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CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel

  • Epidemiology
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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.

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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.

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The authors declare that they have no conflict of interest.

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Author notes

  1. Stacey J. Winham

    Present address: Department of Health Sciences Research, Division of Biostatistics and Informatics, Mayo Clinic, Rochester, MN, USA

Authors and Affiliations

  1. 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

    Daniel L. Hertz & Howard L. McLeod

  2. UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Daniel L. Hertz, Alison A. Motsinger-Reif & Howard L. McLeod

  3. Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA

    Alison A. Motsinger-Reif

  4. Department of Statistics, North Carolina State University, Raleigh, NC, USA

    Alison A. Motsinger-Reif & Stacey J. Winham

  5. Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    Amy Drobish, Howard L. McLeod, Lisa A. Carey & E. Claire Dees

  6. Department of Medicine, Division of Hematology-Oncology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Howard L. McLeod, Lisa A. Carey & E. Claire Dees

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Electronic supplementary material

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10549_2012_2054_MOESM1_ESM.docx

Supplementary Table 1: SNP Information: rsID, allelic position and change, resulting protein change, polymerase chain reaction annealing temperature and primers. (DOCX 12 kb)

10549_2012_2054_MOESM2_ESM.docx

Supplementary Table 2: Genotyping results: call rate, variant allele frequency, uncorrected p values of Hardy–Weinberg Equilibrium test in combined cohort and Caucasian subcohort, variant allele frequency in Caucasian subcohort and expected allele frequency in Caucasians from The International HapMap Project or dbSNP database. (DOCX 12 kb)

10549_2012_2054_MOESM3_ESM.docx

Supplementary Table 3: Haplotype Results: Complete breakdown of number of individuals who fall into each haplotype category as defined for CYP3A4/3A5 in Baker et al. [26] and ABCB1 in Sissung et al. [27] followed by the grouping for the association study. (CYP3A4/3A5 *2 carriers vs. other and ABCB1 Diplotype 1–3 vs. 4 and 5). (DOCX 11 kb)

10549_2012_2054_MOESM4_ESM.docx

Supplementary Table 4: Severe neuropathy (≥ grade 3) in toxicity cohort (N = 109) by genotype or haplotype, comparing variant carriers with wild-type homozygous patients. (DOCX 11 kb)

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Hertz, D.L., Motsinger-Reif, A.A., Drobish, A. et al. CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel. Breast Cancer Res Treat 134, 401–410 (2012). https://doi.org/10.1007/s10549-012-2054-0

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