The Effect of Polymorphism in UGT1A4 on Clinical Outcomes of Adjuvant Tamoxifen Therapy for Patients With Breast Cancer in China

• Published in: Clinical breast cancer 2019-04, Vol.19 (2), p.e370-e375
• Main Authors: Lan, Bo, Ma, Fei, Han, Mei, Chen, Shanshan, Wang, Wenna, Li, Qiao, Fan, Ying, Luo, Yang, Cai, Ruigang, Wang, Jiayu, Yuan, Peng, Zhang, Pin, Li, Qing, Xu, Binghe
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Hormonal - therapeutic use; Aromatase Inhibitors - therapeutic use; Asian Continental Ancestry Group; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Chemotherapy, Adjuvant; China - epidemiology; Chinese breast cancer patients; Disease free survival; Endocrine therapy; Female; Genetic Association Studies; Genotype; Glucuronosyltransferase - genetics; Humans; Polymorphism, Single Nucleotide; Prognosis; Promoter Regions, Genetic; Single nucleotide polymorphism; Tamoxifen - therapeutic use; UDP-glucuronosyltransferases 1A4
• ISSN: 1526-8209; 1938-0666
• DOI: 10.1016/j.clbc.2018.12.009

UGT1A4 is a major enzyme responsible for the glucuronidation of tamoxifen (TAM) and its metabolites. Genetic variations in the UGT1A4 gene could have a significant impact on the clinical efficacy of TAM. This study was performed to validate the association between UGT1A4 polymorphisms and the clinical outcomes for patients with breast cancer who received adjuvant TAM. A total of 773 patients with breast cancer who received adjuvant TAM (n = 321) or aromatase inhibitors (n = 452) at the National Cancer Center in China were analyzed. Through a series of screenings, the single nucleotide polymorphism rs869283 (c.-1180G>A) in the promoter region of the UGT1A4 gene was selected. The associations of rs869283 genotype with disease-free survival (DFS) and clinicopathologic characteristics were analyzed. A total of 608 (78.7%) patients were wild-type G/G genotype, 154 (19.9%) patients were G/A genotype, and 11 (1.4%) patients were A/A genotype. In the TAM treatment group, patients with A/A or G/A genotype had a lower 5-year DFS rate than those with the wild-type G/G genotype (69.3% vs. 83.7%; P = .031). The rs869283 genotype remained an independent prognostic marker for DFS in multivariate analysis (hazard ratio, 1.74; P = .014). No association between the rs869283 genotype and DFS was found in patients who received AIs (P = .772). Our findings showed that patients with the UGT1A4 rs869283 G/A or A/A genotype received less benefit from adjuvant TAM treatment than those with the G/G genotype. Further studies are warranted to confirm our findings. More markers are needed to guide adjuvant endocrine therapy decisions for patients with breast cancer. In this study, we found that patients with breast cancer with rs869283 variations (G/A or A/A) in the UGT1A4 gene, accounting for 21.3% of the population, received less benefit from adjuvant tamoxifen treatment. The efficacy of adjuvant aromatase inhibitors could not be influenced by this polymorphism.