Genotype-based selection of treatment of patients with advanced colorectal cancer (SETICC): a pharmacogenetic-based randomized phase II trial

Abad, Albert; Martínez-Balibrea, Eva; Vieitez, José María; Alonso-Orduna, V.; Alfonso, Pilar; Manzano, José Luís; Massutí, Bartomeu; Benavides, Manuel; Carrato, Alfredo; Zanui, Montserrat; Gállego, Javier; Grávalos, Cristina; Conde, V.; Provencio, Mariano; Valladares‐Ayerbes, Manuel; Salazar, Ramón; Sastre, Javier; Montagut, Clara; Rivera, Fernando; Aranda, Enrique

doi:10.1093/annonc/mdx737

Cited by 12 publications

(6 citation statements)

References 17 publications

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“…Oxaliplatin was not identified as cause of even a single case of exceptionally severe CIPN due to occult CMT. These insights deepen the current understanding of the pharmacogenomics of oxaliplatin that are a very active area of investigation [23][24][25] due to its imminent importance for clinical oncology. There are a few limitations to the present study.…”

Section: Discussionmentioning

confidence: 94%

Neurological safety of oxaliplatin in patients with uncommon variants in Charcot-Marie-tooth disease genes

Le‐Rademacher

Lopez

Kanwar³

et al. 2020

Journal of the Neurological Sciences

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Oxaliplatin therapy can be complicated by chemotherapy-induced peripheral neuropathy (CIPN). Other neurotoxic chemotherapies have been linked to single nucleotide variants (SNV) in Charcot-Marie-Tooth disease (CMT) genes. Whether oxaliplatin carries increased risks of CIPN due to SNV in CMT-associated genes is unknown.353 patients receiving oxaliplatin in NCCTG N08CB were serially evaluated for CIPN using a validated patient-reported outcome (PRO) instrument, the CIPN20 questionnaire (sensory scale). 49 canonical CMT-associated genes were analyzed for rare and common SNV by nextgen sequencing.The 157 patients with the highest and lowest susceptibility to CIPN (cases and controls) harbored 270 nonsynonymous SNV in CMT-associated genes (coding regions). 143 of these were rare, occurring only once ("singletons"). CIPN cases had 0.84 singletons per patient compared with 0.98 in controls. An imbalance in favor of cases was noted only in few genes including PRX, which was previously highlighted as a candidate CIPN gene in patients receiving paclitaxel. However, the imbalance was only modest (5 singleton SNV in cases and 2 in controls). Therefore, while singleton SNV were common, they did overall not portend an increased risk of CIPN. Furthermore, testing CMT-associated genes using recurrent non-synonymous SNV did not reveal any significant association with CIPN.Genetic analysis of patients from N08CB provides clinical guidance that oxaliplatin chemotherapy decisions should not be altered by the majority of SNV that may be encountered in CMT-associated genes when common genetic tests are performed, such as exome or genome sequencing. Oxaliplatin's CIPN risk appears unrelated to CMT-associated genes.

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Section: Discussionmentioning

confidence: 94%

Neurological safety of oxaliplatin in patients with uncommon variants in Charcot-Marie-tooth disease genes

Le‐Rademacher

Lopez

Kanwar³

et al. 2020

Journal of the Neurological Sciences

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“…Several research projects are currently ongoing to bring the ultimate proofs of the clinical validity and utility of pharmacogenomics implementation to improve patients management and to increase drug safety. Several clinical implementation projects are ongoing in Europe and in the US and the results of some genotype directed clinical trials have been published demonstrating the feasibility of this approach and its applicability in the clinical practice [79][80][81] .…”

Section: Resultsmentioning

confidence: 99%

The use of pharmacogenetics to increase the safety of colorectal cancer patients treatedwith fluoropyrimidines

Matti¹,

Roncato²,

Fratte³

et al. 2019

CDR

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Fluoropyrimidines (FP) are given in the combination treatment of the advanced disease or as monotherapy in the neoadjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast, head and neck and gastric cancer. FP present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening toxicity. With the high number of patients receiving FP-based therapies, and the significant effects of toxicities on their quality of life, the prevention of FP-related adverse events is of major clinical interest. Host genetic variants in the rate limiting enzyme dihydropyrimidine dehydrogenase (DPYD) gene are related to the occurrence of extremely severe, early onset toxicity in FP treated patients. The pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by the currently available pharmacogenetic guidelines. Several prospective implementation projects are ongoing to support the introduction of up-front genotyping of the patients in clinical practice. Multiple pharmacogenetic studies tried to assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic pathways, TYMS and MTHFR , but no additional clinically validated genetic markers of toxicity are available to date. The development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic markers. Moreover, the investigation of the genetic variation in the patients immunological system, a pivotal target in cancer treatment, could bring notable advances in the field. This review will describe the most recent literature on the use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients.

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“…aggression) through early intervention. Personalisation can include the use of genetic information to apply medical screening and treatments (Abad et al 2018;Virolainen et al 2022); taking preventative or remedial measures for those at genetic risk for learning problems (Selzam et al 2017); and more broadly, using genetic potential for success in particular areas for life design/career planning (K. Hill 2009).…”

Section: Benefitsmentioning

confidence: 99%

Genomics and Justice: Investigating judges’, lawyers’ and non-lawyers’ genetic literacy and views on applications of genomics

Selita

2023

Preprint

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This publication brings together multidisciplinary research to create a meaningful picture of what genomic advances mean for individuals and societies, and societies’ readiness for the genomic and post-genomic era. Readiness requires adaptation to the immense progress in genomics to enable beneficial use and minimise harmful use of genetic advances and of the powers they create. The work focuses on three key directions. First, it introduces the powers created by genetic advances – the power of polygenic prediction, the power of environmental engineering, and the power of genetic engineering. Second, it provides an assessment of the immeasurable potential benefits these powers present for individuals and societies, and of the legal protection in place. Thirdly, it provides an examination of readiness of key stakeholders – the judiciary and lawyers – as the main mediators between genetic advances and outcomes for societies; and compares those to views of non-lawyers. This assessment covers the essential elements of readiness: genetics literacy, and realistic views on how these powers should be used across different sectors and life aspects. In addition, the publication reports on several elements of societal readiness such as: views of judges and lawyers on whether laws are sufficient, if and when they should be updated, and how they should be updated; and judges’ and lawyers’ confidence in own knowledge. The results showed that societies are not ready, and call for a number of short- and long-term interventions to regulate the outcomes of advances. The work concludes with an overview of the steps needed for achieving Genomic Era readiness.

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Genotype-based selection of treatment of patients with advanced colorectal cancer (SETICC): a pharmacogenetic-based randomized phase II trial

Abstract: NCT01071655.

Cited by 12 publications

References 17 publications

Neurological safety of oxaliplatin in patients with uncommon variants in Charcot-Marie-tooth disease genes

Neurological safety of oxaliplatin in patients with uncommon variants in Charcot-Marie-tooth disease genes

The use of pharmacogenetics to increase the safety of colorectal cancer patients treatedwith fluoropyrimidines

Genomics and Justice: Investigating judges’, lawyers’ and non-lawyers’ genetic literacy and views on applications of genomics

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