Docetaxel-induced neuropathy: A pharmacogenetic case-control study of 150 women with early-stage breast cancer

Figures & data

Table I. Characteristics of 150 Danish patients with early-stage breast cancer according to docetaxel-induced peripheral neuropathy (DIPN) (grades 2–4) N = 75, or no DIPN (grades 0–1) N = 75.

		All		Patients with DIPN (grades 2–4)		Patients without DIPN (grades 0–1)
Table I		N	%	N	%	N	%	p-Value
Number of patients		150		75		75
Age, years	Median	53		54		52		0.59*
	range	29–74		29–70		36–74
	SD	8.36		8.54		8.24
BMI	< 25	77	51	31	41	46	61	0.008^†
	25–29	48	32	25	33	23	31
	≥ 30	25	17	19	25	6	8
Menopausal status	Pre	60	40	25	33	35	47	0.10^†
	Post	90	60	50	67	40	53
Surgery	Mastectomy	37	25	16	21	21	28	0.34^†
	BCS‡	113	75	59	79	54	72
Tumor size	< 2 cm	89	59	40	53	49	65	0.14^†
	≥ 2 cm	61	41	35	47	26	35
Histology**	Ductal	129	86	64	85	65	87	0.95^†
	Lobular	11	7	6	8	5	7
	Other	10	7	5	7	5	7
Tumor grade**	I	20	13	12	16	8	11	0.79^†
	II	66	44	31	41	35	47
	III	54	36	27	36	27	36
	Unknown	10	7	5	7	5	7
Estrogen receptor status	ER+	103	69	49	65	54	72	0.45^†
	ER 0%	46	31	25	33	21	28
	Unknown	1	1	1	1	0	0
Human epidermal growth factor receptor 2 (HER2)	Positive	40	27	22	29	18	24	0.44^†
	Negative	109	73	52	69	57	76
	Unknown	1	1	1	1	0	0
Number of positive lymph nodes	None	94	63	56	75	38	51	0.002^†
	> 1	56	37	19	25	37	49
Alcohol consumption (units/week)	0	24	16	14	19	10	13	0.48^†
	1–14	118	79	56	75	62	83
	> 14	8	5	5	7	3	4
Diabetes	yes	144	96	70	93	74	99	0.10^†
	no	6	4	5	7	1	1
Performance status (ECOG)	0	120	80	57	76	63	84	0.45^†
	1	9	6	5	7	4	5
	Unknown	21	14	13	17	8	11
Regimen ^††	D100	108	72	55	73	53	71	0.72^†
	D75	42	28	20	27	22	29
	Median	300		300		300		0.001*
	Mean	312		294		331
	Range	75–450		75–450		75–450

*Wilcoxon rank sum test; ^† χ²-test; ‡ Breast conserving surgery, **Only ductal and lobular carcinomas are graded – the rest were recorded as unknown, ^††D100 = 3 cycles of epirubicin (90 mg/m²) and cyclophosphamide (600 mg/m²) followed by 3 cycles of docetaxel (100 mg/m²), D75 = six cycles of cyclophosphamide (600 mg/m²) and docetaxel (75 mg/m²).

Table II. Frequency of GSTP1 and ABCB1 genotypes among patients with docetaxel-induced peripheral neuropathy (DIPN) (grades 2–4) N = 75 and patients without DIPN N = 75 (grades 0–1).

			Frequency of genotype All (N = 150)		Frequency of genotype + DIPN (N = 75)		Frequency of genotype − DIPN (N = 75)		Fishers exact test
Primary analysis	rs number	Geno-type	n	%	n	%	n	%
Glutathione S-transferase pi 1 (GSTP1)	1695	A/A	62	41	30	40	32	43	0.90
		A/G	67	45	35	47	32	43
		G/G	21	14	10	13	11	15
	1138272	C/C	124	83	56	75	68	91	0.01
		C/T	24	16	18	24	6	8
		T/T	2	1	1	1	1	1
ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1)	2032582	G/G	49	33	22	29	27	36	0.27
		G/T	71	47	35	47	36	48
		T/T	28	19	18	24	10	13
		A/T	1	1	0	0	1	1
		A/G	1	1	0	0	1	1
	1128503	C/C	47	31	20	27	27	36	0.20
		C/T	75	50	37	49	38	51
		T/T	28	19	18	24	10	13
	1045642	C/C	32	21	14	19	18	24	0.46
		C/T	67	45	32	43	35	47
		T/T	51	34	29	39	22	29

Table III. Frequency of TUBB2A, NAT2, ERCC1, ATP7A, CYP3A5, CYP3A4, CHST3, SLCO1B3 and SLC10A2 genotypes among patients with docetaxel-induced peripheral neuropathy (DIPN) (grades 2–4) N = 75 and patients without neuropathy N = 75 (grades 0–1).

			Frequency of genotype All (N = 150)		Frequency of genotype + DIPN (N = 75)		Frequency of genotype − DIPN (N = 75)		Fishers exact test
Explorative analysis	rs number	Geno-typ	N	%	N	%	N	%
TUBB2A*	909964	C/C	8	5	4	5	4	5	0.96
		C/T	59	40	29	39	30	41
		T/T	80	54	41	55	39	53
	909965	A/A	81	55	42	57	39	53	0.93
		A/G	58	39	28	38	30	41
		G/G	8	5	4	5	4	5
	9501929	A/A	131	89	65	88	66	90	0.59
		A/G	15	10	9	12	6	8
		G/G	1	1	0	0	1	1
	3734492	A/G	3	2	1	1	2	3	0.62
		G/G	144	96	73	99	71	97
	13219681	A/G	16	11	9	12	7	10	0.79
		G/G	131	89	65	88	66	90
NAT2	1799931	A/G	4	3	2	3	2	3	1.00
		G/G	146	97	73	97	73	97
ERCC1	3212986	A/A	6	4	3	4	3	4	0.91
		A/C	53	35	25	33	28	37
		C/C	91	61	47	63	44	59
ATP7A	2227291	C/C	5	3	2	3	3	4	0.62
		C/G	55	37	25	33	30	40
		G/G	90	60	48	64	42	56
CYP3A5	776746	A/A	2	1	1	1	1	1	0.74
		A/G	22	15	9	12	13	17
		G/G	126	84	65	87	61	81
CYP3A4	2740574	A/A	136	91	68	91	68	91	1.00
		A/G	13	9	7	9	6	8
		G/G	1	1	0	0	1	1
CHST3	4148950	A/A	34	23	20	27	14	19	0.40
		A/G	65	43	29	39	36	48
		G/G	51	34	26	35	25	33
	1871450	A/A	34	23	20	27	14	19	0.40
		A/G	65	43	29	39	36	48
		G/G	51	34	26	35	25	33
SLCO1B3	11045585	A/A	110	73	52	69	58	77	0.24
		A/G	36	24	22	29	14	19
		G/G	4	3	1	1	3	4
SLC10A2	rs2301159	C/C	93	62	45	60	48	64	0.78
		C/T	50	33	27	36	23	31
		T/T	7	5	3	4	4	5

*three patients were not genotyped in TUBB2A.

Table IV. Odds ratio of neuropathy (grades 2+) after docetaxel treatment among patients with early-stage breast cancer in Denmark.

		Univariate logistic regression		Multiple logistic regression^†
		OR (95%CI)	p	OR (95% CI)	p
BMI	< 25	1.0	0.006	1.0	0.02
	25–29	1.61 (0.78–3.34)		1.29 (0.56–2.97)
	≥ 30	4.70 (1.69–13.09)		4.80 (1.60–14.41)
Number of positive lymph nodes	None	1.0	0.003	1.0	0.02
	> 1	0.35 (0.17–0.69)		0.39 (0.18–0.86)
Cumulative dose of docetaxel mg/m^2	75–299	1.0	< 0.0001	1.0	< 0.0001
	300–450	0.19 (0.08–0.45)		0.17 (0.07–0.42)
Glutathione S-transferases pi 1 (GSTP1) rs1138272	C/C	1.0	0.01	1.0	0.01
	C/T	3.30 (1.29–8.40)		3.85 (1.34–11.09)
	T/T*

*Two patients with T/T genotype are calculated as C/T; ^†Adjusted for BMI, number of positive lymph nodes, cumulated dose of docetaxel and rs1138272.

Table V. Frequency of haplotypes and association with docetaxel-induced peripheral neuropathy in an unadjusted time-to-neuropathy analysis, N = 147.

Haplotypes	Nucleotide by phase	With DIPN (%) N = 72	Without DIPN (%) N = 75	Unadjusted time-to neuropathy HR	95% CI	P
GSTP1 (rs1695, rs1138272)
GSTP1*A/GSTP1*A	AC/AC	29 (40)	32 (43)	Ref (1.0)
GSTP1*A/GSTP1*B	AC/GC	20 (28)	30 (40)	0.79	0.44–1.39	0.4
GSTP1*A/GSTP1*C	AC/GT	13 (18)	2 (3)	2.10	1.08–4.07	0.03
GSTP1*B/GSTP1*B	GC/GC	5 (7)	6 (8)	^†
GSTP1*B/GSTP1*C	GC/GT	4 (6)	4 (5)	^†
GSTP1*C/GSTP1*C	GT/GT	1 (1)	1 (1)	^†
ABCB1 (rs104542, rs2032582, rs1128503)
Wt/Wt	CGC/CGC	12 (17)	15 (20)	Ref. (1.0)
Wt/Full var	GCG/TTT	23 (32)	25 (33)	1.05	0.52–2.12	0.9
Full var/ Full var	TTT/TTT	15 (21)	10 (13)	1.74	0.81–3.72	0.2
Other	***/***	22 (31)	25 (33)

Wt, wildtype; var, variant; Ref, reference.

GSTP1*A; 105 Ile → 114 Ala, GSTP1*B; 105Val → 114 Ala, GSTP1*C; 105 Val→ 114 Val.

Data were only available for 147 patients in the time-to-neuropathy analysis

^†not included because of limited number of patients.