Pharmacogenetics of capecitabine in advanced breast cancer patients.
OBJECTIVE
Germinal gene polymorphisms can explain a part of the interpatient pharmacodynamic variability of anticancer drugs, particularly fluoropyrimidines. Genes for which polymorphisms may potentially influence pharmacodynamics of fluoropyrimidines, including capecitabine, are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD).


METHODS
The aim of this prospective pilot study was to analyze the effect of TS, MTHFR, and DPD gene polymorphisms on toxicity and efficacy in advanced breast cancer patients receiving capecitabine as monotherapy. Germinal polymorphisms of TS (6 bp deletion in the 3' region and 28 bp repeats, including G>C mutation in the 5' region), MTHFR (677C>T and 1298A>C), and DPD (IVS14+1G>A) were determined in 105 consecutive patients.


RESULTS
A trend toward a higher global toxicity grade 3 and 4 was observed in patients homozygous for the TS 3RG allele compared with patients heterozygous for the 3RG allele or patients not carrying the 3RG allele (50% versus 19% versus 13% respectively, P=0.064). The sole patient bearing the DPD IVS14+1G>A mutation (heterozygous) deceased from hematologic toxicity. The median response duration was 5.8 months (95% confidence interval, 4.3-7.2). Duration of response was significantly shortened in patients homozygous for the 3RG allele compared with others (P=0.037).


CONCLUSIONS
The present data suggest that 3RG3RG breast cancer patients are not good candidates for capecitabine therapy. In addition, attention should be paid to DPD deficiency in breast cancer patients receiving capecitabine. These preliminary data require further confirmation on a larger number of patients.
Largillier
Rémy
R
Centre Antoine Lacassagne, Nice, and Pharmacokinetic Unit, La Timone University Hospital, Marseille, France.
Etienne-Grimaldi
Marie-Christine
MC
Formento
Jean-Louis
JL
Ciccolini
Joseph
J
Nebbia
Jean-François
JF
Ginot
Aurélie
A
Francoual
Mireille
M
Renée
Nicole
N
Ferrero
Jean-Marc
JM
Foa
Cyril
C
Namer
Moïse
M
Lacarelle
Bruno
B
Milano
Gérard
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D008954:Models, Biological; D008969:Molecular Sequence Data; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D013940:Thymidylate Synthase / Q000235:genetics*
D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D005472:Fluorouracil