Prevalence of CYP2D6*2, CYP2D6*4, CYP2D6*10, and CYP3A5*3 in Thai breast cancer patients undergoing tamoxifen treatment

Figures & data

Figure 1 TAM-metabolic pathways and selected CYP450 enzymes.

Notes: TAM was metabolized by CYP450 enzyme to its active metabolites: END and 4OHT. END was created via NDMT and 4OHT.
Abbreviations: TAM, tamoxifen; CYP450, cytochrome P450; END, endoxifen; 4OHT, 4-hydroxy-tamoxifen; NDMT, N-desmethyl tamoxifen.

Figure 2 A diagram of CYP2D6, CYP3A5 polymorphisms, and breast cancer outcomes from previous research.

Abbreviations: TAM, tamoxifen; NDMT, N-desmethyl-tamoxifen; 4OHT, 4-hydroxy-tamoxifen; END, endoxifen; OS, overall survival; PFS, progress-free survival; CB, clinical benefit; IDFS, invasive disease-free survival; DFS, disease-free survival.

Table 1 Prevalence of CYP2D6 and CYP3A5 polymorphisms in Caucasians, Asians, and Thais

Allele/genotype	Prevalence (%)
	Caucasians	Asians	Thais
CYP2D6
*1	76.7^Citation24	49.0–100.0^Citation14	35.0^Citation8–47.0^Citation16
*2	0.0^Citation24	19.0^Citation14	9.6^Citation8
*4	11.7^Citation24	<1.0^Citation14	0.9^Citation8
*10	0.4^Citation24	51.0^Citation14	53.0^Citation16
*1/*1	63.9^Citation24	30.2–100.0^Citation14	15.7^Citation8–27.1^Citation16
*1/*2	0.0^Citation24	26.6^Citation14	3.5^Citation8
*2/*2	0.0^Citation24	7.2^Citation14	3.5^Citation8
*1/*4	15.0^Citation24	0.7^Citation14	0.0^Citation8
*4/*4	1.5^Citation24	0.0^Citation14	0.0^Citation8
*2/*4	0.0^Citation24	0.0^Citation14	1.8^Citation8
*1/*10	0.0^Citation24	38.9^Citation14	39.0^Citation16
*2/*10	0.0^Citation24	0.0^Citation14	7.0^Citation8
*4/*10	0.75^Citation24	0.0^Citation14	0.0^Citation8
*10/*10	0.0^Citation24	30.9^Citation14	33.9^Citation16
CYP3A5
*1	2.2^Citation24	30.0^Citation14	80.0^Citation9
*3	97.8^Citation24	70.0^Citation14	20.0^Citation9
*1/*1	0.0^Citation24	8.5^Citation14	63.0^Citation9
*1/*3	4.4^Citation24	43.6^Citation14	33.0^Citation9
*3/*3	95.6^Citation24	47.9^Citation14	4.0^Citation9

Note: Adapted from Copyright © 2013. PLoS One. Fernández-Santander A, Gaibar M, Novillo A, et al. Relationship between genotypes SULT1A2 and CYP2D6 and tamoxifen metabolism in breast cancer patients. 2013;8(7):e70183.²⁴ © 2011 The Authors. British Journal of Clinical Pharmacology © 2011. The British Pharmacological Society. Lim JS, Chen XA, Singh O, et al. Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients. 2011;71(5):737–750.¹⁴

Table 2 Phenotype classification by the conventional method

Genotype	Phenotype	Genotype	Phenotype
Functional/functional	EM	Reduced/reduced	IM
Functional/reduced	EM	Reduced/null	IM
Functional/null	EM	Null/null	PM

Notes: Functional alleles = CYP2D6*1, CYP2D6*2, and CYP3A5*1. Reduced allele = CYP2D6*10. Null alleles = CYP2D6*4 and CYP3A5*3.

Abbreviations: EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer.

Table 3 Demographic data of Thai breast cancer patients undergoing TAM treatment

Demographic and clinical data	N (%)
Age (years)
18–30	1 (0.7)
30–40	17 (12.7)
40–50	54 (40.3)
>50	62 (46.3)
TAM administration (years)
<0.5	26 (19.4)
0.5–1	23 (17.2)
1–3	57 (42.5)
>3	28 (20.9)
History of treatment
Chemotherapy	89 (17.6)
Operations	43 (8.5)
Radiation	42 (8.3)
Stage of breast cancer
Stage 0	1 (0.7)
Stage I	44 (32.8)
Stage II	58 (43.3)
Stage III	24 (17.9)
Stage IV	6 (4.5)
Unidentified	1 (0.7)
ER+	132 (98.5)
PR+	97 (72.4)
HER2+	76 (56.7)
Menopausal status
Premenopausal	71 (53.0)
Perimenopausal	14 (10.4)
Postmenopausal	49 (36.6)

Abbreviations: TAM, tamoxifen; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.

Table 4 Prevalence of CYP2D6*2, CYP2D6*4, CYP2D6*10, and CYP3A5*3 in Thai breast cancer patients undergoing TAM treatment (N=134)

Genotype (phenotype)	Prevalence (%)
CYP2D6
CYP2D6*1/*1 (EM)	13 (9.7)
CYP2D6*1/*2 (EM)	3 (2.2)
CYP2D6*2/*2 (EM)	5 (3.7)
CYP2D6*4/*4 (PM)	2 (1.5)
CYP2D6*1/*10 (EM)	21 (15.7)
CYP2D6*2/*10 (EM)	13 (9.7)
CYP2D6*4/*10 (IM)	5 (3.7)
CYP2D6*10/*10 (IM)	72 (53.7)
CYP3A5
CYP3A5*1/*1 (EM)	18 (13.4)
CYP3A5*1/*3 (EM)	64 (47.8)
CYP3A5*3/*3 (PM)	52 (38.8)

Abbreviations: TAM, tamoxifen; EM, extensive metabolizer; PM, poor metabolizer; IM, intermediate metabolizer.

Figure 3 Prevalence of combined CYP2D6 and CYP3A5 phenotype in Thai breast cancer patients undergoing TAM treatment (N=134).

Notes: Outer arrow line indicates prevalence of combined CYP2D6 and CYP3A5 phenotype. Outer doughnut chart indicates prevalence of CYP2D6 phenotype. Inner doughnut chart indicates prevalence of CYP3A5 phenotype.
Abbreviations: TAM, tamoxifen; EM, extensive metabolizer; PM, poor metabolizer; IM, intermediate metabolizer.

Table 5 Phenotype frequency (%) of CYP2D6 with CYP3A5 (N=134)

CYP2D6 phenotype	CYP3A5 phenotype			Total (%)
	EM	IM	PM
EM	31 (23.1)	0 (0.0)	24 (17.9)	55 (41.0)
IM	51 (38.1)	0 (0.0)	26 (19.4)	77 (57.5)
PM	0 (0.0)	0 (0.0)	2 (1.5)	2 (1.5)
Total (%)	82 (61.2)	0 (0.0)	52 (38.8)	134 (100.0)

Abbreviations: EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer.

Table 6 Determination of the CYP2D6*4 allele from the CYP2D6*2 and CYP2D6*10 assays

Patient	CYP2D6 genotype
	2850C>T	100C>T	2850C>T and 100C>T
1	CYP2D6*1/*2	CYP2D6*10/*10	CYP2D6*4/*10
2	CYP2D6*1/*2	CYP2D6*10/*10	CYP2D6*4/*10
3	CYP2D6*1/*2	CYP2D6*10/*10	CYP2D6*4/*10
4	CYP2D6*1/*2	CYP2D6*10/*10	CYP2D6*4/*10
5	CYP2D6*1/*2	CYP2D6*10/*10	CYP2D6*4/*10
6	CYP2D6*2/*2	CYP2D6*10/*10	CYP2D6*4/*4
7	CYP2D6*2/*2	CYP2D6*10/*10	CYP2D6*4/*4

Table 7 Prevalence of CYP2D6 and CYP3A5 polymorphisms in Caucasians and Thais

Allele/genotype (phenotype)	Prevalence (%)
	Caucasians^Citation24	Thais (this study)
CYP2D6
*1 (wild type)	76.7	72.9
*2 (wild type)	0.0	3.2
*4 (null allele)	11.7	1.1
*10 (reduced allele)	0.4	22.8
*1/*1 (EM)	63.9	9.7
*1/*2 (EM)	0.0	2.2
*2/*2 (EM)	0.0	3.7
*1/*4 (EM)	15.0	0.0
*4/*4 (PM)	1.5	1.5
*2/*4 (EM)	0.0	0.0
*1/*10 (EM)	0.0	15.7
*2/*10 (EM)	0.0	9.7
*4/*10 (IM)	0.75	3.7
*10/*10 (IM)	0.0	53.7
CYP3A5
*1 (wild type)	2.2	37.3
*3 (null allele)	97.8	62.7
*1/*1 (EM)	0.0	13.4
*1/*3 (EM)	4.4	47.8
*3/*3 (PM)	95.6	38.8

Note: Adapted from Copyright © 2013. PLoS One. Fernández-Santander A, Gaibar M, Novillo A, et al. Relationship between genotypes SULT1A2 and CYP2D6 and tamoxifen metabolism in breast cancer patients. 2013;8(7):e70183.²⁴ The phenotype classification in this table was defined by the authors of this article.

Abbreviations: EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer.

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