Association of Molecular Markers With Toxicity Outcomes in a Randomized Trial of Chemotherapy for Advanced Colorectal Cancer: The FOCUS Trial

Braun, Michael; Richman, Susan D.; Thompson, Lindsay C; Daly, Catherine; Meade, Angela; Adlard, Julian; Allan, James M.; Parmar, Mahesh; Quirke, Philip; Seymour, Michel

doi:10.1200/jco.2008.21.6283

Cited by 115 publications

(93 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genotypes were determined by polymerase chain reaction (PCR)-based assays (restriction fragment length polymorphism (RFLP) and/or real-time) according to published methods. [11][12][13][14] or as recommended by the manufacturer. Positive and negative controls were included in each reaction as quality control.…”

Section: Genotyping Analysismentioning

confidence: 99%

Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome

et al. 2014

View full text Add to dashboard Cite

The folate metabolism pathway has a crucial role in tumorigenesis as it supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. Despite its importance, little is known about the influence of the folate pathway on gastrointestinal stromal tumour (GIST), a rare tumour with an incidence ranging between 6 and 19.6 cases per million worldwide. The importance of folate metabolism led us to investigate the influence of polymorphisms in the genes coding folate-metabolising enzymes on GIST susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 13 polymorphisms in 8 genes in 60 cases and 153 controls. The TS 6-bp deletion allele (formerly rs34489327, delTInsTTAAAG) was associated with reduced risk of GIST (OR = 0.20, 95% CI 0.05-0.67, P = 0.0032). Selected polymorphisms in patients stratified by age, gender, and other main molecular and clinical characteristics showed that few genotypes may show a likely correlation. We also observed a significant association between the RFC AA/AG genotype and time to progression (HR = 0.107, 95% CI 0.014-0.82; P = 0.032). Furthermore, we observed a tendency towards an association between the SHMT1 variant allele (TT, rs1979277) and early death (HR = 4.53, 95% CI 0.77-26.58, P = 0.087). Aware of the strengths and limitations of the study, these results suggest that polymorphisms may modify the risk of GIST and clinical outcome, pointing to the necessity for further investigations with information on folate plasma levels and a larger study population. INTRODUCTIONFolate metabolism supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. DNA methylation status is essential for normal development and maintenance of cellular homeostasis and functions in adult organisms, including silencing of repetitive DNA elements, proper expression of genetic information and maintenance of genomic structural integrity. 1 The accurate maintenance of DNA synthesis, repair, and methylation patterns is fundamental, and its balance in mature cells is maintained by the concerted action of more than 30 enzymes. 2 These enzymes are highly polymorphic, and several functional genetic polymorphisms have been attracting research interest, as they may be responsible for altered DNA synthesis, repair and methylation processes, all of which are crucial in relation to carcinogenesis. Aberrant methylation patterns have been associated with various diseases including cancer and neurodegenerative diseases. 3,4 In addition, polymorphisms in genes involved in the folate metabolisms have been associated with cancer risk, including colorectal and gastric cancer, vascular disease, depression, and Down's syndrome. 5 Currently, there are evidences of an association between DNA methylation level and polymorphisms in folate metabolism genes. 6,7

show abstract

Section: Genotyping Analysismentioning

confidence: 99%

Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Differences in toxicities experienced and responses in patients who have received the same chemotherapy agent or regimen are commonly observed [10,11], and these are likely to be a result of polymorphic genetic variation in genes involved in drug metabolism and DNA repair and apoptosis [5,12]. Recently, numerous clinical studies have elucidated that genes involved in drug transportation, drug metabolism, DNA repair, and apoptosis may modulate platinum-based chemotherapeutic efficacy and drug-related toxicity outcomes [13,14]. Therefore, the identification of genetic markers may enable us to predict the toxicity outcome with platinum-based chemotherapy and select optimal regimens for personalized therapy.…”

Section: Introductionmentioning

confidence: 99%

Association Between CASP8 and CASP10 Polymorphisms and Toxicity Outcomes With Platinum-Based Chemotherapy in Chinese Patients With Non-Small Cell Lung Cancer

Qian

Yang

et al. 2012

The Oncologist

View full text Add to dashboard Cite

Caspase-8 and caspase-10 play crucial roles in both cancer development and chemotherapy efficacy. In this study, we aimed to comprehensively assess single nucleotide polymorphisms (SNPs) of the caspase-8 (CASP8) and caspase-10 (CASP10) genes in relation to toxicity outcomes with first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 13 tag SNPs of CASP8 and CASP10 in 663 patients with advanced NSCLC treated with platinum-based chemotherapy regimens. Associations between SNPs and chemotherapy toxicity outcomes were identified in a discovery set of 279 patients and then validated in an independent set of 384 patients. In both the discovery and validation sets, variant homozygotes of CASP8 rs12990906 and heterozygotes of CASP8 rs3769827 and CASP10 rs11674246 and rs3731714 had a significantly lower risk for severe toxicity overall. However, only the association with the rs12990906 variant was replicated in the validation set for hematological toxicity risk. In a stratified analysis, we found that some other SNPs, including

show abstract

“…A recent meta-analysis reported that although the toxicity relationships were much stronger with the UGT1A1 Ã 28 homozygous variant, associations were also found with the UGT1A1 Ã 28 heterozygous variant (21). At least three prospective randomized phase III trials (22)(23)(24), however, did not confirm these initial results, suggesting that the influence of the UGT1A1 Ã 28 allele on the toxicity of irinotecan is modest and that its assessment should not be mandatory in routine clinical practice (23).…”

Section: Discussionmentioning

confidence: 63%

High-Dose FOLFIRI plus Bevacizumab in the Treatment of Metastatic Colorectal Cancer Patients with Two Different UGT1A1 Genotypes: FFCD 0504 Study

Manfrédi

Bouché

Rougier

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

High-dose FOLFIRI has an acceptable safety profile and promising efficacy. UDP-glucuronosyltransferase: (UGT1A1) polymorphism may be predictive of toxicity and efficacy of irinotecan. This phase II study aimed to evaluate the combination of high-dose FOLFIRI plus bevacizumab in patients with previously untreated metastatic colorectal cancer (MCRC) based on their UGT1A1 genotype. Patients with the UGT1A1 Ã 1/ Ã 1 (group 1) or Ã 1/ Ã 28 (group 2) genotype received bevacizumab plus high-dose FOLFIRI every 2 weeks. Using the Bryant and Day design with objective response rate and toxicity as the primary endpoints, 54 patients in each group were required with a planned interim analysis after inclusion of 17 patients per group. We planned to stop the trial at the interim analysis if 7 patients exhibited an objective response (OR) and/or !3 patients exhibited severe toxicity. At the interim analysis, ORs were higher than the number expected: 52.9% (group 1) and 58.8%

show abstract

Association of Molecular Markers With Toxicity Outcomes in a Randomized Trial of Chemotherapy for Advanced Colorectal Cancer: The FOCUS Trial

Abstract: These results do not support the routine clinical use of the evaluated polymorphisms, including UGT1A1*28. Further investigation of XRCC1, ERCC2, and GSTP1 as potential predictors of irinotecan toxicity is warranted.

Cited by 115 publications

References 31 publications

Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome

Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome

Association Between CASP8 and CASP10 Polymorphisms and Toxicity Outcomes With Platinum-Based Chemotherapy in Chinese Patients With Non-Small Cell Lung Cancer

High-Dose FOLFIRI plus Bevacizumab in the Treatment of Metastatic Colorectal Cancer Patients with Two Different UGT1A1 Genotypes: FFCD 0504 Study

Contact Info

Product

Resources

About