<em>CYP2D6</em> polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study

Abstract

Introduction and aimsTamoxifen 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.MethodsA 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.ResultsSNP/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.ConclusionsCYP2D6 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.

Association of single nucleotide polymorphisms of cytochrome P450 enzymes with experience of vasomotor, vaginal and musculoskeletal symptoms among breast cancer patients: a systematic review

“…( p = 0.06) • Hazard ratios of developing hot flashes/night sweats: o PM vs EM: 1.94 (95% CI: 1.12–3.35) o IM vs EM: 1.16 (95% CI: 0.81–1.64) Ruddy et al, 2013 [ 36 ]; USA Oncology centre at a local cancer institute Stage I-III breast cancer patients undergoing tamoxifen therapy ( N = 99) CYP2D6 • CYP2D6 metabolic activity classes (including a rare allele (RA) class – individuals in this class have an EM phenotype) • Occurrence of hot flashes • Level of bother caused by hot flashes • Questionnaire developed based on the Breast Cancer Prevention Trial scale of menopausal symptoms Comparison between CYP2D6 metabolic activity classes • The proportion of patients having developed hot flashes is similar between the UM/EM/RA group and IM group. (67% vs 69%) • The proportion of patients expressing that they are at least slightly bothered by hot flashes is similar between the UM/EM/RA group and IM group (63% vs 69%) • The proportion of patients expressing that they are at least moderately bothered by hot flashes is similar between the UM/EM/RA group and IM group (34% vs 38%) Wickramage et al, 2017 [ 37 ]; Sri Lanka Hospital clinic at the National Cancer Institute in Sri Lanka Breast cancer patients undergoing tamoxifen treatment ( N = 24) CYP2D6 • SNPs of CYP2D6 • Occurrence of hot flashes • Occurrence of hot flashes reported in clinical records The CYP2D6*4 SNP (1846 G > A) • The existence of the CYP2D6*4 SNP in patients was not associated with the occurrence of hot flashes among them ( p = 0.437) The CYP2D6*41 SNP (Combination of 2988 G > A, 2850 C > T and -1584C) • The existence of the CYP2D6*41 SNP in patients was not associated with the occurrence of hot flashes among them ( p = 0.271) Zembutsu et al, 2017 [ 38 ]; Japan and Singapore Multi-sites; Hospitals, cancer centres and cancer institutes in Japan and Singapore Oestrogen receptor -positive, human epidermal growth factor receptor 2-negative, invasive breast cancer patients undergoing tamoxifen therapy ( N = 279) CYP2D6 • SNPs/Genotypes of CYP2D6 • Occurrence of hot flashes • Not specified • There was no significant difference in hot flashes occurrence between patients bearing the wt CYP2D6 and those having the CYP2D6 SNPs/genotypes investigated in this study ( p = 0.25) Abbreviation : CYP cytochrome P450, EM extensive metaboliser, IM intermediate metaboliser, PM poor metaboliser, RA rare allele, SNP single nucleotide poly...…”

“…The publication year ranges between 2005 and 2018. The single-country studies were conducted in Australia [28], Canada [26,32], the Czech Republic [25], the Netherlands [27,31], Sri Lanka [37] or the United States [29,30,33,36]. Three further studies involved an international collaboration of research groups [34,35,38].…”

The Role of CYP2D6 Polymorphisms in Determining Response to Tamoxifen in Metastatic Breast Cancer Patients: Review and Egyptian Experience

“…However, about 30%-50% of those patients may develop relapse. Previous studies provided evidence that allelic variations in cytochrome P450-2D6 enzyme highly affect response to tamoxifen by modulating the metabolism of tamoxifen into its pharmacologically active metabolite endoxifen (Wickramage et al, 2017). Although CYP2D6 polymorphisms has been investigated in many studies in the western countries, the results of its role on tamoxifen concentrations as well as its impact on the clinical outcomes of the treated patients are conflicting and still not clear (Markopoulos et al, 2014).…”

Translational genomic research: the role of genetic polymorphisms in MBSR program among breast cancer survivors (MBSR[BC])

“…A recent article reported that functional CYP2D6 single-nucleotide polymorphisms (SNPs) were significantly associated with adverse effect fatty liver following the tamoxifen therapy. Therefore, alternative treatment can be used for patients with CYP2D6 SNPs (rs28371725 and rs16947) [18].…”