Abstract P3-12-09: CYP2D6*10 genotype was associated with worse outcome of premenopausal breast cancer patients receiving adjuvant tamoxifen but not toremifene: A single institution expericence

Abstract

Abstract Background: Tamoxifen(TAM), a selective estrogen receptor modulator(SERM), is the most widely used adjuvant endocrine therapy for premenopausal breast cancer patients. Cytochrome P-450(CYP450) enzyme, CYP2D6, is involved in the conversion of tamoxifen to endoxifen which is one of the main active metabolites of tamoxifen in vivo. Variants of CYP2D6 gene may result in a decreased enzyme activity and lead to poor prognosis of the patients. Different from caucasians, the most common polymorphism among Chinese women is allelic variant *10, which generates a 188 C to T transition, resulting in a lower activity of the enzyme. Based on some retrospective studies, tamoxifen-treated patients with the CYP2D6*10 T/T genotype have a worse clinical outcome. Toremifene(TOR), another kind of SERM is not metabolited by CYP2D6 enzyme thus may not be influenced by its polymorphism. We conducted this study to validate the association between CYP2D6*10 genotype and the outcomes of patients receiving TAM and TOR respectively. Methods: A total of 276 patients with primary early-stage ER-positive breast cancer received adjuvant tamoxifen (n=169) or toremifene (n=107) therapy at Natinal Cancer Center from 2004-2012 were analyzed. All patients had received 5-year endocrine therapy after completion of surgery. TaqMan SNP genotyping assays was performed on CYP2D6*10 from blood samples. The association of CYP2D6 *10 genotype with disease free survival (DFS) and clinicopathological characteristics was analyzed in patients receiving tamoxifen and toremifen. Results: 32.6% (90 of 276) of the patients were homozygous for wild-type C/C genotype, 47.1% (130 of 276) were heterozygous for C/T genotype, and 20.3% (56 of 276) were homozygous for variant T/T genotype. The frequency of CYP2D6 *10 allele in our study was 43.8%. The 5-year DFS rate for tamoxifen and toremifene treatment group were 81.6% and 83.2% respectively. There was no significant difference of DFS between the two groups(P=0.274). Among 169 patients in tamoxifen group, 5-year DFS rate was considerably lower in patients with homozygous variant T/T genotype than those with wild-type C/C or C/T genotype (73.4% versus 83.2%, P=0.004). And the T/T genotype was found to be a significant prognostic marker for DFS in multivariate analysis (hazard ratio = 4.7; P<0.001) after adjusting for patient's characteristics mentioned above. For the toremifene group, there was no difference of DFS between T/T genotype and the others(P=0.332). For all the 56 homozygous variant T/T genotype patients, patients receiving toremifene treatment had a much higher 5-year DFS rate than those receiving tamoxifen but unfortunately it was not statistically significant (90.0% versus 73.4%, P=0.192). Conclusions: About one fifth of Chinese breast cancer patients had homozygous T/T genotype which might get less benefit from TAM adjuvant treatment. Toremifene may be a better option for this kind of patients. Further large-scale prospective clinical studies are warranted to validate this concept. Citation Format: Lan B, Ma F, Fan Y, Zhai X, Xu B. CYP2D6*10 genotype was associated with worse outcome of premenopausal breast cancer patients receiving adjuvant tamoxifen but not toremifene: A single institution expericence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-09.