UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil

Table 1 Association of UDP-glucuronosyltransferase1A1 and thymidylate synthetase genotypes with tumor response

Genotypes	Tumor response
	n (%)	P value1
UGT1A1*28
TA 6/6	14 (17.9)	0.446
TA 6/7, TA 7/7	8 (24.2)
UGT1A1*6
G/G	11 (15.7)	0.217
G/A, A/A	11 (26.8)
TS promotor
3RG/3RG	3 (17.6)	0.880
3RG/3RC, 3RG/2RG	5 (23.8)
3RC/3RC, 3RC/2RG, 2RG/2RG	12 (19.4)

¹Fisher’s exact test for all genotypes. Tumor response including complete and partial response, 111 patients were assessable for tumor response. UGT1A1: UDP-glucuronosyltransferase1A1; TS: Thymidylate synthetase.

Table 2 Association of UDP-glucuronosyltransferase1A1 in combination with thymidylate synthetase genotypes with tumor response

UGT1A1*28	TS promoter
	3RG/3RG	3RG/3RC, 3RG/2RG	3RC/3RC, 3RC/2RG, 2RG/2RG
TA6/6	2/11 (18.1)	4/13 (30.8)	6/44 (13.6)
TA6/7	1/4 (25)	1/6 (16.7)	5/15 (33.3)
TA7/7	0/2 (0)	0/2 (0)	1/3 (33.3)

Tumor response including complete and partial response, 111 patients were assessable for tumor response, no significant difference was found (Fisher’s exact test). UGT1A1: UDP-glucuronosyltransferase1A1; TS: Thymidylate synthetase.

Table 3 Association of UDP-glucuronosyltransferase1A1 genotypes with toxicity

Genotypes	Delayed diarrhea						Neutropenia
	Grades 2-4			Grades 3/4			Grades 3/4			Grade 4
	n (%)	P value1	P value2	n (%)	P value1	P value2	n (%)	P value1	P value2	n (%)	P value1	P value2
UGT1A1*28
TA 6/6	25 (27.8)	< 0.0005	< 0.0005	14 (15.6)	0.228	0.178	23 (25.6)	0.088	0.055	7 (7.8)	0.043	0.017
TA 6/7	2 (37.5)			6 (18.8)			10 (31.3)			2 (6.3)
TA 7/7	8 (100)			3 (37.5)			5 (62.5)			3 (37.5)
UGT1A1*6
G/G	24 (31.2)	0.564	0.346	10 (13)	0.12	0.057	23 (29.9)	1	0.748	8 (10.4)	0.857	0.473
A/G	19 (39.6)			11 (22.9)			14 (29.2)			4 (8.3)
A/A	2 (40)			2 (40)			1 (20)			0 (0)

¹Fisher’s exact test for all genotype;

²Exact test of Cochran-Armitage trend test across genotypes. Toxicity grade by National Cancer Institute Common Toxicity Criteria version 3.0. A total of 130 patients were assessable for toxicity. Significant differences were found on grades 2-4 delayed diarrhea and grade 4 neutropenia for UGT1A1*28 genotypes. UGT1A1: UDP-glucuronosyltransferase1A1.

Table 4 Association between UDP-glucuronosyltransferase1A1 genotypes and pharmacokinetics parameters

Genotype	AUC CPT-11		AUC SN-38		AUC SN-38G		AUC SN-38G/AUC SN-38 ratio
	Median	P value	Median	P value	Median	P value	Median	P value
UGT1A1*28
TA6/6	5554.57	0.1631	176.40	0.1491	582.14	0.9881	3.178	0.1581
TA6/7	6919.11		213.25		591.86		3.330
TA7/7	9049.03		390.00		584.63		1.488
UGT1A1*6
G/G	5811.73	0.9532	189.62	0.3202	529.96	0.2342	2.924	0.5912
G/A	6582.17		231.50		679.17		3.759
UGT1A1*28+*6
TA6/6 + G/G	5297.41	0.2821	169.62	0.0841	529.96	0.3861	2.924	0.1881
TA6/7 + G/G, TA6/6 + G/A	6649.50		217.87		679.17		3.680
TA7/7 + G/G TA6/7+ G/A	6213.46		297.89		584.63		1.488
UGT1A1*28
TA6/6, TA6/7	6030.13	0.8842	191.92	0.0672	582.14	1.0002	3.177	0.0572
TA7/7	9049.03		390.00		584.63		1.488
UGT1A1*28+*6
TA6/6 + G/G, TA6/7 + G/G, TA6/6 + G/A	6030.13	0.7482	183.37	0.0612	582.14	0.9152	3.177	0.0782
TA7/7 + G/G, TA6/7 + G/A	6213.46		297.89		584.63		1.488

¹Kruskal-Wallis test;

²Mann-Whitney U test. 34 patients were assessable for pharmacokinetics parameters. CPT-11: Irinotecan; UGT1A1: UDP-glucuronosyltransferase1A1; AUC: Area under concentration curve.