TY - JOUR
T1 - CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel
AU - Hertz, Daniel L.
AU - Motsinger-Reif, Alison A.
AU - Drobish, Amy
AU - Winham, Stacey J.
AU - McLeod, Howard L.
AU - Carey, Lisa A.
AU - Dees, E. Claire
N1 - Funding Information:
Acknowledgments We would like to thank Anne Misher for assistance with genotyping and Janelle Hoskins for guidance on choosing candidate SNPs. This study was supported by the Breast Cancer Research Foundation (LAC), Lineberger Comprehensive Cancer Center, a Clinical and Translational Science Award 5UL1RR025747-04, the National Institute of Health-National Institute of General Medical Sciences T32GM081057 and NIH SPORE in Breast Cancer 5P50CA058223. Daniel Hertz is an American Foundation for Pharmaceutical Education Pre-Doctoral Fellow in clinical pharmaceutical science. They have received research funding from pharmaceutical companies that are not related to the current work: Millennium Pharmaceuticals, Roche-Genentech, GlaxoSmithKline, and Novartis (ECD). This report has original material and there have been no other previous reports or publications to disclose.
PY - 2012/7
Y1 - 2012/7
N2 - Paclitaxel is one of the most frequently used chemotherapeutic agents for the treatment of breast cancer patients. Using a candidate gene approach, we hypothesized that polymorphisms in genes relevant to the metabolism and transport of paclitaxel are associated with treatment efficacy and toxicity. Patient and tumor characteristics and treatment outcomes were collected prospectively for breast cancer patients treated with paclitaxel-containing regimens in the neoadjuvant setting. Treatment response was measured before and after each phase of treatment by clinical tumor measurement and categorized according to RECIST criteria, while toxicity data were collected from physician notes. The primary endpoint was achievement of clinical complete response (cCR) and secondary endpoints included clinical response rate (complete response + partial response) and grade 3+ peripheral neuropathy. The genotypes and haplotypes assessed were CYP1B1*3, CYP2C8*3, CYP3A4*1B/ CYP3A5*3C, and ABCB1*2. A total of 111 patients were included in this study. Overall, cCR was 30.1 % to the paclitaxel component. CYP2C8*3 carriers (23/111, 20.7 %) had higher rates of cCR (55 % vs. 23 %; OR = 3.92 [95 % CI: 1.46-10.48], corrected p = 0.046). In the secondary toxicity analysis, we observed a trend toward greater risk of severe neuropathy (22 % vs. 8 %; OR = 3.13 [95 % CI: 0.89-11.01], uncorrected p = 0.075) in subjects carrying the CYP2C8*3 variant. Other polymorphisms interrogated were not significantly associated with response or toxicity. Patients carrying CYP2C8*3 are more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment, but may also be at increased risk of experiencing severe peripheral neurotoxicity.
AB - Paclitaxel is one of the most frequently used chemotherapeutic agents for the treatment of breast cancer patients. Using a candidate gene approach, we hypothesized that polymorphisms in genes relevant to the metabolism and transport of paclitaxel are associated with treatment efficacy and toxicity. Patient and tumor characteristics and treatment outcomes were collected prospectively for breast cancer patients treated with paclitaxel-containing regimens in the neoadjuvant setting. Treatment response was measured before and after each phase of treatment by clinical tumor measurement and categorized according to RECIST criteria, while toxicity data were collected from physician notes. The primary endpoint was achievement of clinical complete response (cCR) and secondary endpoints included clinical response rate (complete response + partial response) and grade 3+ peripheral neuropathy. The genotypes and haplotypes assessed were CYP1B1*3, CYP2C8*3, CYP3A4*1B/ CYP3A5*3C, and ABCB1*2. A total of 111 patients were included in this study. Overall, cCR was 30.1 % to the paclitaxel component. CYP2C8*3 carriers (23/111, 20.7 %) had higher rates of cCR (55 % vs. 23 %; OR = 3.92 [95 % CI: 1.46-10.48], corrected p = 0.046). In the secondary toxicity analysis, we observed a trend toward greater risk of severe neuropathy (22 % vs. 8 %; OR = 3.13 [95 % CI: 0.89-11.01], uncorrected p = 0.075) in subjects carrying the CYP2C8*3 variant. Other polymorphisms interrogated were not significantly associated with response or toxicity. Patients carrying CYP2C8*3 are more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment, but may also be at increased risk of experiencing severe peripheral neurotoxicity.
KW - CYP2C83
KW - Clinical complete response
KW - Neoadjuvant breast cancer therapy
KW - Paclitaxel
KW - Pharmacogenetics
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U2 - 10.1007/s10549-012-2054-0
DO - 10.1007/s10549-012-2054-0
M3 - Article
C2 - 22527101
AN - SCOPUS:84863981895
SN - 0167-6806
VL - 134
SP - 401
EP - 410
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 1
ER -