CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study

Ishani Wickramage,1 Kamani Hemamala Tennekoon,1 Merenchi Arachchige Yasantha Ariyaratne,2 Asanka Sudeshini Hewage,1 Tharmini Sundralingam,1 1Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo, Sri Lanka; 2National Cancer Institute, Maharagama, Sri...

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Autores principales:	Wickramage I, Tennekoon KH, Ariyaratne MAY, Hewage AS, Sundralingam T
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	CYP2D6 tamoxifen fatty liver SNP Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/2a0a43ca283d402fbdb8713e47f04772
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spelling	oai:doaj.org-article:2a0a43ca283d402fbdb8713e47f047722021-12-02T02:48:40ZCYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study1179-1314https://doaj.org/article/2a0a43ca283d402fbdb8713e47f047722017-03-01T00:00:00Zhttps://www.dovepress.com/cyp2d6-polymorphisms-may-predict-occurrence-of-adverse-effects-to-tamo-peer-reviewed-article-BCTThttps://doaj.org/toc/1179-1314Ishani Wickramage,1 Kamani Hemamala Tennekoon,1 Merenchi Arachchige Yasantha Ariyaratne,2 Asanka Sudeshini Hewage,1 Tharmini Sundralingam,1 1Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo, Sri Lanka; 2National Cancer Institute, Maharagama, Sri Lanka Introduction and aims: Tamoxifen is an adjuvant drug effective in treating hormone receptor – positive breast cancer. However, 30%–50% of patients relapse and many develop adverse effects, such as hot flashes and fatty liver. Allelic variations altering the activity of cytochrome P450-2D6 enzyme affect response to tamoxifen by modulating metabolism of tamoxifen into its pharmacologically active metabolite endoxifen. Although association between CYP2D6 polymorphisms and recurrence of breast cancer in patients on tamoxifen had been reported, little evidence exists on association between these polymorphisms and adverse effects to tamoxifen. This study explored the association between CYP2D6 polymorphisms and tamoxifen effects, hitherto not studied in Sri Lanka. Methods: A retrospective preliminary study was carried out on 24 breast cancer patients on tamoxifen for minimally 3 months attending National Cancer Institute, Maharagama, Sri Lanka. They were not on CYP2D6-inhibiting drugs, chemotherapy or other endocrine therapy, and had no conditions that could occur as adverse effects to tamoxifen before starting the therapy. Their blood samples were collected, DNA was extracted and genotyped using SNaPshot Multiplex sequencing based single-nucleotide polymorphism (SNP) assay. Results: SNP/allele frequencies detected: 1846G>A (confirmatory of 4 null allele)=8.3%; 2549delA (confirmatory of 3 null allele)=50%; 100C>T (suggestive of 10 reduced functional allele, in addition to other alleles)=0%; combination of 2988G>A, -1584C and 2850C>T (strongly suggestive of 41 or other reduced functional allele)=4.8%. Occurrence of heterozygous 2988G>A SNP with -1584C and 2850C>T was significantly higher among those with ultrasound-diagnosed fatty liver following the commencement of tamoxifen therapy (P=0.029). Adverse effects occurred at a significantly higher frequency among postmenopausal women (P=0.041). Three patients who developed recurrence of breast cancer had no association with SNPs tested. Conclusions: CYP2D6 SNP combination 2988G>A, -1584C and 2850C>T, strongly suggestive of 41 reduced functional allele, is likely to be useful in predicting occurrence of adverse effect fatty liver in breast cancer patients on tamoxifen, thereby alternative treatment can be considered and lifestyle modifications implemented. Larger sample studies are recommended with the measurement of tamoxifen and metabolite levels. Alternative therapy should be considered for postmenopausal patients. Keywords: fatty-liver, 2988G>A, CYP2D641, intermediate-metabolizer, SNPWickramage ITennekoon KHAriyaratne MAYHewage ASSundralingam TDove Medical PressarticleCYP2D6tamoxifenfatty liverSNPNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBreast Cancer: Targets and Therapy, Vol Volume 9, Pp 111-120 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	CYP2D6 tamoxifen fatty liver SNP Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	CYP2D6 tamoxifen fatty liver SNP Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Wickramage I Tennekoon KH Ariyaratne MAY Hewage AS Sundralingam T CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study
description	Ishani Wickramage,1 Kamani Hemamala Tennekoon,1 Merenchi Arachchige Yasantha Ariyaratne,2 Asanka Sudeshini Hewage,1 Tharmini Sundralingam,1 1Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo, Sri Lanka; 2National Cancer Institute, Maharagama, Sri Lanka Introduction and aims: Tamoxifen is an adjuvant drug effective in treating hormone receptor – positive breast cancer. However, 30%–50% of patients relapse and many develop adverse effects, such as hot flashes and fatty liver. Allelic variations altering the activity of cytochrome P450-2D6 enzyme affect response to tamoxifen by modulating metabolism of tamoxifen into its pharmacologically active metabolite endoxifen. Although association between CYP2D6 polymorphisms and recurrence of breast cancer in patients on tamoxifen had been reported, little evidence exists on association between these polymorphisms and adverse effects to tamoxifen. This study explored the association between CYP2D6 polymorphisms and tamoxifen effects, hitherto not studied in Sri Lanka. Methods: A retrospective preliminary study was carried out on 24 breast cancer patients on tamoxifen for minimally 3 months attending National Cancer Institute, Maharagama, Sri Lanka. They were not on CYP2D6-inhibiting drugs, chemotherapy or other endocrine therapy, and had no conditions that could occur as adverse effects to tamoxifen before starting the therapy. Their blood samples were collected, DNA was extracted and genotyped using SNaPshot Multiplex sequencing based single-nucleotide polymorphism (SNP) assay. Results: SNP/allele frequencies detected: 1846G>A (confirmatory of 4 null allele)=8.3%; 2549delA (confirmatory of 3 null allele)=50%; 100C>T (suggestive of 10 reduced functional allele, in addition to other alleles)=0%; combination of 2988G>A, -1584C and 2850C>T (strongly suggestive of 41 or other reduced functional allele)=4.8%. Occurrence of heterozygous 2988G>A SNP with -1584C and 2850C>T was significantly higher among those with ultrasound-diagnosed fatty liver following the commencement of tamoxifen therapy (P=0.029). Adverse effects occurred at a significantly higher frequency among postmenopausal women (P=0.041). Three patients who developed recurrence of breast cancer had no association with SNPs tested. Conclusions: CYP2D6 SNP combination 2988G>A, -1584C and 2850C>T, strongly suggestive of 41 reduced functional allele, is likely to be useful in predicting occurrence of adverse effect fatty liver in breast cancer patients on tamoxifen, thereby alternative treatment can be considered and lifestyle modifications implemented. Larger sample studies are recommended with the measurement of tamoxifen and metabolite levels. Alternative therapy should be considered for postmenopausal patients. Keywords: fatty-liver, 2988G>A, CYP2D641, intermediate-metabolizer, SNP
format	article
author	Wickramage I Tennekoon KH Ariyaratne MAY Hewage AS Sundralingam T
author_facet	Wickramage I Tennekoon KH Ariyaratne MAY Hewage AS Sundralingam T
author_sort	Wickramage I
title	CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study
title_short	CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study
title_full	CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study
title_fullStr	CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study
title_full_unstemmed	CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study
title_sort	cyp2d6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/2a0a43ca283d402fbdb8713e47f04772
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CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study

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