Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients

Abstract

Tamoxifen (TAM), a selective oestrogen receptor modulator, is one of the most used treatments in oestrogen receptor-positive (ER+) early and metastatic breast cancer (BC) patients. The response to TAM has a high degree of inter-individual variability. This is mainly due to genetic variants in CYP2D6 gene, as well as other genes encoding proteins involved in the TAM pharmacokinetic and/or pharmacodynamic. Therefore, prediction of the TAM response using these genetic factors together with other non-genetic variables may be relevant to improve breast cancer treatment. Thus, in this work, we used genetic polymorphisms and clinical variables for TAM response modelling. One hundred sixty-two ER + BC patients with 2 years of TAM treatment were retrospectively recruited, and the genetic polymorphisms CYP2D6*4, CYP3A4*1B (CYP3A4*1.001), CYP3A5*3, UGT2B7*2, UGT2B15*2, SULT1A1*2, and ESRA V364E were analyzed by PCR-RFLP. Concomitantly, the therapeutic response was obtained from clinical records for association with genotypes using univariate and multivariate biostatistical models. Our results show that UGT2B15*1/*2 genotype protects against relapse (OR = 0.09; p = 0.02), CYP3A5*3/*3 genotype avoids endometrial hyperplasia (OR = 0.07; p = 0.01), SULT1A1*1/*2 genotype avoids vaginal bleeding (OR = 0.09; p = 0.03) and ESRA 364E/364E genotype increases the probability of vaginal bleeding (OR = 5.68; p = 0.02). Logistic regression models, including genomic and non-genomic variables, allowed us to obtain preliminary predictive models to explain relapse (p = 0.010), endometrial hyperplasia (p = 0.002) and vaginal bleeding (p = 0.014). Our results suggest that the response to TAM treatment in ER + BC patients might be associated with the presence of the studied genetic variants in UGT2B15, CYP3A5, SULT1A1 and ESRA genes. After clinical validation protocols, these models might be used to help to predict a percentage of BC relapse and adverse reactions, improving the individual response to TAM-based treatment.

Prevalence of Cyp2d6*4 and Its Possible Relation to Therapeutic Outcomes of Adjuvant Tamoxifen Therapy in Egyptian Premenopausal Women With Breast Cancer

“…60 An interesting study on Chilean patients with breast cancer showed significant impact of CYP3A5*3 A/G genotype (but not CYP2D6*4) on endometrial hyperplasia in patients on tamoxifen therapy. 61 Regarding the other tamoxifen-related adverse effects like hot flashes, vaginal bleeding and development of ovarian cysts, no significant relation with the variant CYP2D6*4 in the present study (P > 0.9) (table 5). These finding coincde with other studies for the same variant.…”

DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival

“…The second CpG site (cg27034150) is in the promoter region of SULT1A1, which is a sulfotransferase involved in the metabolism of drugs. Its involvement in tamoxifen metabolism has been reported previously [ 45 – 47 ]. The third CpG site (cg01503450) is situated in the promoter region of LARP4B, a gene involved in RNA translation, and could be a tumor suppressor gene [ 48 – 50 ].…”

Influence of polymorphism of enzymes of the UDP family-glucuronyl transferases on the biotransformation of tamoxifen in the therapy of luminal forms of breast cancer

“…It was shown that among the many UGT isoforms involved in TAM detoxification (including UGT1A8, UGT1A10, and UGT2B7), UGT1A4 was identified as the main UGT isoform involved in the glucuronidation of TAM and its metabolites. UGT2B7 demonstrated the highest affinity and activity for trans-4-hydroxytamoxifen [ 26,16,30]. The UGT1A4 gene encodes an enzyme that catalyzes the formation of a glucuronide bound by quaternary ammonium to TAM [4,7,8,18].…”