Clinical implications of genetic polymorphisms on stomach cancer drug therapy

Toffoli, Giuseppe; Cecchin, Erika

doi:10.1038/sj.tpj.6500405

Cited by 5 publications

(5 citation statements)

References 38 publications

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“…In recent years, it has become clear that a pharmacogenic approach is a potential tool for optimizing treatment for several human tumors [24]. The ability of genetic polymorphisms to influence pharmacogenetics of 5-FU, platinum derivatives, anthracyclines, irinotecan, and docetaxel in gastric cancer has been reported.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Factors of Second and Third Line Chemotherapy Using 5-FU with Platinum, Irinotecan, and Taxane for Advanced Gastric Cancer

et al. 2011

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PurposeThe aims of this study are to find out whether the sequence of chemotherapeutic regimens including second- and third-line taxane and irinotecan influences the survival of patients with unresectable gastric carcinoma and to identify clinical characteristics of patients with improved response.Materials and MethodsFifty gastric carcinoma patients who were treated by third-line sequential chemotherapy between November 2004 and July 2010 were enrolled in this study. Their overall survival (OS) and time to progression (TTP) were set up as primary and secondary end points. For the sequence of chemotherapy regimen, two arms were used. Arm A was defined as 5-fluorouracil (5-FU)+cisplatin (FP) or folinic acid, 5-FU and oxaliplati (FOLFOX), followed by folinic acid, 5-FU and irinotecan (FOLFIRI), and paclitaxel or docetaxel plus 5-FU, with or without epirubicin. Arm B was defined as FP or FOLFOX, followed by paclitaxel or docetaxel plus 5-FU, and FOLFIRI.ResultsThe median OS of all patients was 16.0 months (95% confidence interval, 13.6 to 18.3 months), which is longer than historical control of patients who did not receive third-line chemotherapy. The sequence of second and third-line regimen, including irinotecan and taxane, did not present significant difference in OS or TTP after failure of 5-FU with platinum chemotherapy. In survival analysis of patients' clinicopathologic characteristics, poor prognosis was shown in patients with poorly differentiated histologic features, elevated serum carcinoembryonic level, and shorter TTP of first line chemotherapy.ConclusionIt is possible for patients to respond differently to chemotherapy due to differences in clinical features and underlying gene expression profiles. Development of individualized chemotherapy regimens based on gene expression profiles is warranted.

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Section: Discussionmentioning

confidence: 99%

Prognostic Factors of Second and Third Line Chemotherapy Using 5-FU with Platinum, Irinotecan, and Taxane for Advanced Gastric Cancer

et al. 2011

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“…At least 30 different genetic variants of DPYD that result in functional changes in DPD enzyme activity have been identified to date. The most common polymorphic variant associated with DPD deficiency is a splice-site mutation, IV14 + 1G>A (also referred to as DPYD*2A), located on the exon 14-flanking region and causing skipping of 165 base pairs (bp) [55,56]. The frequency of null enzyme activity is very low at <1%, while about 5% have intermediate/deficient enzyme activity [57].…”

Section: Pharmacogenetic Implicationsmentioning

confidence: 99%

“…Given that many cancer centers have employed next-generation sequencing protocols of primarily somatic DNA, but also matched normal Importantly, other pharmacogenetic associations exist that may influence 5-FU activity, including thymidylate synthase (TYMS). TYMS, the gene coding for TS (the primary target of 5-FU), contains 28-bp tandem repeat units found in the 5ʹ untranslated region (UTR) and acts as an enhancer to the TYMS promoter [55,56]. Data suggests that low TYMS expression induced by TYMS 2 R (two repeats) or the 6-bp deletion in the TYMS 3ʹ-UTR increases the cytotoxic effects of 5-FU, whereas high expression induced by TYMS 3R (three repeats) or 6-bp insertion in the 3ʹ-UTR decreases 5-FU efficacy [56].…”

Section: Expert Commentarymentioning

confidence: 99%

“…(3) Due to the KRAS mutation, bevacizumab is favored over cetuximab or panitumumab; due to the UGT1A1 variation and increased risk of irinotecan-induced toxicity [55] (4) , oxaliplatin is favored over irinotecan; and, given the DPYD variation, a reduced dose of 5-FU is recommended by CPIC guidelines (as part of mFOLFOX6 plus bevacizumab regimen). (5) A blood sample is obtained at steady state during the 5-FU continuous infusion; results demonstrate a supratherapeutic AUC of 33 mg·h/l.…”

Section: Expert Commentarymentioning

confidence: 99%

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Personalizing fluoropyrimidine administration in colorectal cancer patients

Patel

Fong

2016

Expert Review of Precision Medicine and Drug Development

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Introduction: Fluoropyrimidines have been a critical component to chemotherapy regimens to treat locally advanced and metastatic colorectal cancer since the 1950s. Clinicians should be aware of the methods that exist to personalize fluoropyrimidine administration to increase efficacy and reduce toxicity. Areas covered: The development of different administration methods (e.g. bolus versus continuous infusion, oral formulations) have advanced the clinical utility of fluoropyrimidines to treat colorectal cancer. Given the high inter-patient variation in fluoropyrimidine drug exposure and susceptibility to pharmacogenetic variation, pharmacokinetic-and pharmacogenetic-guided dosing may also prove fruitful in the quest to normalize drug exposure, reduce toxicity and enhance clinical efficacy. PubMed was used to search for relevant articles relating to 5-fluorouracil administration, fluoropyrimidines (S-1, tegafur, capecitabine, TAS-102), 5-fluorouracil pharmacokinetics and pharmacogenetics, and personalized 5-fluorouracil dosing. Expert commentary: Although fluoropyrimidines are effective against colorectal cancer, room for improvement still exist. Clinically applicable methods to personalize fluoropyrimidine administration include optimizing infusion methods, use of oral formulations, and application of pharmacokineticand/or pharmacogenetic-guided dosing.

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“…With the completion of the human genome map (31,32), inherited factors (such as genetic polymorphisms) have become increasingly studied as potential prognostic and predictive factors in a variety of cancers including gastric cancer (33), hematologic malignancies (34), non-small cell lung cancer (35)(36)(37), colorectal cancer (38), breast cancer (39), and esophageal cancer (40,41). Alongside clinical and tumor molecular prognostic factors, genetic polymorphisms may play key roles by increasing the accuracy and validity of outcome prediction models.…”

Section: Introductionmentioning

confidence: 99%

Genetic Polymorphisms and Head and Neck Cancer Outcomes: A Review

Hopkins

Cescon

Tse

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Head and neck cancer (HNC) patients have variable prognoses even within the same clinical stage and while receiving similar treatments. The number of studies of genetic polymorphisms as prognostic factors of HNC outcomes is growing. Candidate polymorphisms have been evaluated in DNA repair, cell cycle, xenobiotic metabolism, and growth factor pathways. Polymorphisms of XRCC1, FGFR, and CCND1 have been consistently associated with HNC survival in at least two studies, whereas most of the other polymorphisms have either conflicting data or were from single studies. Heterogeneity and lack of description of patient populations and lack of accounting for multiple comparisons were common problems in a significant proportion of studies. Despite a large number of exploratory studies, large replication studies in wellcharacterized HNC populations are warranted. (Cancer Epidemiol Biomarkers Prev 2008;17(3):490 -9)

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Clinical implications of genetic polymorphisms on stomach cancer drug therapy

Cited by 5 publications

References 38 publications

Prognostic Factors of Second and Third Line Chemotherapy Using 5-FU with Platinum, Irinotecan, and Taxane for Advanced Gastric Cancer

Prognostic Factors of Second and Third Line Chemotherapy Using 5-FU with Platinum, Irinotecan, and Taxane for Advanced Gastric Cancer

Personalizing fluoropyrimidine administration in colorectal cancer patients

Genetic Polymorphisms and Head and Neck Cancer Outcomes: A Review

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