Association of CYP1B1 with hypersensitivity induced by taxane therapy in breast cancer patients

Roberta Rizzo; Federica Spaggiari; Monica Indelli; Giorgio Lelli; Olavio R Baricordi; Paola Rimessi; Alessandra Ferlini

doi:10.1007/s10549-010-1034-5

Association of CYP1B1 with hypersensitivity induced by taxane therapy in breast cancer patients

Breast Cancer Res Treat. 2010 Nov;124(2):593-8. doi: 10.1007/s10549-010-1034-5. Epub 2010 Jul 15.

Authors

Roberta Rizzo¹, Federica Spaggiari, Monica Indelli, Giorgio Lelli, Olavio R Baricordi, Paola Rimessi, Alessandra Ferlini

Affiliation

¹ Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, University of Ferrara, Via Fossato di Mortara, 74, 44121, Ferrara, Italy.

PMID: 20632082
DOI: 10.1007/s10549-010-1034-5

Abstract

Taxanes represent a group of anticancer drugs with a wide range of activity against breast cancer. Therapy side effects include haematologic toxicity (neutropenia, leucopenia), peripheral neuropathy and hypersensitivity, and demonstrate inter-individual variations. Since it is known that three genes are implicated in taxane turnover, namely ABCB1 in the transport, CYP2C8 in the metabolism and CYP1B1 in the activity, we explored the association among polymorphisms (single nucleotide polymorphisms, SNPs) in these three genes and the occurrence of taxane-induced toxicity. We studied 95 patients affected by breast cancer and under treatment with taxanes as adjuvant, metastatic or neo-adjuvant therapy. We genotyped them for SNPs in the CYP2C8 (alleles *1, *2, *3 and *4), CYP1B1 (alleles *1 and *3) and ABCB1 (1236 C>T; 2677 G>T/A; 3435 C>T) genes by real-time PCR assay. We observed a significant association between the CYP1B1*3 allele and a lower occurrence of hypersensitivity reactions to taxane treatment. We speculate that the highest production of 4-hydroxyestradiol (4-OHE2) metabolite by CYP1B1*3 allele could increase the formation of the 4-OHE2-taxane adduct and possibly inhibit taxane toxicity. We suggest that CYP1B1 might affect taxane hypersensitivity therefore representing, if confirmed in a large cohort of patients, an exploratory hypersensitivity predictive biomarker.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
Aged
Antineoplastic Agents, Phytogenic / adverse effects*
Antineoplastic Agents, Phytogenic / pharmacokinetics
Aryl Hydrocarbon Hydroxylases / genetics
Breast Neoplasms / drug therapy*
Breast Neoplasms / enzymology
Breast Neoplasms / genetics
Breast Neoplasms, Male / drug therapy*
Breast Neoplasms, Male / enzymology
Breast Neoplasms, Male / genetics
Chemotherapy, Adjuvant
Chi-Square Distribution
Cytochrome P-450 CYP1B1
Cytochrome P-450 CYP2C8
Cytochrome P-450 Enzyme System / genetics*
Cytochrome P-450 Enzyme System / metabolism
Docetaxel
Drug Hypersensitivity / enzymology
Drug Hypersensitivity / genetics*
Female
Gene Frequency
Genetic Predisposition to Disease
Humans
Italy
Logistic Models
Male
Middle Aged
Neoadjuvant Therapy
Odds Ratio
Paclitaxel / adverse effects*
Paclitaxel / pharmacokinetics
Phenotype
Polymorphism, Single Nucleotide*
Retrospective Studies
Risk Assessment
Risk Factors
Taxoids / adverse effects*
Taxoids / pharmacokinetics
Treatment Outcome

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents, Phytogenic
Taxoids
Docetaxel
Cytochrome P-450 Enzyme System
Aryl Hydrocarbon Hydroxylases
CYP1B1 protein, human
CYP2C8 protein, human
Cytochrome P-450 CYP1B1
Cytochrome P-450 CYP2C8
Paclitaxel