Abstract P6-08-09: Genetic polymorphisms (SNPs) as predictive markers for paclitaxel-induced peripheral neuropathy (PNP) and capecitabine-induced hand-foot syndrome (HFS) in HER-2 negative metastatic breast cancer patients
Authors: Lam Siu W , Frederiks Charlotte N , van der Straaten Tahar , de Groot Steffen M , Jager Agnes , Bos Monique MEM , Linn Sabine C , van den Bosch Joan , Braun Hans J , van der Velden Ankie MT , Los Maartje , Portielje Jojanneke EA , Kroep Judith R , Honkoop Aafke H , Smorenburg Carolien H , Tanis Bea , van Riel Johanna MGH , Meerum Terwogt Jetske M , den Boer Marien O , Douma Joep , Jeurissen Frank , Berends Johan , Guchelaar Henk-Jan , Boven Epie 
Published: May 2015

Abstract
Background
Newly identified SNPs in genes encoding metabolizing enzymes (CYP2C8, CYP3A4) and drug target (TUBB2A) of paclitaxel have been associated with PNP1-3. A recent GWAS has found novel SNPs in EPHA5 and FGD4 possibly predictive for PNP4. Likewise, SNPs in genes (CDA, CES2) involved in capecitabine activation may play a role in HFS5. Here, we attempted to confirm these SNPs as predictive markers for PNP and HFS in patients (pts) receiving first-line paclitaxel (T) and bevacizumab (A) without or with capecitabine (X).
Patients and methods
In the phase II ATX trial (NTR1348;BOOG2006-06), 312 pts were randomized 1:1 to AT (T 90 mg/m2 d1, 8, 15 & A 10 mg/kg d1, 15 q4w x 6 cycles → A 15 mg/kg d1 q3w for next cycles) or ATX (T 90 mg/m2 d1, 8, A 15 mg/kg d1 & X 825 mg/m2 bid d1–14 q3w x 8 cycles → the same dose of A & X q3w for next cycles). Toxicity was graded by using NCI CTCAE v3 at each cycle.
Germline DNA was isolated for genotyping CYP2C8*3 (1196A&gt;G & 416G&gt;A), CYP3A4*22 (522-191C&gt;T), EPHA5 2895G&gt;A, FGD4 2044-236G&gt;A, CES2 823C&gt;G, TUBB2A 101C&gt;T, TUBB2A 112G&gt;A, CDA 943insC and CDA 451C&gt;T. Results of TUBB2A and CDA SNPs will be presented at the meeting.
The association between SNPs and toxicity was analyzed for 1) maximum grade of treatment-related toxicity per patient by Pearson’s X2 or Fisher's exact test; 2) cumulative dose level of drugs until first grade ≥1 toxicity or first dose reduction by Kaplan-Meier curve and Gehan-Breslow test.
Results
188 pts had SNPs genotyped; characteristics reflected the trial cohort. Table 1 shows the maximum grade of PNP. When grouped into grades 0–1 and 2–3, no differences in rates of PNP were noted among SNPs. Median cumulative dose of T until grade ≥1 PNP was 1,800 mg/m2 (95% CI 1,534–2,065). Carriers of the CYP2C8 416 A-allele had a significantly lower cumulative dose of T until grade ≥1 PNP compared to those with a homozygous G/G genotype (Gehan-Breslow p=0.011). Carriers of the FGD4 2044-236 A-allele had a significantly higher cumulative dose until first dose reduction of T compared to those with a homozygous G/G genotype (Gehan-Breslow p=0.037).
Table 1. toxicity by maximum grade per patient Grade 0123Paclitaxel-treated patients (N=188)PNP, No. (%)62 (33)33 (36)41 (22)17 (9)Capecitabine-treated patients (N=93)HFS, No. (%)17 (18)21 (23)25 (27)30 (32)
For ATX-treated pts, rates of HFS are shown in Table 1. With regard to maximum grade of HFS, there was a trend of a lower rate of grade 2–3 HFS for CES 823C/G compared to C/C genotype (33% vs 64%, Fisher’s exact p=0.059). The median cumulative dose of X until grade ≥1 HFS was 98.7 g/m2 (95%CI 82.1–115). CES 823C&gt;G was not associated with the cumulative dose of X until grade ≥1 HFS or dose reduction.
Conclusions
Our results indicate that CYP2C8 416G&gt;A and FGD4 2044-236G&gt;A might be predictive markers for paclitaxel-induced neurotoxicity, whereas reported associations of other SNPs with toxicity could not be confirmed.
1Hertz et al. Ann Oncol 2013, 2De Graan et al. Clin Cancer Res 2013, 3Leandro-Garcia et al. Clin Cancer Res 2012, 4Baldwin et al. Clin Cancer Res 2012, 5Caronia et al. Clin Cancer Res 2011
Financial support from Roche Netherlands.
Citation Format: Siu W Lam, Charlotte N Frederiks, Tahar van der Straaten, Steffen M de Groot, Agnes Jager, Monique MEM Bos, Sabine C Linn, Joan van den Bosch, Hans J Braun, Ankie MT van der Velden, Maartje Los, Jojanneke EA Portielje, Judith R Kroep, Aafke H Honkoop, Carolien H Smorenburg, Bea Tanis, Johanna MGH van Riel, Jetske M Meerum Terwogt, Marien O den Boer, Joep Douma, Frank Jeurissen, Johan Berends, Henk-Jan Guchelaar, Epie Boven. Genetic polymorphisms (SNPs) as predictive markers for paclitaxel-induced peripheral neuropathy (PNP) and capecitabine-induced hand-foot syndrome (HFS) in HER-2 negative metastatic breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-09.