title: CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel.
abstract: 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.
authors.affiliation: UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, 120 Mason Farm Road, CB 7361, Chapel Hill, NC 27599, USA. danhertz@email.unc.edu
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hertz
authors.forename: Alison A
authors.initials: AA
authors.lastname: Motsinger-Reif
authors.forename: Amy
authors.initials: A
authors.lastname: Drobish
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Winham
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D047368:Tumor Burden / Q000187:drug effects
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D017239:Paclitaxel