AUTHOR=Miranda Carla , Galleguillos Macarena , Torres Roberto , Tardón Karla , Cáceres Dante D. , Lee Kuen , Redal María A. , Varela Nelson M. , Quiñones Luis A. 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.661443

DOI=10.3389/fphar.2021.661443

ISSN=1663-9812

ABSTRACT=<p>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 <italic>CYP2D6</italic> 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 <italic>CYP2D6*4, CYP3A4*1B (CYP3A4*1.001), CYP3A5*3, UGT2B7*2, UGT2B15*2, SULT1A1*2</italic>, and <italic>ESRA V364E</italic> 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 <italic>UGT2B15</italic>*1/*2 genotype protects against relapse (OR = 0.09; <italic>p</italic> = 0.02), <italic>CYP3A5</italic>*3/*3 genotype avoids endometrial hyperplasia (OR = 0.07; <italic>p</italic> = 0.01), <italic>SULT1A1</italic>*1/*2 genotype avoids vaginal bleeding (OR = 0.09; <italic>p</italic> = 0.03) and <italic>ESRA 364E/364E</italic> genotype increases the probability of vaginal bleeding (OR = 5.68; <italic>p</italic> = 0.02). Logistic regression models, including genomic and non-genomic variables, allowed us to obtain preliminary predictive models to explain relapse (<italic>p</italic> = 0.010), endometrial hyperplasia (<italic>p</italic> = 0.002) and vaginal bleeding (<italic>p</italic> = 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 <italic>UGT2B15</italic>, <italic>CYP3A5, SULT1A1</italic> and <italic>ESRA</italic> 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.</p>