Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients.
BACKGROUND
* Numerous clinical studies, including a few prospective ones, have reported conflicting results on the impact of gene polymorphisms related to fluorouracil (FU) and oxaliplatin pharmacodynamics.


CONCLUSIONS
* This prospective study is the first to report that clinical response to FOLFOX is significantly related to methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (677C-->T and 1298A-->C), with a response rate of 37, 53, 63 and 80% in patients harbouring no, one, two or three favourable MTHFR alleles, respectively. * Only polymorphisms of genes related to oxaliplatin pharmacodynamics (GSTpi 105Ile-->Val and XPD 751Ly-->Gln) influenced progression-free survival. * These results corroborate the observation that response was related to the cumulative FU dose, whereas progression-free survival was related to the cumulative oxaliplatin dose.


OBJECTIVE
To test prospectively the predictive value of germinal gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity and responsiveness of colorectal cancer (CRC) patients receiving FOLFOX therapy.


METHODS
Advanced CRC patients (n= 117) receiving FOLFOX 7 therapy were enrolled. Gene polymorphisms relevant for FU [thymidylate synthase (TYMS, 28 bp repeats including the G-->C mutation + 6 bp deletion in 3'UTR), methylenetetrahydrofolate reductase (MTHFR, 677C-->T, 1298A-->C), dihydropyrimidine deshydrogenase (IVS14+1G-->A) and Oxa: glutathione S-transferase (GST) pi (105Ile-->Val, 114Ala-->Val), excision repair cross-complementing group 1 (ERCC1) (118AAT-->AAC), ERCC2 (XPD, 751Lys-->Gln) and XRCC1 (399Arg-->Gln)] were determined (blood mononuclear cells).


RESULTS
None of the genotypes was predictive of toxicity. Response rate (54.7% complete response + partial response) was related to FU pharmacogenetics, with both 677C-->T (P= 0.042) and 1298A-->C (P= 0.004) MTHFR genotypes linked to clinical response. Importantly, the score of favourable MTHFR alleles (677T and 1298C) was positively linked to response, with response rates of 37.1, 53.3, 62.5 and 80.0% in patients bearing no, one, two or three favourable alleles, respectively (P= 0.040). Polymorphisms of genes related to Oxa pharmacodynamics showed an influence on progression-free survival, with a better outcome in patients bearing GSTpi 105 Val/Val genotype or XPD 751Lys-containing genotype (P= 0.054).


CONCLUSIONS
These results show that response to FOLFOX therapy in CRC patients may be driven by MTHFR germinal polymorphisms.
Etienne-Grimaldi
Marie-Christine
MC
Centre Antoine Lacassagne, Oncopharmacology Unit, EA 3836, Nice, France. marie-christine.etienne@nice.fnclcc.fr
Milano
Gérard
G
Maindrault-Goebel
Frédérique
F
Chibaudel
Benoist
B
Formento
Jean-Louis
JL
Francoual
Mireille
M
Lledo
Gérard
G
André
Thierry
T
Mabro
May
M
Mineur
Laurent
L
Flesch
Michel
M
Carola
Elisabeth
E
de Gramont
Aimery
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D002955:Leucovorin; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D017384:Sequence Deletion; D016019:Survival Analysis
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D042943:Dihydrouracil Dehydrogenase (NADP); D042965:Methylenetetrahydrofolate Reductase (NADPH2); D005982:Glutathione Transferase; D002955:Leucovorin; D005472:Fluorouracil