title: CYP2D6polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study.
abstract: OBJECTIVE
  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 betweenCYP2D6polymorphisms 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 betweenCYP2D6polymorphisms 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
  CYP2D6SNP 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.
authors.affiliation: Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo, Sri Lanka.
authors.forename: Ishani
authors.initials: I
authors.lastname: Wickramage
authors.affiliation: Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo, Sri Lanka.
authors.forename: Kamani Hemamala
authors.initials: KH
authors.lastname: Tennekoon
authors.affiliation: National Cancer Institute, Maharagama, Sri Lanka.
authors.forename: Merenchi Arachchige Yasantha
authors.initials: MA
authors.lastname: Ariyaratne
authors.affiliation: Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo, Sri Lanka.
authors.forename: Asanka Sudeshini
authors.initials: AS
authors.lastname: Hewage
authors.affiliation: Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo, Sri Lanka.
authors.forename: Tharmini
authors.initials: T
authors.lastname: Sundralingam
keywords: 2988G>A; CYP2D6*41; SNP; fatty-liver; intermediate-metabolizer