Background Gene variants, such as single nucleotide polymorphisms, have a clinical relevance in the oncological field, when they affect genes encoding enzymes involved in drug metabolism, influencing drug toxicity, treatment compliance and efficacy.
Purpose The purpose of this work is to obtain data to choose a personalised therapy based on individual gene variations, minimise adverse events (AE) and avoid the discontinuation of therapy resulting in tumour progression.
Material and methods A retrospective study was conducted on 57 males and females, age ≥18, with colorectal cancer, in therapy with five protocols using different combinations of 5-fluorouracil, irinotecan and oxaliplatin.
The study evaluated the number of cases where therapy was temporarily discontinued or suspended due to AE that concerned haematological, neurological and gastrointestinal toxicity according to the CTCAE system, which provides a numerical grading scale for AE description.
The prevalence of polymorphisms and association between toxicity and polymorphisms were evaluated calculating odds ratios (OR) with 95% confidence interval.
The Chi-square statistical significance test was applied.
Results 10 polymorphisms were analysed. In order of prevalence they are:
UGT1A1*28 (38.6%, n=22)
GSTPi (26.32%, n=15)
ABCC2rs818 (17.54%, n=10)
DPYDc496A>G (15.79%, n=9)
SLC31A1 (12.28%, n=7)
ABCC2rs717 (10.53%, n=6)
DPYDc. 1129–5923C>G (3.51%, n=2)
DPYD*2Ac. 1905+1 G>A and DPYD*13 c. 1679T>G (1.75%, n=1)
DPYDc. 2846A>T (0%).
OR values found the association between toxicity above 2nd grade and the presence of polymorphisms. The association is:
Strong positive for DPYD*2Ac. 1905+1 G>A (OR=10.68) and UGT1A1*28 (OR=7.43)
Moderate positive for DPYDc. 1129–5923C>G (OR=3.58) and SLC31A1 (OR=2.13)
Moderate negative for ABCC2rs818 (OR=0.33).
Absent for DPYD*13 c. 1679T>G, DPYDc496A>G, ABCC2rs717 and GSTPi.
Conclusion Often patients express different polymorphisms at the same time, developing a toxicity related to the total effects of all the polymorphic variants. This problem is particularly important for chemotherapeutics that are administered at very high doses, close to toxic doses, and takes on a clinical and economic relevance. The study of genes, involved in the metabolism and transport of many drugs, permits the prediction of drug toxicity and efficacy and, based on individual variations, establishing a personalised and safe therapy before the onset of the treatment.
References and/or Acknowledgements 1. Common Terminology Criteria for Adverse Events(CTCAE). U S department of health and human services, national institutes of health, national cancer instituteJune 14, 2010.
2. Sheskin DJ. Handbook of parametric and non parametric statistical procedures2004. IIIed Boca Raton:Chapman & Hall/CRC.
3. Panczyk M. Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20years. World J Gastroenterol2014August 7;20(29):9775–9827.
No conflict of interest
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