ABCB1 Genetic Variation Influences the Toxicity and Clinical Outcome of Patients with Androgen-Independent Prostate Cancer Treated with Docetaxel

Abstract

Purpose: Polymorphisms that are associated with ABCB1expression and function may be linked to treatment efficacy and the development of neutropenia and neurotoxicity in patients with androgen-independent prostate cancer receiving docetaxel. Experimental Design: Patients with androgen-independent prostate cancer treated with docetaxel alone (n = 23) or docetaxel and thalidomide (n = 50) were genotyped for the ABCB1 1236C>T, 2677 G>T/A, and 3435 C>T alleles by direct sequencing, and diplotypes were constructed using an EM algorithm.The data were then compared with duration to onset of peripheral neuropathy, neutropenia grade, and survival after docetaxel. Results: For patients receiving docetaxel alone, individuals carrying a diplotype consisting of the 1236C-2677G-3435C linked alleles had improved overall survival after treatment (P = 0.0017). Additionally, patients treated with docetaxel and thalidomide carrying a diplotype consisting of the 2677T-3435T haplotype had a shorter median survival (P = 0.045). After adjusting for a particular set of polymorphisms and diplotype groupings, a hazard ratio of 10.87 was found for patients carrying the 2677GG genotype versus patients carrying other genotypes (P = 0.0048) in the docetaxel and thalidomide cohort. Among both treatment arms together, individuals carrying the 2677GG genotype also had a significantly longer time to neuropathy (P = 0.035). Finally, there was a strong trend toward patients carrying the 2677TT-3435TT diplotype having higher grades of neutropenia (P = 0.053). Conclusion:The data suggest that docetaxel-induced neuropathy, neutropenia grade, and overall survival could be linked to ABCB1 allelic variants with ensuing negative implications for docetaxel treatment in patients carrying ABCB1 variant genotypes.

Association of the ABCB1 3435C>T polymorphism and treatment outcomes in advanced gastric cancer patients treated with paclitaxel-based chemotherapy

“…In cancers that already overexpress ABCB1 compared with normal tissue, polymorphisms might be more deterministic in efflux phenotypes than an expression difference itself. In contrast, in normal tissues where ABCB1 is expressed at low basal levels, it is likely that polymor-phisms influence drug penetration by altering expression (18).…”

“…The haplotypes were named as follows: 11 for alleles without mutations (2677G-3435C), 12 for alleles with (2677G-3435T), 21 for alleles with (2677T/A-3435C), and 22 for alleles carrying both mutations (2677T/A-3435T). The diplotype nomenclature was used as described previously (18).…”

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).…”

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

“…The inferred population frequencies agreed well with Kroetz et al 35 who analyzed the haplotype structure of the ABCB1 gene in 100 Caucasian from a human variation panel and the frequencies estimated by the EM algorithm in STATA 10 (StataCorp, College Station, TX, USA). To test an allele dose effect, the resulting 13 haplotypes (with phase information) were grouped into diplotype 1-4 based on the 1236C4T, 2677G4TA and 3435C4T SNPs in a manner similar to Sissung et al 36 The 'full wild-type' is thus CGC/CGC (diplotype 1) and the 'full variant type' TTT/TTT (diplotype 3) and the heterotype CGC/TTT (diplotype 2) ( Table 1). This approach can possibly reveal effects of interplay between cis variants and are suggested by some to add valuable information that is impossible to achieve by assessing the SNPs separately.…”