significant increases in inflammation as measured by CD68, but 5-Fu/LV treatment did modulate blood vessel morphology. Tandem mass tag proteomics analysis identified 6,049 proteins, 7 of which were differentially expressed with a P-value of < 0.05 and a fold change of >1.5. The present data demonstrate that 5-Fu/LV increases anxiety and significantly impairs spatial memory retention.
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Project description:Abstract Background. Epidermal growth factor receptor (EGFR) is a targetable molecule in basal-like breast cancer, which comprises most “triple negative” breast cancer (TNBC), the only breast cancer subtype without established targeted therapy. Methods. In this randomized phase II trial, metastatic TNBC patients received the anti-EGFR antibody cetuximab (250mg/kg/week iv) with carboplatin (AUC2/wk iv) added on progression, or concomitant cetuximab + carboplatin. Molecular subtyping was done on archival specimens and those with accessible tumors provided fresh tissue, before and after 7-14 days of therapy, for microarray analyses to explore EGFR pathway inhibition. Results. Of 102 TNBC patients 74% were of the basal-like molecular subtype. Response rate to cetuximab was 6% (2/31), and was 16% (4/25) to cetuximab + carboplatin after progression. Upfront cetuximab + carboplatin produced responses in 17% (12/71); 31% responded or had prolonged disease stabilization. Time to progression was 2.1 months (95% CI 1.8-5.5) and overall survival 10.4 months (95% CI 7.7-13.1) for those treated with the combination regimen. Among 16 patients with evaluable serial biopsies, genomic patterns of the EGFR pathway showed activated status in 13 and inhibition by therapy in 5. Conclusions. While most TNBC were basal-like, a significant proportion were different subtypes. The aggressive nature of metastatic TNBC leads to limited survival. Despite a promising preclinical rationale and evidence of EGFR pathway activation in most, targeted treatment with cetuximab as a single agent had marginal activity and cetuximab added to carboplatin demonstrated modest activity. Serial biopsies as part of metastatic breast cancer studies are feasible, and this study confirmed that the EGFR pathway was inhibited by therapy in only a minority suggesting ligand-independent activation in most tumors. Tissue acquisition and drug selection based upon individualized pathway activation status should be an important part of future studies of TNBC. This series contains 36 microarrays that are from 18 patients with fresh frozen tissue available from the metastatic site. Pretreatment samples (Bx0) are available for two patients. Pretreatment and post single agent treatment (7-14 days after start of treatment with cetuximab; BxSingle) are available for three patients. Pretreatment and post combination treatment (7-14 days after start of treatment with cetuximab plus carboplatin; BxCombo) are available for eight patients. Two patients have a pretreatment sample, a sample after 7-14 days of treatment with single agent cetuximab, and a third sample 7-14 days on cetuximab plus carboplatin after switching to the combination arm upon progression on the single agent arm. Samples were hybridized with Stratagene common reference spiked with RNA from two breast cancer cell lines (ME16C and MCF-7) on Custom 1x44K Agilent microarrays. Arrays were scanned on an Axon 4000B scanner and analyzed with GenePix Pro software.
2012-07-13 | E-GEOD-23428 | biostudies-arrayexpress
Project description:Primary objectives: To assess whether the rate of best confirmed response of 5-FU/FA plus oxaliplatin plus cetuximab is superior to 5-FU/FA plus oxaliplatin as first-line treatment for epidermal growth factor receptor-expressing metastatic colorectal cancer.
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Project description:Cetuximab is an epidermal growth factor receptor (EGFR)-blocking antibody approved for treatment of metastatic colorectal cancer. We examined differences in global gene expression between the syngeneic DiFi colorectal cancer cells, and a subline of DiFi cells with acquired resistance to cetuximab (DiFi5). We used Affymetrix HG-U133A array to compare the expression pattern of genes that are up-regulated or down-regulated between the parental DiFi colorectal cancer cells and the cetuximab-resistant DiFi5 cells. We generated a cetuximab-resistant DiFi subline, termed DiFi5, by chronic exposure of parental DiFi cells to serially increased doses of cetuximab (from 0.5 nM to 5 nM) for over 1 year. The resulting DiFi5 subline exhibits significant resistance to cetuximab-induced apoptosis. After we confirmed that the phenotype was stable over a period of time of more than 6 months, the RNA from DiFi and DiFi5 cells were extracted and hybridized to an Affymetrix HG-U133A array according to the manufacturerâs instructions. Following the hybridization, the array was scanned using a laser confocal scanner, and microarray image data were analyzed using DNA-Chip Analyzer (dChip), version 1.3, by the Sequencing and Microarray Facility at MD Anderson Cancer Center.
2016-07-17 | E-GEOD-71210 | biostudies-arrayexpress
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| S-EPMC3871512 | biostudies-literature
Project description:Primary objectives: To assess whether the progression-free survival time under 5-FU/FA plus irinotecan plus cetuximab is longer than that under 5-FU/FA plus irinotecan as first-line treatment for epidermal growth factor receptor-expressing metastatic colorectal cancer.
Primary endpoints: Progression free survival
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2012-12-01 | E-GEOD-36790 | biostudies-arrayexpress