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

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.

Replication of Genetic Polymorphisms Reported to Be Associated with Taxane-Related Sensory Neuropathy in Patients with Early Breast Cancer Treated with Paclitaxel

“…2, 11, and [16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Any studies investigating genetic variations only associated with pharmacokinetic, outcome, or taxane resistance endpoints but not sensory peripheral neuropathy/neurotoxicity were excluded.…”

“…Several SNPs in ABCB1 have previously been commonly reported to be associated with TRSN (16)(17)(18)(19)(20)(22)(23)(24)(25)(26). Two of such SNPs are ABCB1, rs1045642 (P ¼ 0.03), and rs2032582 (P ¼ 0.02).…”

A Search for Predictive Factors for Hypersensitivity Reactions to Paclitaxel and Platinum Salts in Chemotherapy for Gynecologic Pelvic Neoplasms

“…Along with these genetic risk factors there are also environmental risk factors that are as yet only partially adjustable and not fully understood [17,18,19]. …”

Are pharmacogenomic biomarkers an effective tool to predict taxane toxicity and outcome in breast cancer patients? Literature review

“…The impact of genetic variants on taxane response is unclear: Several studies did not find any relationship between taxane-related gene polymorphisms and response, while others did [54,55], and the most studied genes have been CYP3A4, CYP2C8 and ABCB1 [56][57][58][59]. Recently, new genome-wide association studies (GWAS) have been reported, searching to correlate data of taxane pharmacogenomics with toxicity [60]; this method enables the simultaneous view on a huge amount of known genetic variation in humans, such as the case of the polymorphism CYP1A1 rs1048943 A/G, in association with the risk of development of breast cancer [61].…”