Association of CYP1B1 with hypersensitivity induced by taxane therapy in breast cancer patients.
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.
Rizzo
Roberta
R
Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, University of Ferrara, Via Fossato di Mortara, 74, 44121, Ferrara, Italy.
Spaggiari
Federica
F
Indelli
Monica
M
Lelli
Giorgio
G
Baricordi
Olavio R
OR
Rimessi
Paola
P
Ferlini
Alessandra
A
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D018567:Breast Neoplasms, Male / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D065633:Cytochrome P-450 CYP1B1; D065727:Cytochrome P-450 CYP2C8; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000077143:Docetaxel; D004342:Drug Hypersensitivity / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007558:Italy; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016017:Odds Ratio; D017239:Paclitaxel / Q000009:adverse effects* / Q000493:pharmacokinetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D043823:Taxoids / Q000009:adverse effects* / Q000493:pharmacokinetics; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C450259:CYP2C8 protein, human; D065633:Cytochrome P-450 CYP1B1; D065727:Cytochrome P-450 CYP2C8; D017239:Paclitaxel