Relationship between UGT1A1*6/*28 gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy

Figures & data

Table 1 Treatment regimens

Tumor	Regimen	No. of patients (n=81)	Dose of CPT-11 (mg/m^2)	Days on which CPT-11 was administered	Cycle (weeks)
Lung cancer	IP	36	60	1, 8, 15	4
	CPT-11 monotherapy	8	60	1, 8, 15	4
	IP plus bevacizumab	1	60	1, 8, 15	3
Colorectal cancer	IP	1	130	1	3
	FOLFIRI	22	180	1	2
	FOLFIRI plus bevacizumab/cetuximab	2	180	1	2
	CPT-11 plus bevacizumab	1	180	1	3
	CPT-11, capecitabine plus bevacizumab	1	180	1	2
Esophageal cancer	IP	2	130	1	3
	FOLFIRI	1	180	1	2
	CPT-11 plus apatinib mesylate	6	150	1	2

Abbreviations: CPT-11, irinotecan; IP, irinotecan plus cisplatin; FOLFIRI, folinic acid, 5-fluorouracil plus irinotecan.

Figure 1 Detection of gene polymorphisms in UGT1A1*6 and UGT1A1*28 quality control genes by DFMH.

Notes: UGT1A1 gene polymorphisms were detected using different fluorescent probes specific for UGT1A1*6 or UGT1A1*28 wild-type or mutant genotypes. The time to reach the specific fluorescence ST was determined for each channel using the fluorescence detector software, Microseq (Tianlong Science and Technology Co., Ltd., Xi’an, China). ΔST was calculated to set the range of ΔST values indicative of each UGT1A1 polymorphism, which could then be used to determine the genotype of each patient. The results were as follows: (A) UGT1A1*6 (G/G), ΔST =−2.9896; (B) UGT1A1*6 (G/A), ΔST =−0.7286; (C) UGT1A1*6 (A/A), ΔST =10.6859; (D) UGT1A1*28 (TA6/6), ΔST =−7.2983; (E) UGT1A1*28 (TA6/7), ΔST =0.8421; and (F) UGT1A1*28 (TA7/7), ΔST =14.8599. The maximum value of ΔST is 5. Therefore, the ΔST values of UGT1A1*6 (G/A), UGT1A1*6 (G/G), and UGT1A1*6 (A/A) were between −2.0657 and 5.000, <−2.0657, and >5.000, respectively, and the ΔST values of UGT1A1*28 (TA6/7), UGT1A1*28 (TA6/6), and UGT1A1*6 (TA7/7) were between −3.5868 and 5.000, <−3.5868, and >5.000, respectively.
Abbreviations: DFMH, digital fluorescence molecular hybridization; ST, signal intensity.

Figure 2 UGT1A1 gene polymorphisms in patients.

Notes: Blood samples from the patients were analyzed by DFMH, and the results are as follows: (A) ΔST =−3.1828, representing UGT1A1*6 (G/G); (B) ΔST =0.4192, representing UGT1A1*6 (G/A); (C) ΔST =12.0046, representing UGT1A1*6 (A/A); (D) ΔST =−6.5741, representing UGT1A1*28 (TA6/6); (E) ΔST =1.6713, representing UGT1A1*28 (TA6/7); and (F) ΔST =5.6336, representing UGT1A1*28 (TA7/7).
Abbreviations: DFMH, digital fluorescence molecular hybridization; ST, signal intensity.

Table 2 Clinical characteristics of patients with irinotecan-based treatment in this study

Characteristics	No. of patients (n=81)	Frequency (%)
Mean age, years (range)	58 (28–79)
Gender
Male	67	82.72
Female	14	17.28
ECOG performance status
0	47	58.02
1	31	38.27
2	2	2.47
3	1	1.23
Type of tumor
Lung cancer	45	55.56
Colorectal cancer	27	33.33
Esophageal cancer	9	11.11
Habit of smoking and drinking
Smoking	20	24.69
Drinking	5	6.17
Smoking and drinking	31	38.27
None	25	34.57
Line of treatment
First line	30	37.04
Second line	47	58.02
Third line	4	4.94
Cycle of treatment
Second cycle	34	41.98
Third cycle	24	29.63
≥ fourth cycle	23	28.40

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

Table 3 Distribution of UGT1A1 gene polymorphisms

Genotype	No. of patients (n=81)	Ratio (%)
UGT1A1*6
G/G	62	76.54
G/A	17	20.99
A/A	2	2.47
UGT1A1*28
TA6/6	61	75.31
TA6/7	16	19.75
TA7/7	4	4.94
UGT1A1 combinations
G/G TA6/6	44	54.32
G/G TA6/7	14	17.28
G/A TA6/6	15	18.52
G/G TA7/7	4	4.94
G/A TA6/7	2	2.47
A/A TA6/6	2	2.47

Table 4 Relationship between UGT1A1*6/*28 genotype and the incidence of adverse reactions associated with CPT-11

Genotyping	Leukopenia, n (%)		Neutropenia, n (%)		Nausea and vomiting, n (%)		Diarrhea, n (%)
	Grades I–II	Grades III–IV	Grades I–II	Grades III–IV	Grades I–II	Grades III–IV	Grades I–II	Grades III–IV
G/G (n=62)	19 (30.65)	7 (11.29)	14 (22.58)	11 (17.74)	26 (41.94)	4 (6.45)	17 (27.41)	3 (4.84)
G/A (n=17)	5 (29.41)	1 (5.88)	0 (0)	3 (17.65)	8 (47.06)	0 (0)	3 (17.65)	3 (17.65)
A/A (n=2)	0 (0)	0 (0)	0 (0)	0 (0)	1 (50.00)	0 (0)	0 (0)	0 (0)
P-value	1.000	1.000	0.067	1.000	0.908	0.614	0.739	0.305
TA6/6 (n=61)	18 (29.51)	7 (11.48)	10 (16.39)	11 (18.03)	27 (44.26)	3 (4.92)	15 (24.59)	4 (6.56)
TA6/7 (n=16)	5 (31.25)	1 (6.25)	3 (18.75)	2 (12.50)	7 (43.75)	1 (6.35)	4 (25.00)	2 (12.50)
TA7/7 (n=4)	1 (25.00)	0 (0)	1 (25.00)	1 (25.00)	1 (25.00)	0 (0)	1 (25.00)	0 (0)
P-value	1.000	1.000	0.757	0.646	0.844	1.000	1.000	0.707
Wild-type (n=44)	13 (29.55)	6 (13.64)	10 (22.73)	8 (18.18)	19 (43.18)	3 (6.38)	12 (27.27)	2 (4.55)
Single-site mutant (n=29)	10 (34.48)	2 (9.60)	3 (10.34)	5 (17.24)	13 (44.83)	1 (3.45)	7 (24.13)	3 (10.34)
Two-site mutant (n=8)	1 (12.50)	0 (0)	1 (12.50)	1 (12.50)	3 (37.50)	0 (0)	1 (12.50)	1 (12.50)
P-value	0.483	0.357	0.365	0.926	1.000	1.000	0.670	0.354

Table 5 Relationship between UGT1A1*6/*28 genotype and the incidence of adverse reactions associated with different tumors

Tumor	Genotyping	Leukopenia, n (%)		Neutropenia, n (%)		Nausea and vomiting, n (%)		Diarrhea, n (%)
		Grades I–II	Grades III–IV	Grades I–II	Grades III–IV	Grades I–II	Grades III–IV	Grades I–II	Grades III–IV
Lung cancer	G/G (n=35)	7 (20.00)	6 (17.14)	4 (11.43)	4 (11.43)	6 (17.14)	4 (11.43)	10 (28.57)	2 (5.71)
	G/A A/A (n=10)	3 (30.00)	0 (0)	0 (0)	0 (0)	4 (40.00)	0 (0)	2 (20.00)	0 (0)
P-value		0.811	0.379	0.561	0.561	0.270	0.561	0.893	1.000
Colorectal cancer	G/G (n=20)	7 (35.00)	1 (5.00)	5 (25.00)	6 (30.00)	15 (75.00)	0 (0)	5 (25.00)	1 (5.00)
	G/A A/A (n=7)	1 (14.29)	0 (0)	0 (0)	1 (14.29)	4 (57.14)	0 (0)	1 (14.29)	3 (42.86)
P-value		0.633	1.000	0.283	0.633	0.633	NG	1.000	0.042
Lung cancer	TA6/6 (n=34)	7 (20.59)	5 (14.71)	2 (5.88)	3 (8.82)	8 (23.53)	3 (8.82)	8 (23.53)	2 (5.88)
	TA6/7 TA7/7 (n=11)	3 (27.27)	1 (9.09)	2 (18.18)	1 (9.09)	2 (18.18)	1 (9.09)	4 (36.36)	0 (0)
P-value		0.963	1.000	0.247	1.000	1.000	1.000	0.657	1.000
Colorectal cancer	TA6/6 (n=20)	6 (30.00)	1 (5.00)	4 (20.00)	5 (25.00)	14 (70.00)	0 (0)	5 (25.00)	2 (10.00)
	TA6/7 TA7/7 (n=7)	2 (28.57)	0 (0)	1 (14.28)	2 (28.57)	5 (71.43)	0 (0)	1 (14.29)	2 (28.57)
P-value		1.000	1.000	1.000	1.000	1.000	NG	1.000	0.269
Lung cancer	Wild-type (n=24)	4 (16.67)	5 (20.83)	2 (8.33)	3 (12.50)	3 (12.50)	3 (12.50)	6 (25.00)	2 (8.33)
	Mutant type (n=21)	6 (28.57)	1 (4.76)	2 (9.52)	1 (4.76)	6 (28.57)	1 (4.76)	6 (28.57)	0 (0)
P-value		0.549	0.253	1.000	0.700	0.331	0.700	1.000	0.491
Colorectal cancer	Wild-type (n=15)	5 (33.33)	1 (6.67)	4 (26.67)	4 (26.67)	11 (73.33)	0 (0)	4 (26.67)	0 (0)
	Mutant type (n=12)	3 (25.00)	0 (0)	1 (8.33)	3 (25.00)	8 (66.67)	0 (0)	2 (16.67)	4 (33.33)
P-value		0.696	1.000	0.342	1.000	1.000	NG	0.662	0.028

Abbreviation: NG, not given.

Table 6 Relationship between UGT1A1 genotype and the incidence of adverse reactions in patients of different ages

Age	Genotyping	Leukopenia, n (%)		Neutropenia, n (%)		Nausea and vomiting, n (%)		Diarrhea, n (%)
		Grades I–II	Grades III–IV	Grades I–II	Grades III–IV	Grades I–II	Grades III–IV	Grades I–II	Grades III–IV
<60	G/G (n=36)	13 (36.11)	5 (13.89)	6 (16.67)	7 (19.44)	16 (44.44)	0 (0)	10 (27.78)	0 (0)
	G/A A/A (n=12)	3 (27.27)	1 (9.09)	0 (0)	2 (18.18)	3 (27.27)	0 (0)	0 (0)	3 (25.00)
P-value		0.724	1.000	0.313	1.000	0.394	NG	0.101	0.013
≥60	G/G (n=26)	6 (23.08)	2 (7.69)	8 (30.77)	4 (15.38)	10 (38.46)	4 (15.38)	7 (26.92)	3 (11.54)
	G/A A/A (n=7)	2 (33.33)	0 (0)	0 (0)	1 (16.67)	6 (85.71)	0 (0)	1 (14.28)	0 (0)
P-value		1.000	1.000	0.154	1.000	0.039	0.555	0.652	1.000
<60	TA6/6 (n=34)	11 (32.35)	5 (14.71)	6 (17.65)	6 (17.65)	11 (32.35)	0 (0)	7 (20.59)	2 (5.88)
	TA6/7 TA7/7 (n=14)	3 (27.27)	1 (9.09)	1 (9.09)	3 (21.43)	6 (42.86)	0 (0)	4 (28.57)	1 (7.14)
P-value		0.684	0.810	0.626	1.000	0.719	NG	0.826	1.000
≥60	TA6/6 (n=27)	7 (25.93)	2 (7.41)	4 (14.81)	5 (18.52)	16 (59.26)	3 (11.11)	8 (29.63)	2 (7.41)
	TA6/7 TA7/7 (n=6)	3 (50.00)	0 (0)	3 (50.00)	0 (0)	2 (40.00)	1 (20.00)	1 (16.67)	1 (16.67)
P-value		0.336	1.000	0.093	0.556	0.375	1.000	1.000	0.464
<60	Wild-type (n=24)	7 (29.17)	4 (16.67)	5 (20.83)	4 (16.67)	9 (37.50)	0 (0)	6 (25.00)	0 (0)
	Mutant type (n=24)	6 (33.33)	2 (11.11)	1 (5.56)	5 (20.83)	9 (37.50)	0 (0)	5 (20.83)	3 (12.50)
P-value		0.754	0.663	0.190	1.000	1.000	NG	1.000	0.233
≥60	Wild-type (n=20)	6 (30.00)	2 (10.00)	5 (25.00)	4 (20.00)	10 (50.00)	3 (15.00)	7 (35.00)	2 (10.00)
	Mutant type (n=13)	5 (38.46)	0 (0)	3 (23.08)	1 (9.09)	7 (53.85)	1 (9.09)	3 (23.07)	1 (7.69)
P-value		0.714	0.508	1.000	0.625	1.000	1.000	0.701	1.000

Abbreviation: NG, not given.

Table 7 Relationship between UGT1A1 genotypes and tumor response

Tumor	Genotyping	PR, n (%)	P-value	SD, n (%)	P-value	PD, n (%)	P-value
Lung cancer	G/G (n=21)	3 (14.28)	0.320	13 (61.90)	0.443	5 (23.81)	1.000
	G/A A/A (n=9)	3 (33.33)		4 (44.44)		2 (22.22)
	TA6/6 (n=23)	5 (21.74)	1.000	13 (56.52)	1.000	5 (21.74)	1.000
	TA6/7 TA7/7 (n=7)	1 (14.29)		4 (57.14)		2 (28.57)
	Wild-type (n=14)	2 (14.29)	0.657	9 (64.29)	0.484	3 (21.43)	1.000
	Mutant type (n=16)	4 (25.00)		8 (50.00)		4 (25.00)
Colorectal cancer	G/G (n=14)	4 (28.57)	0.530	8 (57.14)	0.603	2 (14.28)	1.000
	G/A A/A (n=5)	0 (0)		4 (80.00)		1 (20.00)
	TA6/6 (n=15)	2 (13.33)	0.178	10 (66.67)	0.603	3 (20.00)	1.000
	TA6/7 TA7/7 (n=4)	2 (50.00)		2 (50.00)		0 (0)
	Wild-type (n=11)	2 (18.18)	1.000	7 (63.64)	1.000	2 (18.18)	1.000
	Mutant type (n=8)	2 (25.00)		5 (62.50)		1 (12.50)

Abbreviations: PR, partial response; SD, stable disease; PD, progressive disease.