CYP2C83 increases risk of neuropathy in breast cancer patients treated with paclitaxel

Paclitaxel-induced neuropathy is an adverse event that often leads to therapeutic disruption and patient discomfort. We attempted to replicate a previously reported association between increased neuropathy risk and CYP2C8*3 genotype. Demographic, treatment, and toxicity data were collected for pacli...

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Bibliographic Details
Published in:	Annals of oncology Vol. 24; no. 6; pp. 1472 - 1478
Main Authors:	Hertz, D.L., Roy, S., Motsinger-Reif, A.A., Drobish, A., Clark, L.S., McLeod, H.L., Carey, L.A., Dees, E.C.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-06-2013 Oxford University Press
Subjects:	Adult African Americans - genetics Aged Aged, 80 and over Antineoplastic agents Antineoplastic Agents, Phytogenic - therapeutic use Aryl Hydrocarbon Hydroxylases - genetics Biological and medical sciences Breast Neoplasms - drug therapy Breast Neoplasms - enzymology Breast Neoplasms - genetics chemotherapy-induced peripheral neuropathy Cohort Studies Cytochrome P-450 CYP2C8 cytochrome P450 2C83 European Continental Ancestry Group - genetics Female Genetic Variation - genetics Gynecology. Andrology. Obstetrics Humans Mammary gland diseases Medical sciences Middle Aged Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Original paclitaxel Paclitaxel - adverse effects Paraneoplastic Polyneuropathy - chemically induced Paraneoplastic Polyneuropathy - enzymology Paraneoplastic Polyneuropathy - genetics pharmacogenetics Pharmacology. Drug treatments race Risk Factors Treatment Outcome Tumors Young Adult cytochrome P450 2C83 paclitaxel race pharmacogenetics chemotherapy-induced peripheral neuropathy Antineoplastic agent Breast disease Isozyme Neuropathy Taxane derivatives Paclitaxel Race Genetics Peripheral nerve disease Antimitotic Human Nervous system diseases Pharmacogenetics Enzyme Cytochrome P450 Patient Breast cancer cytochrome P450 2C8 Malignant tumor Mammary gland diseases Chemotherapy Treatment 3 Risk factor Cancer
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Summary:	Paclitaxel-induced neuropathy is an adverse event that often leads to therapeutic disruption and patient discomfort. We attempted to replicate a previously reported association between increased neuropathy risk and CYP2C83 genotype. Demographic, treatment, and toxicity data were collected for paclitaxel-treated breast cancer patients who were genotyped for the CYP2C83 K399R (rs10509681) variant. A log-rank test was used in the primary analysis of European-American patients. An additional independent replication was then attempted in a cohort of African-American patients, followed by modeling of the entire patient cohort with relevant covariates. In the primary analysis of 209 European patients, there was an increased risk of paclitaxel-induced neuropathy related to CYP2C83 status [HR (per allele) = 1.93 (95% CI: 1.05–3.55), overall log-rank P = 0.006]. The association was replicated in direction and magnitude of effect in 107 African-American patients (P = 0.043). In the Cox model using the entire mixed-race cohort (n = 411), each CYP2C83 allele approximately doubled the patient's risk of grade 2+ neuropathy (P = 0.004), and non-Europeans were at higher neuropathy risk than Europeans of similar genotype (P = 0.030). The increased risk of paclitaxel-induced neuropathy in patients who carry the CYP2C8*3 variant was replicated in two racially distinct patient cohorts.
Bibliography:	This work was presented in part at the 35th Annual San Antonio Breast Cancer Symposium, 5–9 December 2012, San Antonio, TX. This report has original material and there have been no other previous reports or publications to disclose.
ISSN:	0923-7534 1569-8041
DOI:	10.1093/annonc/mdt018