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

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...

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Autores principales:	Carla Miranda, Macarena Galleguillos, Roberto Torres, Karla Tardón, Dante D. Cáceres, Kuen Lee, María A. Redal, Nelson M. Varela, Luis A. Quiñones
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	breast cancer pharmacokinetics pharmacodynamics polymorphism ADR Relapse Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/f2e5127fbe534d109f3127cf26b36452
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spelling	oai:doaj.org-article:f2e5127fbe534d109f3127cf26b364522021-12-01T01:27:54ZPreliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients1663-981210.3389/fphar.2021.661443https://doaj.org/article/f2e5127fbe534d109f3127cf26b364522021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.661443/fullhttps://doaj.org/toc/1663-9812Tamoxifen (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 CYP2D64, CYP3A41B (CYP3A41.001), CYP3A53, UGT2B72, UGT2B152, SULT1A12, 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 UGT2B151/2 genotype protects against relapse (OR = 0.09; p = 0.02), CYP3A53/3 genotype avoids endometrial hyperplasia (OR = 0.07; p = 0.01), SULT1A11/*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.Carla MirandaMacarena GalleguillosRoberto TorresKarla TardónDante D. CáceresKuen LeeKuen LeeMaría A. RedalMaría A. RedalNelson M. VarelaNelson M. VarelaLuis A. QuiñonesLuis A. QuiñonesFrontiers Media S.A.articlebreast cancerpharmacokineticspharmacodynamicspolymorphismADRRelapseTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	breast cancer pharmacokinetics pharmacodynamics polymorphism ADR Relapse Therapeutics. Pharmacology RM1-950
spellingShingle	breast cancer pharmacokinetics pharmacodynamics polymorphism ADR Relapse Therapeutics. Pharmacology RM1-950 Carla Miranda Macarena Galleguillos Roberto Torres Karla Tardón Dante D. Cáceres Kuen Lee Kuen Lee María A. Redal María A. Redal Nelson M. Varela Nelson M. Varela Luis A. Quiñones Luis A. Quiñones Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients
description	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 CYP2D64, CYP3A41B (CYP3A41.001), CYP3A53, UGT2B72, UGT2B152, SULT1A12, 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 UGT2B151/2 genotype protects against relapse (OR = 0.09; p = 0.02), CYP3A53/3 genotype avoids endometrial hyperplasia (OR = 0.07; p = 0.01), SULT1A11/*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.
format	article
author	Carla Miranda Macarena Galleguillos Roberto Torres Karla Tardón Dante D. Cáceres Kuen Lee Kuen Lee María A. Redal María A. Redal Nelson M. Varela Nelson M. Varela Luis A. Quiñones Luis A. Quiñones
author_facet	Carla Miranda Macarena Galleguillos Roberto Torres Karla Tardón Dante D. Cáceres Kuen Lee Kuen Lee María A. Redal María A. Redal Nelson M. Varela Nelson M. Varela Luis A. Quiñones Luis A. Quiñones
author_sort	Carla Miranda
title	Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients
title_short	Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients
title_full	Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients
title_fullStr	Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients
title_full_unstemmed	Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients
title_sort	preliminary pharmacogenomic-based predictive models of tamoxifen response in hormone-dependent chilean breast cancer patients
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/f2e5127fbe534d109f3127cf26b36452
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Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients

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