The effect of CYP2D6 *10 polymorphism on adjuvant tamoxifen in Asian breast cancer patients: a meta-analysis

Figures & data

Figure 1 Study flow diagram for the process of selecting the final 15 studies.

Table 1 Characteristics and quality assessment of the included studies

Study ID	Country	Sample size	Menopause status (pre + post)	Follow-up (months)a	Endpoints	Genotyping method	HWE	NOS
Xu et al^Citation35	China	152	–	63 (4–122)	DFS	RT-PCR	Y	6
Kiyotani et al^Citation26	Japan	67	35+32	96 (19.2–259.2)	RFS, recurrence	TaqMan	Y	7
Sirachainan et al^Citation29	Thailand	39	31+8	52.3–97.4	DFS	Pyrosequencing	Y	6
Sukasem et al^Citation30	Thailand	48	30+18	67.2	DFS	Microarray	Y	7
Teh et al^Citation7	Mixed*	95	33+62	–	Recurrence	TaqMan	Y	7
Chamnanphon et al^Citation25	Thailand	57	38+19	48 (2–172)	DFS, recurrence	Microarray	Y	6
Tian et al^Citation31	China	200	–	31.5 (9–58)	DFS	TaqMan	Y	7
Wei and Xu^Citation33	China	257	–	–	DFS, OS	RT-PCR	Y	5
Xiao et al^Citation34	China	87	0+87	35 (12–43)	DFS, recurrence	TaqMan	Y	6
Wang et al^Citation32	China	171	–	60	OS	RT-PCR	Y	5
Zhang et al^Citation38	China	296	174+122	–	OS	Sequencing	#	6
Lei et al^Citation27	China	72	65+7	85 (20–144)	DFS, OS	Pyrosequencing	Y	6
Sensorn et al^Citation28	Thailand	73	47+26	87.6 (60–171.6)	DFS	RT-PCR	Y	7
Yu et al^Citation36	China	106	–	–	DFS	RT-PCR	Y	5
Zeng et al^Citation37	China	76	–	30.5 (5–40)	Recurrence, OS	RT-PCR	Y	5

Notes:

* Mixed includes patients in Malaysia, China, and India.

# HWE of Zhang et al³⁸ was unknown and could not be estimated.

a Data presented as median (range).

Abbreviations: DFS, disease-free survival; HWE, Hardy–Weinberg equilibrium; NOS, Newcastle–Ottawa scale; OS, overall survival; RFS, relapse-free survival; RT-PCR, real time-polymerase chain reaction.

Figure 2 Forest plot to estimate the effect of CYP2D6 *10 polymorphism on the DFS of breast cancer patients taking tamoxifen.

Note: Weights are from random effects analysis.
Abbreviations: DFS, disease-free survival; HR, hazard ratio.

Table 2 Results of the effect of CYP2D6 *10 polymorphism on the DFS of breast cancer patients taking tamoxifen

Comparison	Studies	Overall effect			Heterogeneity		Publication bias
		HR (95% CI)	Z	p-value	I^2, %	p-value	Begg’s test	Egger’s test
TT vs CC	4	1.79 (1.14–2.80)	2.54	0.011	44.50	0.144	1	0.91
CT vs CC	4	2.02 (1.04–3.91)	2.09	0.037	36.30	0.194	0.734	0.351
TT vs CT/CC	4	2.19 (1.07–4.50)	2.13	0.033	52.60	0.097	0.308	0.012
TT/CT vs CC	2	1.80 (0.81–4.00)	1.45	0.147	53.00	0.145	1	–
TT vs CT	2	2.03 (1.41–2.93)	3.79	0	0.00	0.958	1	–

Notes: Different from DFS, the pooled results of the endpoint of OS showed that there was no relationship between CYP2D6 *10 polymorphism and OS of female breast cancer patients with adjuvant tamoxifen. As shown in Table 3, all the genetic models did not support any evidence of association (TT vs CC: HR =1.05, 95% CI =0.35–3.11, p=0.934; CT vs CC: HR =1.29, 95% CI =0.83–2.00, p=0.225; TT vs CT/CC: HR =0.96, 95% CI =0.62–1.48, p=0.858; TT/CT vs CC: HR =1.57, 95% CI =0.89–2.77, p=0.119). For the additive comparison model of TT vs CT, which was reported by only one study, the result was negative as well.

Abbreviations: DFS, disease-free survival; HR, hazard ratio; OS, overall survival.

Table 3 Results of the effect of CYP2D6 *10 polymorphism on the OS of female breast cancer patients taking tamoxifen

Comparison	Studies	Overall effect			Heterogeneity		Publication bias
		HR (95% CI)	Z	p-value	I^2, %	p-value	Begg’s test	Egger’s test
TT vs CC	3	1.05 (0.35–3.11)	0.08	0.934	73.10	0.024	1.00	0.320
CT vs CC	3	1.29 (0.83–2.00)	1.14	0.255	0.00	0.844	1.00	0.751
TT vs CT/CC	2	0.96 (0.62–1.48)	0.18	0.858	0.00	0.578	1.00	–
TT/CT vs CC	2	1.57 (0.89–2.77)	1.56	0.119	0.00	0.468	1.00	–
TT vs CT	1	1.36 (0.58–3.18)	0.71	0.478	–	–	–	–

Notes: The results of the endpoint of recurrence are shown in Figure 3 and Table 4. CYP2D6 *10 polymorphism was found to be associated with the increased risk of relapse of breast cancer in different genetic models (TT vs CC: OR =4.07, 95% CI =1.88–8.80, p<0.001; TT vs CT/CC: OR =3.69, OR =2.13–6.41, p<0.001; TT/CT vs CC: 2.52, 95% CI =1.24–5.13, p=0.011; T allele vs C allele: 2.99, 95% CI =1.46–6.11, p=0.029). However, in the heterozygous model, heterozygous variant of CYP2D6 *10 gene did not increase the risk of relapse (CT vs CC: OR =1.39, 95% CI =0.62–3.13, p=0.427).

Abbreviations: HR, hazard ratio; OS, overall survival.

Figure 3 Forest plot to estimate the effect of CYP2D6 *10 polymorphism on the recurrence of breast cancer in patients taking tamoxifen in the comparison of (A) TT vs CC; (B) CT/TT vs CC; (C) TT vs CT/TT and (D) T vs C allele.

Note: Weights are from random effects analysis.
Abbreviations: CI, confidence interval; OR, odds ratio.

Table 4 Results of the effect of CYP2D6 *10 polymorphism on the recurrence of breast cancer in patients taking tamoxifen

Comparison	Overall effect			Heterogeneity		Publication bias
	OR (95% CI)	Z	p-value	I^2, %	p-value	Begg’s test	Egger’s test
TT vs CC	4.07 (1.88–8.80)	3.57	0	40.20	0.154	0.22	0.11
CT vs CC	1.39 (0.62–3.13)	0.79	0.427	0.00	0.725	0.462	0.331
TT vs CT/CC	3.69 (2.13–6.41)	4.65	0	40.90	0.148	0.806	0.51
TT/CT vs CC	2.52 (1.24–5.13)	2.55	0.011	14.10	0.325	0.22	0.073
T vs C*	2.99 (1.46–6.11)	3	0.003	63.10	0.029	0.462	0.141

Note:

* Random effects model was used for the comparison of allele genetic model as heterogeneity is significant.

Abbreviation: OR, odds ratio.

Figure 4 Begg’s funnel plots to examine publication bias for reported comparisons of CYP2D6 *10 polymorphism with recurrence in the comparison of (A) CT vs CC and (B) TT vs CC in Asian breast cancer patients treated with tamoxifen.

Abbreviations: OR, odds ratio; SE, standard error.

Figure 5 Sensitivity analysis of the comparison of allele genetic model (T vs C allele) in the recurrence analysis.

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