Prevention of fluoropyrimidine toxicity: do we still have to try our patient's luck?

Danesi, Romano; Re, Marzia Del; Ciccolini, Joseph; Schellens, Jan H.M.; Schwab, Matthias; Schaik, Ron H.N. van; Kuilenburg, André B. P.

doi:10.1093/annonc/mdw448

Cited by 12 publications

(7 citation statements)

References 5 publications

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“…, 5-FU and capecitabine) and irinotecan, respectively [ 19 , 23 ]. Nevertheless, since the current guidelines do not provide a firm consensus on the clinical validity of pretreatment DPYD and UGT1A1 screening [ 7 , 8 ], the implementation of these pharmacogenetic tests in the daily clinical practice remains a highly debated issue, especially regarding DPYD genotyping [ 25 , 26 ]. The lack of evidence from prospective studies, together with some inconsistent results from retrospective series, in particular about DPYD , slowed a widespread consensus on these tests and the definition of conclusive recommendations on the implementation in the clinical practice of a “genotype-guided” dosing of cytotoxic agents.…”

Section: Discussionmentioning

confidence: 99%

DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer

Cremolini

Antoniotti

et al. 2017

Oncotarget

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Our study addresses the issue of the clinical reliability of three candidate DPYD and one UGT single nucleotide polymorphisms in predicting 5-fluorouracil- and irinotecan-related adverse events. To this purpose, we took advantage of a large cohort of metastatic colorectal cancer patients treated with first-line 5-fluorouracil- and irinotecan-based chemotherapy regimens (i.e., FOLFIRI or FOLFOXIRI) plus bevacizumab in the randomized clinical trial TRIBE by GONO (clinicaltrials.gov: NCT00719797), in which adverse events were carefully and prospectively collected at each treatment cycle. Here we show that patients bearing DPYD c.1905+1G/A and c.2846A/T genotypes, together with UGT1A1*28 variant carriers, have an increased risk of experiencing clinically relevant toxicities, including hematological AEs and stomatitis. No carrier of the DPYD c.1679T>G minor allele was identified. Present results support the preemptive screening of mentioned DPYD and UGT1A1 variants to identify patients at risk of clinically relevant 5-fluoruracil- and irinotecan-related AEs, in order to improve treatments’ safety through a “genotype-guided” approach.

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Section: Discussionmentioning

confidence: 99%

DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer

Cremolini

Antoniotti

et al. 2017

Oncotarget

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“…Many DPYD variants have been discovered [6–9], but most of them do not impair enzyme activity or their functional effect is unclear, with the exception of the splice site mutation in intron 14 (c.1905+1G>A, DPYD *2A) and the non-synonymous variant c.2846A>T (p.D949V), strongly associated with partial or complete loss of enzymatic activity and severe ADRs [10, 11]. Numerous efforts have been made to investigate the best approach to assess DPD deficiency and reduce the risk of toxicity [12] but, despite a strong laboratory rationale and cost-effectiveness of genotyping [13], the issue is still debated as contrasting recommendations on the implementation of DPYD analysis in clinical practice have been issued [14–16], fueling a debate on the usefulness of this test in the management of patients who are candidates to fluoropyrimidine treatment [17–19]. For these reasons, this study was designed to provide further evidence on the role of DPYD assessment by evaluating a large cohort of patients to discover which mutations should be tested to reduce the risk of ADRs and avoid unjustified costs of screening extremely rare DPYD genotypes.…”

Section: Introductionmentioning

confidence: 99%

DPYD6 plays an important role in fluoropyrimidine toxicity in addition to DPYD2A and c.2846A>T: a comprehensive analysis in 1254 patients

Cinieri²,

Michelucci

et al. 2019

Pharmacogenomics J

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Dihydropyrimidine dehydrogenase (DPYD) is a highly polymorphic gene and classic deficient variants (i.e., c.1236G>A/HapB3, c.1679T>G, c.1905+1G>A and c.2846A>T) are characterized by impaired enzyme activity and risk of severe adverse drug reactions (ADRs) in patients treated with fluoropyrimidines. The identification of poor metabolizers by pre-emptive DPYD screening may reduce the rate of ADRs but many patients with wild-type genotype for classic variants may still display ADRs. Therefore, the search for additional DPYD polymorphisms associated with ADRs may improve the safety of treatment with fluoropyrimidines. This study included 1254 patients treated with fluoropyrimidine-containing regimens and divided into cohort 1, which included 982 subjects suffering from gastrointestinal G≥2 and/or hematological G≥3 ADRs, and cohort 2 (control group), which comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment. Both groups were screened for DPYD variants c.496A>G, c.1236G>A/HapB3, c.1601G>A (DPYD*4), c.1627A>G (DPYD*5), c.1679T>G (DPYD*13), c.1896T>C, c.1905 + 1G>A (DPYD*2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with toxicity. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2, while c.1905+1G>A and c.2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A/HapB3 were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c.2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p < 0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p = 0.06). In conclusion, c.2194G>A is associated with clinically-relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T variants and should be evaluated pre-emptively to reduce the risk of fluoropyrimidine-associated ADRs.

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“…However, the European Society of Medical Oncology (ESMO) consensus guidelines for the management of patients with metastatic colorectal cancer state that “DPD testing (....) remains an option but is not routinely recommended” and “none of the current strategies are adequate to mandate routine DPD testing” 16 . Danesi et al 17 argued strongly against these statements and pointed out that they “do not reflect the current awareness of the importance of testing for DPD deficiency …. (and) the Royal Dutch Pharmacists Association, the French GPCO-Unicancer group and the Italian Association of Medical Oncology-Italian Society of Pharmacology working groups have issued recommendations on preemptive DPD analysis for rational dose adaptation.” Further insights into the disagreements among regulatory bodies and professional societies regarding PGx may be found in a review by Gillis et al 4 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic testing in oncology: a Brazilian perspective

Suarez‐Kurtz

2018

Clinics

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Pharmacogenetics, a major component of individualized or precision medicine, relies on human genetic diversity. The remarkable developments in sequencing technologies have revealed that the number of genetic variants modulating drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to rare mutations (minor allele frequency, MAF<1%) in addition to polymorphisms (MAF>1%) in pharmacogenes. This has major implications for the conceptual development and clinical implementation of pharmacogenetics. Drugs used in cancer treatment have been major targets of pharmacogenetics studies, encompassing both germline polymorphisms and somatic variants in the tumor genome. The present overview, however, has a narrower scope and is focused on germline cancer pharmacogenetics, more specifically, on drug/gene pairs for which pharmacogenetics-informed prescription guidelines have been published by the Clinical Pharmacogenetics Implementation Consortium and/or the Dutch Pharmacogenetic Working Group, namely, thiopurines/TPMT, fluoropyrimidines/UGT1A1, irinotecan/UGT1A1 and tamoxifen/CYP2D6. I begin by reviewing the general principles of pharmacogenetics-informed prescription, pharmacogenetics testing and the perceived barriers to the adoption of routine pharmacogenetics testing in clinical practice. Then, I highlight aspects of the pharmacogenetics testing of the selected drug-gene pairs and finally present pharmacogenetics data from Brazilian studies pertinent to these drug-gene pairs. I conclude with the notion that pharmacogenetics testing has the potential to greatly benefit patients by enabling precision medicine applied to drug therapy, ensuring better efficacy and reducing the risk of adverse effects.

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Prevention of fluoropyrimidine toxicity: do we still have to try our patient's luck?

Cited by 12 publications

References 5 publications

DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer

DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer

DPYD6 plays an important role in fluoropyrimidine toxicity in addition to DPYD2A and c.2846A>T: a comprehensive analysis in 1254 patients

Pharmacogenetic testing in oncology: a Brazilian perspective

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Prevention of fluoropyrimidine toxicity: do we still have to try our patient's luck?

Cited by 12 publications

References 5 publications

DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer

DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer

DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: a comprehensive analysis in 1254 patients

Pharmacogenetic testing in oncology: a Brazilian perspective

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DPYD6 plays an important role in fluoropyrimidine toxicity in addition to DPYD2A and c.2846A>T: a comprehensive analysis in 1254 patients