Copyright
©The Author(s) 2017.
World J Gastroenterol. Aug 28, 2017; 23(32): 5913-5924
Published online Aug 28, 2017. doi: 10.3748/wjg.v23.i32.5913
Published online Aug 28, 2017. doi: 10.3748/wjg.v23.i32.5913
Table 1 Thymidylate synthase polymorphisms’ groups per untranslated region
Low expression | Medium expression | High expression | |
TYMS 3’UTR | del/del | ins/del | ins/ins |
del/LOH | ins/LOH | ||
TYMS 5’UTR | 2RG | 2RG/3RG | 3RG |
2RG/3RC | 2RG/3RG | 3RG/3RC | |
3RC | 2RG/3RCLOH | 2RGLOH/3RG | |
2RG/3RGLOH | |||
2RGLOH/3RC |
Table 2 Clinicopathologic data for patients with metastatic colorectal cancer n (%)
Clinicopathologic data | Relapses | De novo metastatic | Total |
48 (53.9) | 41 (46.1) | 89 (100) | |
Age | 65 (40-84.1) | 64 (27-86) | 65 (27-86) |
Male | 34 (70.8) | 23 (56.1) | 57 (64.8) |
Primary site | |||
Colon | 20 (41.7) | 26 (63.4) | 46 (51.7) |
Rectum | 28 (58.3) | 15 (36.6) | 43 (48.3) |
Histological grade | |||
I + II | 27 (56.3) | 28 (68.3) | 55 (61.8) |
III + IV | 21 (43.7) | 13 (31.7) | 34 (38.2) |
KRAS mutation | 22 (45.8) | 18 (43.9) | 40 (44.9) |
BRAF V600E mut | 2 (4.2) | 3 (7.3) | 5 (5.6) |
TYMS LOH | 15 (31.3) | 11 (26.8) | 26 (29.2) |
Fluoropyrimidine-based CT | |||
Monotherapy or with | 5 (10.4) | 5 (12.2) | 10 (11.2) |
Irinotecan | 18 (37.5) | 10 (24.4) | 28 (31.4) |
Oxaliplatin | 22 (45.8) | 22 (53.7) | 44 (49.4) |
Oxaliplatin and irinotecan | 3 (6.3) | 3 (7.3) | 6 (6.7) |
Bevacizumab | 31 (64.6) | 30 (73.2) | 61 (68.5) |
No chemotherapy | 0 (0.0) | 1 (2.4) | 1 (1.1) |
Overall survival | |||
Deaths | 30 (62.5) | 33 (80.5) | 63 (70.8) |
Time1 in mo | 21.4 (12.2-30.6) | 18.2 (14.3-22.0) | 19.8 (15.8-23.9) |
Progression-free survival | |||
Events | 44 (91.7) | 41 (100.0) | 85 (95.5) |
Time1 in mo | 10.8 (9.0-12.5) | 9.9 (7.0-12.8) | 10.6 (8.8-12.5) |
Follow-up in mo | 14.2 (0-72.5) | 17.0 (0.8-119.8) | 14.8 (0-119.8) |
Table 3 Association between thymidylate synthase polymorphisms and patient characteristics
Polymorphism | Characteristic | RR (95%CI) | P value |
2R | Age < 65-years-old | 1.708 (1.158-2.520) | 0.090 |
2RG/3RG | Grade 1-2 | 1.449 (1.077-1.948) | 0.044 |
2RG/3RC | Female | 1.943 (1.152-3.275) | 0.036 |
ins/ins | KRAS G12D | 3.563 (1.163-10.912) | 0.045 |
3RG/3RC | KRAS wild-type | 1.753 (1.156-2.657) | 0.031 |
Table 4 Risk groups of thymidylate synthase polymorphisms
Group | Relapsed | De novo metastatic | Total |
TYMS 5’UTR | |||
Low expression | |||
2RG | 2 (4.2) | 6 (14.6) | 8 (9.0) |
2RG/3RC | 8 (16.7) | 3 (7.3) | 11 (12.4) |
3RC | 6 (12.5) | 5 (12.2) | 11 (12.4) |
Medium expression | |||
2RG/3RG | 4 (8.3) | 4 (9.8) | 8 (9) |
2RG/3RCLOH | 7 (14.6) | 3 (7.3) | 10 (11.2) |
2RG/3RGLOH | 3 (6.3) | 2 (4.9) | 5 (5.6) |
2RGLOH/3RC | 1 (2.1) | 2 (4.9) | 3 (3.4) |
High expression | |||
3RG | 4 (8.3) | 4 (9.8) | 8 (9.0) |
3RG/3RC | 9 (18.8) | 8 (19.5) | 17 (19.1) |
2RGLOH/3RG | 4 (8.3) | 4 (9.8) | 8 (9.0) |
TYMS 3’UTR | |||
Low expression | |||
del/del | 6 (12.5) | 7 (17.1) | 13 (14.6) |
Medium expression | |||
ins/del | 19 (39.6) | 10 (24.4) | 29 (32.6) |
del/LOH | 1 (2.1) | 3 (7.3) | 4 (4.5) |
High expression | |||
ins/ins | 8 (16.7) | 13 (31.7) | 21 (23.6) |
ins/LOH | 14 (29.2) | 8 (19.5) | 22 (24.7) |
Table 5 Univariate Cox regression analysis for clinicopathological features and genotype
Variable | PFS | OS | ||||
HR | 95%CI | P value | HR | 95%CI | P value | |
KRAS mutated | 1.390 | 0.895-2.164 | 0.142 | 1.669 | 0.996-2.797 | 0.052 |
BRAF V600E | 0.884 | 0.356-2.196 | 0.791 | 1.514 | 0.545-4.207 | 0.426 |
LOH | 1.013 | 0.632-1.624 | 0.957 | 1.020 | 0.592-1.758 | 0.944 |
TYMS 5’UTR | 0.561 | 0.845 | ||||
2R | 1.000 | 1.000 | ||||
2R/3R | 1.243 | 0.616-2.508 | 0.543 | 1.276 | 0.556-2.928 | 0.565 |
3R | 0.974 | 0.474-2.003 | 0.944 | 1.239 | 0.535-2.870 | 0.616 |
TYMS 5’UTR | 0.887 | 0.486 | ||||
2RG | 1.000 | 1.000 | ||||
2RG/3RC | 1.151 | 0.535-2.475 | 0.720 | 0.978 | 0.388-2.468 | 0.963 |
2RG/3RG | 1.351 | 0.625-2.921 | 0.444 | 1.688 | 0.689-4.132 | 0.252 |
3RC | 1.038 | 0.428-2.517 | 0.935 | 0.876 | 0.293-2.620 | 0.813 |
3RG/3RC | 0.883 | 0.391-1.995 | 0.764 | 1.648 | 0.660-4.113 | 0.284 |
3RG | 1.107 | 0.433-2.832 | 0.832 | 1.054 | 0.348-3.189 | 0.926 |
TYMS 5’UTR | 0.726 | 0.562 | ||||
2R | 1.000 | 1.000 | ||||
2RG/3RC | 1.864 | 0.738-4.713 | 0.188 | 1.678 | 0.546-5.160 | 0.366 |
2RG/3RCLOH | 0.783 | 0.300-2.044 | 0.617 | 1.044 | 0.328-3.323 | 0.942 |
2RG/3RG | 1.058 | 0.372-3.014 | 0.916 | 1.869 | 0.537-6.504 | 0.325 |
2RG/3RGLOH | 1.936 | 0.630-5.948 | 0.248 | 3.875 | 1.019-14.740 | 0.047 |
2RGLOH/3RC | 1.155 | 0.301-4.441 | 0.834 | 1.091 | 0.126-9.412 | 0.937 |
2RGLOH/3RG | 1.656 | 0.617-4.442 | 0.317 | 1.745 | 0.546-5.576 | 0.348 |
3RC | 1.096 | 0.428-2.806 | 0.848 | 1.070 | 0.325-3.521 | 0.912 |
3RG | 1.163 | 0.432-3.134 | 0.765 | 1.281 | 0.385-4.270 | 0.687 |
3RG/3RC | 1.001 | 0.413-2.426 | 0.998 | 2.144 | 0.758-6.064 | 0.151 |
TYMS 5’UTR groups | 0.812 | 0.489 | ||||
Low expression | 1.063 | 0.633-1.784 | 0.818 | 0.696 | 0.384-1.261 | 0.232 |
Medium expression | 0.888 | 0.518-1.523 | 0.667 | 0.851 | 0.460-1.572 | 0.606 |
High expression | 1.000 | 1.000 | ||||
TYMS 3’UTR | 0.295 | 0.340 | ||||
del/del | 0.602 | 0.305-1.190 | 0.144 | 0.563 | 0.259-1.224 | 0.147 |
ins/del | 0.764 | 0.475-1.228 | 0.267 | 0.910 | 0.522-1.587 | 0.739 |
ins/ins | 1.000 | 1.000 | ||||
TYMS 3’UTR | 0.067 | 1 | 0.095 | |||
del/del | 0.421 | 0.194-0.912 | 0.028 | 0.311 | 0.125-0.772 | 0.012 |
del/LOH | 0.784 | 0.263-2.334 | 0.662 | 0.773 | 0.175-3.417 | 0.734 |
ins/del | 0.438 | 0.240-0.802 | 0.007 | 0.459 | 0.230-0.918 | 0.028 |
ins/LOH | 0.516 | 0.274-0.973 | 0.041 | 0.488 | 0.233-1.020 | 0.057 |
ins/ins | 1.000 | 1.000 | ||||
TYMS 3’UTR groups | 0.225 | 0.187 | ||||
Low expression | 0.639 | 0.323-1.263 | 0.198 | 0.503 | 0.230-1.102 | 0.086 |
Medium expression | 0.435 | 0.435-1.118 | 0.135 | 0.738 | 0.426-1.279 | 0.279 |
High expression | 1.000 | 1.000 |
Table 6 Multivariate Cox regression analysis
PFS | OS | |||||
HR | 95%CI | P value | HR | 95%CI | P value | |
KRAS mutated | 1.600 | 1.011-2.531 | 0.045 | |||
LOH | 1.674 | 0.912-3.071 | 0.096 | |||
Fluoropyrimidine-based CT | ||||||
With irinotecan | 0.600 | 0.372-0.969 | 0.037 | 0.352 | 0.164-0.757 | 0.007 |
Without irinotecan | 1.000 | 1.000 | ||||
With oxaliplatin | 1.000 | |||||
Without oxaliplatin | 2.702 | 1.273-5.738 | 0.010 | |||
TYMS 3’UTR groups | 0.043 | 0.027 | ||||
Low expression | 0.432 | 0.198-0.946 | 0.036 | 0.366 | 0.162-0.827 | 0.016 |
Medium expression | 0.513 | 0.287-0.919 | 0.025 | 0.559 | 0.309-1.013 | 0.055 |
High expression | 1.000 | 1.000 | ||||
Sex | ||||||
Males | 1.580 | 0.916-2.724 | 0.100 |
- Citation: Ntavatzikos A, Spathis A, Patapis P, Machairas N, Peros G, Konstantoudakis S, Leventakou D, Panayiotides IG, Karakitsos P, Koumarianou A. Integrating TYMS, KRAS and BRAF testing in patients with metastatic colorectal cancer. World J Gastroenterol 2017; 23(32): 5913-5924
- URL: https://www.wjgnet.com/1007-9327/full/v23/i32/5913.htm
- DOI: https://dx.doi.org/10.3748/wjg.v23.i32.5913