Multifactorial pharmacogenetic analysis in colorectal cancer patients receiving 5-fluorouracil-based therapy together with cetuximab-irinotecan.

Aim: To examine the predictive value of gene polymorphisms potentially linked to toxicity, clinical response, time to progression and overall survival, following cetuximab-tegafur-uracil (UFT)-irinotecan therapy.

Methods: Fifty-two patients with advanced colorectal cancer were enrolled in an ancillary pharmacogenetic study of the phase II CETUFTIRI trial. Treatment consisted of 21 day cycles of cetuximab (day 1-day 8-day 15, 250 mg m(-2) week(-1) following a 400 mg m(-2) initial dose) together with irinotecan (day 1, 250 mg m(-2)) and UFT-folinic acid (days 1-14, 250 mg m(-2) day(-1) UFT, 90 mg day(-1) folinic acid).

Epidermal growth factor receptor protein detection in head and neck cancer patients: a many-faceted picture.

Purpose: Epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). Despite intensive biomarker studies, a consensual method for assessing EGFR protein expression is still lacking. Here we set out to compare three EGFR detection methods in tumor specimens from HNSCC patients.

Prospective analysis of the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-based therapy in metastatic breast cancer patients.

What Is Already Known About This Subject: • Functional polymorphisms on the VEGF-A gene, known to be linked to cancer risk or to VEGF-A plasma concentrations, have been identified. So far, limited knowledge has been published on the relationships between toxicity/efficacy of bevacizumab-based therapy and VEGF-A polymorphisms (tumoral DNA). We therefore prospectively tested the impact of these five gene polymorphisms (blood DNA) on the pharmacodynamics of bevacizumab-based treatment administered in metastatic breast cancer patients.

Erlotinib in combination with capecitabine (5'dFUR) in resistant pancreatic cancer cell lines.

The combination of capecitabine and the tyrosine kinase inhibitor erlotinib has recently been tested in patients with gemcitabine-refractory pancreatic tumors, with limited success. To understand this lack of efficacy, we studied the molecular effects of these agents in Capan-1 and Capan-2 human pancreatic resistant cancer cells. Erlotinib up-regulated thymidine phosphorylase (+50%) and downregulated dihydropyrimidine dehydrogenase (+55%) in a cell-dependent manner, thus suggesting that the combination should result in synergism.

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients.

What Is Already Known About This Subject: * Numerous clinical studies, including a few prospective ones, have reported conflicting results on the impact of gene polymorphisms related to fluorouracil (FU) and oxaliplatin pharmacodynamics.

What This Study Adds: * This prospective study is the first to report that clinical response to FOLFOX is significantly related to methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (677C-->T and 1298A-->C), with a response rate of 37, 53, 63 and 80% in patients harbouring no, one, two or three favourable MTHFR alleles, respectively. * Only polymorphisms of genes related to oxaliplatin pharmacodynamics (GSTpi 105Ile-->Val and XPD 751Ly-->Gln) influenced progression-free survival.

Influence of the VEGF-A 936C>T germinal polymorphism on tumoral VEGF expression in head and neck cancer.

Aims: Elevated tumoral vascular endothelial growth factor A (VEGF-A) expression is linked to poor survival in head and neck cancer patients. The aim of the present study was to analyze the influence of VEGF-A gene polymorphisms on tumoral VEGF-A expression and to test their prognostic value in head and neck cancer patients.

Materials & Methods: VEGF-A polymorphisms at position -2578C>A, -1498T>C, -1154G>A, -634G>C and 936C>T were analyzed (PCR-RFLP) in tumoral DNA, along with tumoral VEGF-A expression (ELISA), in 49 Caucasian head and neck cancer patients.

K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy.

Purpose: K-Ras mutations predict resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. Because combinations of anti-EGFR with 5-fluorouracil (5-FU)-based chemotherapy are promising treatments, we analyzed the effect of K-Ras mutations in patients having received exclusive 5-FU therapy.

Experimental Design: This study was conducted on 93 stage IV colorectal cancer patients with unresectable measurable liver metastasis receiving 5-FU-leucovorin (56 men and 37 women; 77 cancer deaths).

Epidermal growth factor receptor (EGFR) status and K-Ras mutations in colorectal cancer.

Background: In advanced colorectal cancer, K-Ras somatic mutations predict resistance to mAbs targeting epidermal growth factor receptor (EGFR). Relationships between K-Ras mutations and EGFR status have not been examined so far. We analyzed relationships between K-Ras mutations and EGFR tumoral status based on EGFR germinal polymorphisms, gene copy number and expression.

Candidate mechanisms for capecitabine-related hand-foot syndrome.

Aims: The oral fluoropyrimidine prodrug capecitabine is widely used in oncology. Capecitabine was designed to generate 5FU via the thymidine phosphorylase (TP) enzyme, preferentially expressed in tumoral tissues. Hand-foot syndrome (HFS) is a limiting toxicity of capecitabine.

Methylenetetrahydrofolate reductase (MTHFR) variants and fluorouracil-based treatments in colorectal cancer.

5-fluorouracil (5FU)-based treatments remain the main chemotherapy for colorectal cancer. Optimal cytotoxicity of fluoropyrimidines requires elevated CH(2)FH(4) tumoral concentrations, controlled by the methylenetetrahydrofolate reductase (MTHFR) enzyme, which irreversibly converts CH(2)FH(4) into 5-methyltetrahydrofolate. The MTHFR gene is subject to several polymorphisms, of which the 677C>T and 1298A>C SNPs are the two most commonly linked with altered enzyme activity.

Dihydropyrimidine dehydrogenase activity and the IVS14+1G>A mutation in patients developing 5FU-related toxicity.

Aims: To examine retrospectively the relationship between DPD phenotype/genotype and the intensity of 5FU toxicity.

Methods: One hundred and thirty-one case-reports (81 women, 50 men) with 5FU-related toxicity were analyzed.

Results: The lower the DPD activity (10-504 pmol min(-1) mg(-1)), the higher the toxicity grade was scored (P < 0.

Pharmacogenetics of capecitabine in advanced breast cancer patients.

Purpose: Germinal gene polymorphisms can explain a part of the interpatient pharmacodynamic variability of anticancer drugs, particularly fluoropyrimidines. Genes for which polymorphisms may potentially influence pharmacodynamics of fluoropyrimidines, including capecitabine, are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD).

Experimental Design: The aim of this prospective pilot study was to analyze the effect of TS, MTHFR, and DPD gene polymorphisms on toxicity and efficacy in advanced breast cancer patients receiving capecitabine as monotherapy.

EGFR in colorectal cancer: more than a simple receptor.

Background: Advances in the understanding of tumor biology have led to the development of targeted therapies allowing progress in colorectal cancer treatment. One of the most promising targets is the epidermal growth factor receptor (EGFR).

Method: The presence and distribution of high- and low-affinity EGFR was investigated retrospectively in a group of 82 colorectal cancer samples (43 normal colon-colon cancer paired samples) using a specific ligand binding assay (Scatchard Analysis).

Analysis of the dinucleotide repeat polymorphism in the epidermal growth factor receptor (EGFR) gene in head and neck cancer patients.

Background: Epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in head and neck cancer. The first intron of EGFR gene is polymorphic (9-23 CA repeats) and transcription declines when the number of repeats increases.

Patients And Methods: EGFR polymorphism (fluorescent genotyping) and expression (ligand-binding assay) were analyzed in tumors and normal tissues from 112 patients (100 men, 12 women; mean age 60 years).

Prognostic impact of the epidermal growth factor receptor levels for patients with larynx and hypopharynx cancer.

The aim of this study was to analyse prognostic factors for disease free interval (DFI) and overall survival (OS) among patients with larynx and hypopharynx cancer requiring a total laryngectomy. Three groups of patients were studied according to the type of treatment they received. Fifty-eight patients had total laryngectomy, 71 patients had organ preservation treatment including induction chemotherapy followed by exclusive radiotherapy, 26 patients received induction chemotherapy followed by salvage total laryngectomy.

Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients.

Methylenetetrahydrofolate reductase (MTHFR) controls intracellular CH2FH4 concentrations (required for optimal fluoropyrimidine efficacy) by irreversibly converting CH2FH4 into 5-methyltetrahydrofolate. MTHFR 677C>T and 1298A>C polymorphisms are linked to altered enzyme activity. Thus, mutated MTHFR tumours should, in theory, be more sensitive to 5-fluorouracil (5FU) than wild-type tumours.

Molecular mechanisms underlying the interaction between ZD1839 ('Iressa') and cisplatin/5-fluorouracil.

ZD1839 ('Iressa'), an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is currently being investigated in clinical trials as a treatment for cancer. 'Iressa' is a trademark of the AstraZeneca group of companies. We have previously demonstrated a synergistic interaction between ZD1839 and cisplatin/5-fluorouracil (5FU) in CAL33, a human head and neck cancer cell line that markedly expresses EGFR.

Dihydropyrimidine dehydrogenase circadian rhythm in mouse liver: comparison between enzyme activity and gene expression.

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluorouracil (FU) catabolism. The relevance of the measurement of DPD activity for identifying DPD-deficient patients is lessened by circadian variability in DPD activity. Our purpose was to determine whether or not DPD mRNA is sustained by a circadian rhythm.

[A platypnea-orthodeoxia syndrome].

We report the case of a 68 years old patient with platypnea orthodeoxia syndrome who has been clinically suspected on cutaneous saturation position's variation. It has been confirmed by transthoracic and transesophageal echocardiography (TEE). TEE showed the size of patent foramen ovale (PFO), visualised the right to left shunt.

Prognostic value of tumoral thymidylate synthase and p53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy: phenotypic and genotypic analyses.

Purpose: The aim of this multicenter prospective study was to evaluate the role of intratumoral parameters related to fluorouracil (FU) sensitivity in 103 metastatic colorectal cancer patients receiving FU-folinic acid.

Patients And Methods: Liver metastatic biopsy specimens were obtained for all patients and primary tumor biopsy specimens for 54 patients. Thymidylate synthase (TS), folylpolyglutamate synthetase, and dihydropyrimidine dehydrogenase were measured by radioenzymatic assays; TS promoter polymorphism (2R/2R v 2R/3R v 3R/3R) was determined by polymerase chain reaction; and p53 protein and mutations were analyzed by immunoluminometric assay and denaturing gradient gel electrophoresis, respectively.

The relationship of epidermal growth factor receptor levels to the prognosis of unresectable pharyngeal cancer patients treated by chemo-radiotherapy.

The aim of this study was to analyse prognostic factors for time to treatment failure (TTF) and overall survival (OS) in patients with unresectable cancer of the pharynx. A twice daily (b.i.

Epidermal growth factor receptor expression in 780 breast cancer patients: a reappraisal of the prognostic value based on an eight-year median follow-up.

Purpose: Because new therapeutic approaches target tumors expressing epidermal growth factor receptor (EGFR), the aim was to undertake a thorough analysis of the expression profile of EGFR in breast cancer and to reassess its prognostic value.

Patients And Methods: Tumor EGFR levels were determined by a specific ligand binding assay in 780 consecutive breast cancer patients followed in our institute between 1980 and 1993. Mean age was 61 years (25-85 years).

P53 determination alongside classical prognostic factors in node-negative breast cancer: an evaluation at more than 10-year follow-up.

Background: There is heterogeneity of methods and conflicting results concerning the prognostic value of p53 in node-negative breast cancer. The clinical value of a quantitative method for measuring tumoralp53 content still needs to be evaluated.

Patients And Methods: A long-term retrospective study was conducted on 297 node-negative patients with a median follow-up greater than 10 years (11 years, 101-172 months).

Application of an original RT-PCR-ELISA multiplex assay for MDR1 and MRP, along with p53 determination in node-positive breast cancer patients.

The long-term prognostic value of tumoural MDR1 and MRP, along with p53 and other classical parameters, was analysed on 85 node-positive breast cancer patients receiving anthracycline-based adjuvant therapy. All patients underwent tumour resection plus irradiation and adjuvant chemotherapy (the majority receiving fluorouracil-epirubicin-cyclophosphamide). Median follow-up for the 54 alive patients was 7.