Genotypes of CYP2C8 and FGD4 and their association with peripheral neuropathy or early dose reduction in paclitaxel-treated breast cancer patients
A partir des données d'un essai de phase II incluant 188 patientes atteintes d'un cancer du sein métastatique et évaluant l'efficacité d'un traitement combinant paclitaxel et bevacizumab avec ou sans capécitabine en traitement palliatif de première ligne, cette étude évalue l'association entre des polymorphismes à simple nucléotide des gènes CYP2C8 et FGD4, le risque de neuropathie périphérique induite par le paclitaxel et la réduction précoce des doses de paclitaxel
Background: The purpose of this study was to evaluate single-nucleotide polymorphisms (SNPs) in genes encoding key metabolising enzymes or involved in pharmacodynamics for possible associations with paclitaxel-induced peripheral neuropathy. Methods: The study population consists of 188 women from the multicenter, randomised, phase II ATX trial (BOOG2006-06; EudraCT number 2006-006058-83) that received paclitaxel and bevacizumab without or with capecitabine as first-line palliative therapy of HER2-negative metastatic breast cancer. Genotyping of CYP2C8*3 (c.416G>A), CYP3A4*22 (c.522-191C>T), TUBB2A (c.-101T>C), FGD4 (c.2044-236G>A) and EPHA5 (c.2895G>A) was performed by real-time PCR. Toxicity endpoints were cumulative dose (1) until first onset of grade greater than or equal to1 peripheral neuropathy and (2) until first paclitaxel dose reduction from related toxicity (NCI-CTCAE version 3.0). SNPs were evaluated using the Kaplan–Meier method, the Gehan–Breslow–Wilcoxon test and the multivariate Cox regression analysis. Results: The rate of grade greater than or equal to1 peripheral neuropathy was 67% (n=126). The rate of dose reduction was 46% (n=87). Age greater than or equal to65 years was a risk factor for peripheral neuropathy (HR=1.87, P<0.008), but not for dose reduction. When adjusted for age, body surface area and total cumulative paclitaxel dose, CYP2C8*3 carriers had an increased risk of peripheral neuropathy (HR=1.59, P=0.045). FGD4 c.2044-236 A-allele carriers had an increased risk of paclitaxel dose reduction (HR per A-allele=1.38, P=0.036) when adjusted for total cumulative paclitaxel dose. Conclusions: These findings may point towards clinically useful indicators of early toxicity, but warrant further investigation.