High-throughput pharmacogenetics identifies SLCO1A2 polymorphisms as candidates to elucidate the risk of febrile neutropenia in the breast cancer RAPP-01 trial.

Abstract

The RAPP-01 clinical trial compared two adjuvant chemotherapies, doxorubicin plus docetaxel (arm A) versus doxorubicin plus cyclophosphamide (arm B), in 627 women with breast cancer. It stopped prematurely when three severe adverse events occurred among patients with febrile neutropenia (FN), all in the arm A. FN occurred in 40.8% (126/311) in arm A versus 7.1% (22/316) in arm B. We investigated Single Nucleotide Polymorphisms (SNPs) in drug transporter and metabolism genes potentially incriminated in this excess of FN. Using a dedicated DNA chip, we tested association of SNPs belonging to 97 transporter and 68 metabolizing genes with FN occurrence in 155 patients enrolled in the RAPP-01 trial, 85 in arm A and 70 in arm B. Association study in the 85 patients receiving docetaxel identified two SNPs, rs4762699 and rs2857468, both located in the SLCO1A2 gene. Haplotype T-T was associated with a high risk of FN: 83.3% of patients with at least one copy of T-T versus 32.8% in patients with other haplotypes (odds ratio = 10.25, P = 1.4e-4). In a multivariate logistic model adjusted for treatment arm, effect of haplotype T-T remained significant (odds ratio = 6.84, P = 1.15e-4). FN in patients receiving docetaxel in the RAPP-01 trial is significantly associated with the haplotype T-T in rs4762699 and rs2857468 in the SLCO1A2 transporter gene. This result should be validated in an independent cohort.