Mechanism exploration and clinical verification of new integrated markers of capecitabine clinical effect
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ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2698080 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. Here, we assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Good response was associated with 12p12.1 copy number loss, even in patients with a KRAS mutation, while copy number gain in wild-type KRAS patients was correlated with a poor response. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good response. In wild-type KRAS patients, miRNA expression did not predict response in a multivariate model. Thus, assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of patients eligible for anti-EGFR therapy. Copy number detection was performed using NimbleScan and Nexus software Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 metastisized colorectal cancer patients in a phase III trial (CKTO 2005-02; ClinTrials.gov NCT00208546) of the Dutch Colorectal Cancer Group (DCCG), who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab.
2012-01-01 | E-GEOD-32048 | biostudies-arrayexpress
Project description:In this study our aim was to document recurrent DNA copy number aberration associated breakpoints in primary tumors of colorectal cancer patients that ultimately received systemic treatment in the context of metastatic disease. Such data can be used to catalogue copy number aberration associated breakpoints and thereby affected genes. To this end, high quality arrayCGH data set of clinically well annotated colorectal cancer specimens was generated using FFPE tumor samples from patients from two phase III clinical trials, namely CAIRO and CAIRO2. arrayCGH data of colorectal cancers of patients from 2 clinical trials. 108 patients were treated with capecitabine first line, 110 patients were treated with capecitabine and irinotecan first line and 134 patients were treated with capecitabine, oxaliplatin and bevacizumab.
2014-11-14 | E-GEOD-63216 | biostudies-arrayexpress
Project description:KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. Here, we assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Good response was associated with 12p12.1 copy number loss, even in patients with a KRAS mutation, while copy number gain in wild-type KRAS patients was correlated with a poor response. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good response. In wild-type KRAS patients, miRNA expression did not predict response in a multivariate model. Thus, assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of patients eligible for anti-EGFR therapy. Copy number detection was performed using NimbleScan and Nexus software
2012-01-01 | GSE32048 | GEO
Project description:Response rates of 118 colorectal cancer patients to regiments were evaluated by histoculture drug response assay. Affymetrix SNP 6.0 chips were used to determine genotypes of the same colorectal cancer patients. SNPs associated with chemosensitivity to treatment regiments were identified by genome-wide association study. AV: avastin (Bevacizumab), ER: Erbitux (Cetuximab), FXA: bevacizumab + FOLFOX, FXE: Cetuximab + FOLFOX , FRA: Bevacizumab + FOLFIRI, FRE: Cetuximab + FOLFIRI; Numbers (0-100) represent responsiveness to the given drug regimens; the larger, the better responsive to given regimens
2011-03-25 | GSE21228 | GEO
Project description:Response to drug therapy in individual colorectal cancer (CRC) patients is associated with tumor biology. Here we describe the genomic landscape of tumor samples of a homogeneous well-annotated series of patients with metastatic CRC of two phase III clinical trials, CAIRO and CAIRO2. DNA copy number aberrations of 349 patients are determined. Within three treatment arms, 194 chromosomal sub-regions are associated with progression free survival PFS (uncorrected single-test p-values < 0.005). These sub-regions are filtered for effect on mRNA expression, using an independent data set from The Cancer Genome Atlas (TCGA) which returned 171 genes. Three chromosomal regions are associated with a significant difference in PFS between treatment arms with or without irinotecan. One of these regions, 6q16.1-q21, correlates in vitro with sensitivity to SN-38, the active metabolite of irinotecan. This genomic landscape of metastatic CRC reveals a number of DNA copy number aberrations associated with response to drug therapy. aCGH data of colorectal cancers of patients from 2 clinical trials (CAIRO, CAIRO2). 105 patients were treated with capecitabine first line (CAIRO arm A), 111 patients were treated with capecitabine and irinotecan first line (CAIRO arm B), and 133 patients were treated with capecitabine, oxaliplatin and bevacizumab (CAIRO2 arm A).
2014-11-14 | E-GEOD-36864 | biostudies-arrayexpress
Project description:Background: The efficacy of FOLFIRI plus an antiangiogenesis biologic agent as 2nd line therapy for metastatic colorectal adenocarcinoma is limited. TAS-102 is a novel oral antimetabolite with a distinct mechanism of action from fluoropyrimidines. We evaluated the antitumor efficacy of TAS-102, irinotecan and bevacizumab in patients with pre-treated, advanced colorectal adenocarcinoma in a multicenter, phase II, single-arm study. Methods: Patients with advanced colorectal adenocarcinoma who had progressed after oxaliplatin and fluoropyrimidine and were eligible for treatment with bevacizumab were treated with irinotecan, bevacizumab, and TAS-102 in 28-day cycles. The primary endpoint was progression-free survival (PFS). Results: We enrolled 35 evaluable patients. The study was positive. The median PFS was 7.9 (90% CI 6.2-11.8) months (vs. 6 months in historical control, p=0.018). The median overall survival was 16.5 (90% CI 9.8-17.5) months. Sixty-seven percent of patients experienced grade 3 or higher treatment-related adverse events. The most common toxicities were hematological (neutropenia) and gastrointestinal (diarrhea, nausea, and vomiting). Conclusions: Irinotecan, TAS-102 and bevacizumab is an active 2nd line therapy for patients with metastatic colorectal adenocarcinoma. Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard of care therapy is warranted.
2024-08-26 | GSE275628 | GEO
Project description:Objective: Insights about differences in tumor vasculature and how it reacts to VEGF inhibition is limited, but nevertheless of major relevance to anti-angiogenic therapy. In this study we therefore characterize the effect of bevacizumab combined with chemoradiotherapy (CRT), and explore molecular and genetic markers for response prediction to this combination treatment. Material and Methods: In an academic multicentric randomized phase II study, patients with advanced rectal cancer have been treated with bevacizumab (5mg/kg) in combination with capecitabine (1650mg/m2/day) and radiotherapy (45Gy; 1.8Gy/day) with (50mg/m2) or without oxaliplatin prior to surgery. Of 59 patients, tumor tissue and blood samples were collected before treatment and after the first loading dose of bevacizumab but before CRT (week 3). First, cDNA micro-arrays were performed on the biopsies to investigate differences in gene expression of tumors from patients with and without a pathological complete response (pCR) before start of treatment and to identify biological processes affected by bevacizumab delivery. The paraffin embedded tissue was stained for blood vessels (CD31/CD34) combined with α-SMA (pericytes) and CA-IX (hypoxia). To explore candidate blood-based biomarkers ELISA’s were performed for PDGF-AA, PDGF-BB, THBS-1, IL-8, CYR61 and Ang-2. The expression of all markers was correlated with the pathological response of the patients. Results: Differences in tumoral gene expression are observed between patients with and without a pCR, with the first response group presenting a more angiogenic phenotype before start of treatment and changes in angiogenic processes after bevacizumab delivery. One dose of bevacizumab leads to a decrease in the number of pericyte covered blood vessels, a decrease in circulating PDGF-AA, PDGF-BB and Thrombospondin-1. Patients showing a pCR having less pericyte covered blood vessels, more hypoxia, and less circulating PDGF-BB compared to patients who did not have a pCR after bevacizumab treatment with chemoradiation and bevacizumab. Conclusions: The translational data demonstrate that tumors with an angiogenic expression profile respond better to bevacizumab combined with CRT and points towards a possible role for PDGF, CA-IX and pericyte covered blood vessels for the early response prediction to this treatment. Our findings suggest a role for mural cell recruitment and vessel maturation for the susceptibility of the tumor vasculature to bevacizumab treatment. Further validation of our biological observations and hypothesis generating data in randomized trials is needed.
2016-08-02 | GSE60331 | GEO
Project description:Purpose: The DNA Damage Immune Response (DDIR) assay was developed in breast cancer (BC) based on biology associated with deficiencies in homologous recombination and Fanconi Anemia (HR/FA) pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and oesophageal cancers. In colorectal cancer (CRC) there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in CRC and characterised the biology in DDIR-positive CRC. Methods: Samples and clinical data were assessed according to DDIR status from patients who received either 5FU or FOLFOX within the FOCUS trial (n=361, stage 4), or neo-adjuvant FOLFOX in the FOxTROT trial (n=97, stage 2/3). Whole transcriptome, mutation and immunohistochemistry data of these samples were used to interrogate the biology of DDIR in CRC. Results: Contrary to our hypothesis, DDIR negative patients displayed a trend towards improved outcome for oxaliplatin-based chemotherapy compared to DDIR positive patients. DDIR positivity was associated with Microsatellite Instability (MSI) and Colorectal Molecular Subtype 1 (CMS1). Refinement of the DDIR signature, based on overlapping interferon-related chemokine signalling associated with DDIR positivity across CRC and BC cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in CRC. Conclusions: DDIR positivity does not predict improved response following oxaliplatin treatment in CRC. However, data presented here suggests the potential of the DDIR assay in identifying immune-rich tumours that may benefit from immune checkpoint blockade, beyond current use of MSI status.
2020-12-31 | GSE156915 | GEO
Project description:Metastatic colorectal cancer (mCRC) is associated with multiple somatic copy number alterations (SCNAs). We analyzed SCNAs to estimate overall survival (OS) and progression free suvival (PFS) for mCRC patients treated with bevacizumab in combination with oxaliplatin or irinotecan.
2018-11-21 | GSE110785 | GEO
Project description:Clinical outcomes and ctDNA correlates for CAPOX BETR: A phase II trial of capecitabine, oxaliplatin, bevacizumab, trastuzumab in previously untreated advanced HER2+ gastroesophageal adenocarcinoma
| PRJNA1133828 | ENA