P3-14-03: ABCB1 Single Nucleotide Polymorphismas a Possible Prognostic Factor in Breast Cancer Patients Receiving Docetaxel and Doxorubicin Neoadjuvant Chemotherapy on Systemic Treatment.
Authors: Kim H-J , Lee K-H , Im S-A , Jang IJ , Yi SJ , Keam B , Kim YJ , Han S-W , Oh D-Y , Kim JH , Cho N , Chie EK , Han W , Moon WK , Kim T-Y , Noh D-Y , Park IA , Bang Y-J , Ha SW 
Published: June 2012

Background Expression of the adenosine triphosphate-binding cassette B1 (ABCB1) transporter and P-glycoprotein are associated with resistance to anticancer drugs. The purpose of this thesis was to investigate the role of single nucleotide polymorphism (SNP) in the ABCB1 and CYP3A genes in breast cancer patients who were treated with neoadjuvant docetaxel and doxorubicin chemotherapy.

Material and Methods: Patients with histologically confirmed breast cancer, Stage II or III, referred for neoadjuvant chemotherapy were enrolled. Patients were treated with 3 cycles of neoadjuvant and adjuvant chemotherapy with docetaxel and doxorubicin. The polymorphisms of ABCB1 (C3435T, G2677T/A, and C1236T) were genotyped by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assays. The genotyping of CYP3A was done by the GoldenGate assay (Illumina Inc). The correlation of genetic polymorphisms of ABCB1, CYP3A, and clinical outcomes was analyzed.

Results: A total of 216 patients were enrolled, and the median age was 44 years (range 25–69 years). The overall radiological response rate (RR) was 76.8% while 8.3% of the patients achieved a pathologically complete response. After a follow-up duration of 48.8 months, the median relapse-free survival (RFS) and overall survival (OS) were not reached. ABCB1 3435TT genotype had a longer OS than CT/TT genotype (p=0.045) and a trend toward a lower relapse rate (p=0.284) although it is statistically insignificant. With univariate analysis of the OS, good performance status (PS), invasive ductal carcinoma, initial operable stages, estrogen receptor (ER)-positive, non-triple negative, and the TT genotype of ABCB1 C3435T were associated with a lower risk of death. Multivariate analyses for the OS revealed that PS (HR 4.670, 95% CI=1.066−10.468; p=0.041), initial clinical stage (HR 3.198, CI=1.480−6.907; p=0.003), and triple negative phenotype (HR 3.091, 95% CI=1.245−6.570; p=0.004) were significantly associated with the OS. ABCB1 3435TT genotype was also associated with a lower risk of death with marginal significance not shown to be an independent prognostic factor (HR 0.295 95% CI=0.121−1.122; p=0.071). ABCB1 3435TT genotype had a higher AUC than CC/CT genotype for docetaxel with marginal significance (p =0.054). These higher AUCs in the C3435TT genotype was associated with increased toxicities of neutropenia (p=0.037) and diarrhea (p=0.017). AA (*1/*1)/AG (*1/*3) genotypes of CYP3A5 had a higher AUC than GG (*3/*3) for docetaxel with statistical significance (p=0.024). However, these higher AUCs of CYP3A5*1 allele carrier did not affect the survival and toxicities.

Discussion: This study showed that the genetic polymorphism of ABCB1 C3435T might be associated with a longer OS and have predictive roles after the treatment with the neoadjuvant docetaxel/doxorubicin for stage II and III breast cancer. Our results also suggest that the prediction of docetaxel toxicity might be possible for ABCB1 C3435T polymorphism. Larger prospective studies as well as functional studies in human subjects are warranted.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-03.