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Clinical Trial
. 2016 Nov 22;115(11):1335-1342.
doi: 10.1038/bjc.2016.326. Epub 2016 Oct 13.

Genotypes of CYP2C8 and FGD4 and their association with peripheral neuropathy or early dose reduction in paclitaxel-treated breast cancer patients

Siu W Lam  1 , Charlotte N Frederiks  1 , Tahar van der Straaten  2 , Aafke H Honkoop  3 , Henk-Jan Guchelaar  2 , Epie Boven  1
Affiliations
Clinical Trial

Genotypes of CYP2C8 and FGD4 and their association with peripheral neuropathy or early dose reduction in paclitaxel-treated breast cancer patients

Siu W Lam et al. Br J Cancer. .

Abstract

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 ⩾1 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 ⩾1 peripheral neuropathy was 67% (n=126). The rate of dose reduction was 46% (n=87). Age ⩾65 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.

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Figures

Figure 1
Figure 1
Kaplan–Meier curve of cumulative paclitaxel dose until the occurrence of grade ⩾1 peripheral neuropathy according to CYP2C8*3 (n=180).
Figure 2
Figure 2
SNPs associated with paclitaxel dose reduction. (A) Kaplan–Meier curve of cumulative paclitaxel dose until first dose reduction according to FGD4 c.2044-236G>A (n=186). (B) Kaplan–Meier curve of cumulative paclitaxel dose until first dose reduction according to TUBB2A c.-101T>C (n=182).
See this image and copyright information in PMC

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