Background
Methods
Patients
Treatment and drug administration
Toxicity and response assessment
Genomic DNAs extraction and genotyping of UGT1A and DPYD
Mutation Type | PCR Primer (5′-3′) | Product length |
---|---|---|
UGT1A1*6 [5] | Primer-F: ACGCCTCG TTGTACATCAGAG | 217 bp |
Primer-R: CCTTGTT GTGCAGTAAGTGG | ||
UGT1A1*27
| Primer-F: ACTTACTGCACAACAAGGAGCT | 484 bp |
Primer-R: CACACCTGGGATAGTGGATTTTG | ||
UGT1A1*28 [5] | Primer-F: AGCCAGTTCAACTGTTGTTGC | 208 bp |
Primer-R: TTTGCT CCTGCCAGAGGTTC | ||
UGT1A7*2/*3/*4 [28] | Primer-F: TTTGCCGATGCTCGCTGGACG | 415 bp |
Primer-R: GCTATTTCTAAGACATTTTTGAAAAAATAGGG | ||
UGT1A9*22 [35] | Primer-F: ACTTAACATTGCAGCACAGG | 556 bp |
Primer-R: ATGGGCAAAAGCCTTGAACT | ||
DPYD*5
| Primer-F: ATTCAGTTCACTGCTCACTGAC | 370 bp |
Primer-R: GAGAAAGTTTTGGTGAGGGCA | ||
DPYD c.1896 T > C,
| Primer-F: TGGACAAAGCTCCTTTCTGAATA | 231 bp |
DPYD*2A [36] | Primer-R: CAGCAAAGCAACTGGCAGAT |
Statistical analysis
Results
Genotypes | No. of patients | % |
---|---|---|
UGT1A1*6
| ||
G/G | 431 | 65.2% |
G/A | 198 | 30.0% |
A/A | 32 | 4.8% |
UGT1A1*27
| ||
C/C | 535 | 98.2% |
C/A | 10 | 1.8% |
UGT1A1*28
| ||
TA6/TA6 | 501 | 75.8% |
TA6/TA7 | 152 | 23.0% |
TA7/TA7 | 8 | 1.2% |
UGT1A7
| ||
UGT1A7*1/*1
| 196 | 36.0% |
UGT1A7*1/*2
| 103 | 18.9% |
UGT1A7*1/*3
| 131 | 24.0% |
UGT1A7*2/*2
| 31 | 5.7% |
UGT1A7*2/*3
| 53 | 9.7% |
UGT1A7*3/*3
| 31 | 5.7% |
UGT1A9*22
| ||
T9/T9 | 99 | 18.2% |
T9/T10 | 442 | 81.1% |
T10/T10 | 4 | 0.7% |
DPYD*5
| ||
A/A | 256 | 51.6% |
A/G | 199 | 40.1% |
G/G | 41 | 8.3% |
DPYD*2A
| ||
G/G | 495 | 99.8% |
G/A | 1 | 0.2% |
DPYD c.1896 T > C
| ||
T/T | 395 | 79.6% |
T/C | 96 | 19.4% |
C/C | 5 | 1.0% |
Analysis of chemotherapy-induced toxicities
Severe diarrhea | Severe neutropenia | |||||||
---|---|---|---|---|---|---|---|---|
Factors | Univariate analysis | Multivariate analysis | Univariate analysis | Multivariate analysis | ||||
N/Total(%) |
P value | OR(95%CI) |
P value | N/Total(%) |
P value | OR(95%CI) |
P value | |
Sex | ||||||||
Male | 39/406(9.6%) | 73/406(18.0%) | ||||||
Female | 20/255(7.8%) | 0.439 | NAa
| NA | 63/255(24.7%) | 0.037 | 1.538(0.989–2.393) | 0.056 |
Age | ||||||||
≦65y | 44/545(8.1%) | 119/545(21.8%) | ||||||
>65y | 15/116(12.9%) | 0.096 | NA | NA | 17/116(14.7%) | 0.082 | NA | NA |
Primary tumor locationb
| ||||||||
Left-side colorectum | 48/487(9.9%) | 97/487(19.9%) | ||||||
Right-side colon | 11/174(6.3%) | 0.160 | NA | NA | 39/174(22.4%) | 0.485 | NA | NA |
Chemotherapy regimens | ||||||||
Single IRI based regimens | 8/71(11.3%) | 9/71(12.7%) | ||||||
IRIc + fluorouracil based regimens | 51/590(8.6%) | 0.464 | NA | NA | 127/590(21.5%) | 0.081 | NA | NA |
Line of treatment | ||||||||
First line treatment | 9/98(9.2%) | 30/98(30.6%) | ||||||
≧Second line treatment | 50/563(8.9%) | 0.923 | NA | NA | 106/563(18.8%) | 0.008 | 0.504(0.301–0.845) | 0.009 |
UGT1A1*6
| ||||||||
G/G | 42/431(9.7%) | 79/431(18.3%) | ||||||
G/A | 14/198(7.1%) | 43/198(21.7%) | 1.376(0.854–2.215) | 0.189 | ||||
A/A | 3/32(9.4%) | 0.548 | NA | NA | 14/32(43.8%) | 0.002 | 4.737(1.946–11.533) | 0.001 |
UGT1A1*27
| ||||||||
C/A | 0/10(0.0%) | 109/535(20.4%) | ||||||
C/C | 53/535(9.9%) | 0.609 | NA | NA | 2/10(20.0%) | 0.977 | NA | NA |
UGT1A1*28
| ||||||||
TA6/TA6 | 40/501(8.0%) | 90/501(18.0%) | ||||||
TA6/TA7 | 18/152(11.8%) | 42/152(27.6%) | 2.263(1.395–3.670) | 0.001 | ||||
TA7/TA7 | 1/8(12.5%) | 0.323 | NA | NA | 4/8(50.0%) | 0.004 | 5.910(1.138–30.682) | 0.034 |
UGT1A7
| ||||||||
UGT1A7*1/*1,*1/*2,*2/*2
| 31/330(9.4%) | 54/330(16.4%) | ||||||
UGT1A7*1/*3,*2/*3,*3/*3
| 22/215(10.2%) | 0.747 | NA | NA | 57/215(26.5%) | 0.004 | NA | NA |
UGT1A9*22
| ||||||||
T9/T9 | 10/99(10.1%) | 26/99(26.3%) | ||||||
T9/T10,T10/T10 | 43/446(9.6%) | 0.889 | NA | NA | 85/446(19.1%) | 0.107 | NA | NA |
DPYD*5
| ||||||||
A/A | 16/256(6.3%) | 53/256(20.7%) | ||||||
A/G | 30/240(12.5%) | 0.016 | 2.143(1.136–4.041) | 0.019 | 51/240(21.3%) | 0.881 | NA | NA |
DPYD c.1896 T > C
| ||||||||
T/T | 32/395(8.1%) | 84/395(21.3%) | ||||||
T/T,T/C | 14/101(13.9%) | 0.075 | NA | NA | 20/101(19.8%) | 0.747 | NA | NA |
Severe diarrhea | Severe neutropenia | Severe toxicity | ||||
---|---|---|---|---|---|---|
Genotype | N/Total(%) |
P value | N/Total(%) |
P value | No.(%) |
P value |
UGT1A1*6/*28 panels (N = 661) | ||||||
Wild typea
| 31/368(8.4%) | 59/368(16.0%) | 84/368(22.8%) | |||
Single allele variantsb
| 23/228(10.1%) | 53/228(23.2%) | 66/228(28.9%) | |||
≧2 alleles variantsc
| 5/65(7.7%) | 0.736 | 24/65(36.9%) | <0.001 | 29/65(44.6%) | 0.001 |
UGT1A1*6/*28 and DPYD*5 panels (N = 496) | ||||||
Wild typed
| 5/114(4.4%) | 17/114(14.9%) | 20/114(17.5%) | |||
Single allele variantse
| 22/214(10.3%) | 36/214(16.8%) | 54/214(25.2%) | |||
2 alleles variantsf
| 12/124(9.7%) | 37/124(29.8%) | 44/124(35.5%) | |||
≧3 alleles variantsg
| 7/44(15.9%) | 0.147 | 14/44(31.8%) | 0.008 | 21/44(47.7%) | 0.001 |
Analysis of chemotherapy clinical response
Genotype | Single IRI ± targeted therapy | IRI + fluorouracill ± targeted therapy | ||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
First line treatment | ≧Second line treatment | First line treatment | ≧Second line treatment | |||||||||||||
ORR |
P value | DCR |
P value | ORR |
P value | DCR |
P value | ORR |
P value | DCR |
P value | ORR |
P value | DCR |
P value | |
Sex | ||||||||||||||||
Male | 0/1 (0.0%) | 1/1 (100.0%) | 0/29 (0.0%) | 18/29 (62.1%) | 17/56 (30.4%) | 49/56 (87.5%) | 39/295 (13.2%) | 235/295 (79.7%) | ||||||||
Female | 1/3 (33.3%) | 1.000 | 2/3 (67.7%) | 1.000 | 4/34 (11.8%) | 0.118 | 19/34 (55.9%) | 0.619 | 12/33 (36.4%) | 0.559 | 29/33 (87.9%) | 0.958 | 23/183 (12.6%) | 0.837 | 141/183 (77.0%) | 0.498 |
Age | ||||||||||||||||
≦65y | 1/3 (33.3%) | 2/3 (66.7%) | 4/42 (9.5%) | 28/42 (66.7%) | 28/80 (35.0%) | 71/80 (88.8%) | 56/398 (14.1%) | 317/398 (79.6%) | ||||||||
>65y | 0/1 (0.0%) | 1.000 | 1/1 (100.0%) | 1.000 | 0/21 (0.0%) | 0.292 | 9/21 (42.9%) | 0.070 | 1/9 (11.1%) | 0.216 | 7/9 (77.8%) | 0.343 | 6/80 (7.5%) | 0.11 | 59/80 (73.8%) | 0.24 |
Primary tumor location | ||||||||||||||||
Left-side colorectum | 1/3 (33.3%) | 2/3 (66.7%) | 3/43 (7.0%) | 27/43 (62.8%) | 20/60 (33.3%) | 54/69 (90.0%) | 47/362 (13.0%) | 289/362 (79.8%) | ||||||||
Right-side colon | 0/1 (0.0%) | 1.000 | 1/1 (100.0%) | 1.000 | 1/20 (5.0%) | 1.000 | 10/20 (50.0%) | 0.337 | 9/29 (31.0%) | 0.828 | 24/29 (82.8%) | 0.331 | 15/116 (12.9%) | 0.988 | 87/116 (75.0%) | 0.269 |
UGT1A1*6
| ||||||||||||||||
G/G | 1/4 (25.0%) | 3/4 (75.0%) | 3/46 (6.5%) | 28/46 (60.9%) | 17/54 (31.5%) | 49/54 (90.7%) | 42/310 (13.5%) | 239/301 (77.1%) | ||||||||
G/A | 0/0 (0.0%) | 0/0 (0.0%) | 1/15 (6.7%) | 7/15 (46.7%) | 9/31 (29.0%) | 25/31 (80.6%) | 16/145 (11.0%) | 119/145 (82.1%) | ||||||||
A/A | 0/0 (0.0%) | NA | 0/0 (0.0%) | NA | 0/2 (0.0%) | 0.932 | 2/2 (100.0%) | 0.302 | 3/4 (75%) | 0.175 | 4/4 (100.0%) | 0.295 | 4/23 (17.4%) | 0.615 | 18/23 (78.3%) | 0.483 |
UGT1A1*27
| ||||||||||||||||
C/A | 0/0 (0.0%) | 0/0 (0.0%) | 3/43 (7.0%) | 28/43 (65.1%) | 2/3 (66.7%) | 2/3 (66.7%) | 54/387 (14.0%) | 313/387 (80.9%) | ||||||||
C/C | 1/2 (50.0%) | NA | 2/2 (100.0%) | NA | 0/0 (0.0%) | NA | 0/0 (0.0%) | NA | 26/84 (31.0%) | 0.193 | 74/84 (88.1%) | 0.272 | 0/7 (0.0%) | 0.600 | 6/7 (85.7%) | 0.747 |
UGT1A1*28
| ||||||||||||||||
TA6/TA6 | 1/3 (33.3%) | 2/3 (66.7%) | 4/48 (8.3%) | 29/48 (60.4%) | 15/59 (25.4%) | 52/59 (88.1%) | 53/373 (14.2%) | 293/373 (78.6%) | ||||||||
TA6/TA7,TA7/TA7 | 0/1 (0.0%) | 1.000 | 1/1 (100.0%) | 1.000 | 0/15 (0.0%) | 0.564 | 8/15 (53.3%) | 0.627 | 14/30 (46.7%) | 0.043 | 26/30 (86.7%) | 0.842 | 9/105 (8.6%) | 0.129 | 83/105 (79.0%) | 0.913 |
UGT1A7
| ||||||||||||||||
UGT1A7*1/*1,*1/*2,*2/*2
| 1/2 (50.0%) | 2/2 (100.0%) | 3/32 (9.4%) | 20/32 (62.5%) | 12/47 (25.5%) | 42/47 (89.4%) | 35/241 (14.5%) | 194/241 (80.5%) | ||||||||
UGT1A7*1/*3,*2/*3,*3/*3
| 0/0 (0.0%) | 0.558 | 0/0 (0.0%) | NA | 0/11 (0.0%) | 0.558 | 8/11 (72.7%) | 0.539 | 15/38 (39.5%) | 0.17 | 32/38 (84.2%) | 0.482 | 19/153 (12.4%) | 0.554 | 125/153 (81.7%) | 0.767 |
UGT1A9*22
| ||||||||||||||||
T9/T9 | 0/0 (0.0%) | 0/0 (0.0%) | 0/8 (0.0%) | 5/8 (62.5%) | 6/13 (46.2%) | 11/13 (84.6%) | 5/71 (7.0%) | 61/71 (85.9%) | ||||||||
T9/T10,T10/T10 | 1/2 (50.0%) | 1.000 | 2/2 (100.0%) | NA | 3/35 (8.6%) | 1.000 | 23/35 (65.7%) | 0.863 | 21/72 (29.2%) | 0.226 | 63/72 (87.5%) | 0.776 | 49/323 (15.2%) | 0.071 | 258/323 (79.9%) | 0.241 |
DPYD*5
| ||||||||||||||||
A/A | NA | NA | NA | NA | 8/41 (19.5%) | 34/41 (82.9%) | 32/211 (15.2%) | 174/211 (82.5%) | ||||||||
A/G,G/G | NA | NA | NA | NA | NA | NA | NA | NA | 19/44 (43.2%) | 0.019 | 40/44 (90.9%) | 0.273 | 22/183 (12.0%) | 0.365 | 145/183 (79.2%) | 0.415 |
DPYD c.1896 T > C
| ||||||||||||||||
T/T | NA | NA | NA | NA | 24/69 (34.8%) | 60/69 (87.0%) | 42/314 (13.4%) | 254/314 (80.9%) | ||||||||
T/T,T/C | NA | NA | NA | NA | NA | NA | NA | NA | 3/16 (18.8%) | 0.215 | 14/16 (87.5%) | 0.953 | 12/80 (15.0%) | 0.706 | 65/80 (81.3%) | 0.942 |