Table 2.

TS polymorphisms and their impact on clinical outcome in colorectal cancer

A. TS polymorphisms as predictive and prognostic markers in locally advanced colorectal cancer
Study designResultsPrognostic (OS, PFS)Predictive (RR, PFS, toxicity)Reference
221 stage III colorectal cancer patients treated with 5-FU–based adjuvant chemotherapy (117 treated and 104 untreated patients)(a) Patients with 3R/3R genotype derive less survival benefit from chemotherapy than those with either the 2R/2R or the 2R/3R genotypen/aTS 3R/3R vs TS 2R/3R, 2R/2R (adjuvant chemotherapy)Iacopetta et al. (36)
    Tumor genotyping of TS polymorphisms (TS 2R/3R repeat)TS 3R/3R treatment specific OS ↙ (P = 0.005)
TS 3R/3R vs TS 2R/3R, 2R/2R (no chemotherapy)
n.s. (P = 0.18)
129 colorectal cancer patients treated with FU plus levamisole or leucovorin in the adjuvant setting were included(a) TS 3R/3R genotype showed better outcome(a) TS 3R/3R: OS ↑ (P = 0.020)n/aDotor et al. (31)
    Tumor genotyping of TS polymorphisms (TS 2R/3R repeat, G/C SNP, TS 1494del6)(b) G/C SNP added no prognostic information; TS 1494del6 was protective(b) G/C SNP: OS — (P = 0.18)
(c) 3R/−6bp haplotype showed survival benefit compared with 2R/+6bp haplotype(c) TS 1494del6: OS ↑ (P = 0.012)
166 colorectal cancer patients with Dukes B2 and Dukes C underwent radical resection and received adjuvant 5-FU–based chemotherapy(a) TS 3R/3R genotype showed significantly longer DFS and OS(a) TS 3R/3R: OS ↑ (P = 0.009)(a) TS 3R/3R: PFS ↑ (P = 0.048)Hitre et al. (39)
    Genotyping of TS polymorphisms in peripheral blood mononuclear cells (TS 2R/3R repeat, TS 1494del6)(b) TS 2R/3R and TS +6b/6bp combination showed significantly longer DFS and OS(b) G/C SNP: OS n/a(b) G/C SNP: PFS n/a
(c) TS genotypes and their combinations, which have been reported earlier with high TS expression, show longer OS/PFS (3R/3R with any 3′-UTR genotype and 2R/3R with +6bp/+6bp)(c) TS 2R/3R and TS 1494 +6b/+6bp: OS ↑ (P = 0.043)(c) TS 2R/3R and TS 14946bp: PFS ↑ (P = 0.049)
197 colorectal cancer patients treated with FU plus levamisole or leucovorin in the adjuvant setting were included(a) High-expression variants of TSER 3R G/C, alone or in combination with TS 1494del6 polymorphism, independently predict TTR(a) Low TS expression groupn/aLurje et al. (23)
TTR ↑ (P = 0.003)
    Genotyping of TS polymorphisms (TS 2R/3R repeat, G/C SNP, TS 1494del6)(b) Patients with the TS 3RG/+6bp haplotype are at greatest risk for the development of tumor recurrence(b) High TS expression group
TTR ↓ (P = 0.003)
(c) TS 3RG/+6bp haplotype
TTR ↓ (P = 0.003)
B. TS polymorphisms as predictive and prognostic markers in metastatic colorectal cancer
Study designResultsPrognostic (OS, PFS)Predictive (RR, PFS, toxicity)Reference
89 metastatic colorectal cancer patients received 5-FU–based chemotherapy(a) Patients with TS low-expression genotype (A-group) had an overall better RR, DFS, and OS than the TS high-expression genotype(a) Low TS expression group (A)(a) Low TS expression group (A)Marcuello et al. (46)
OS ↑ (P = 0.03)RR ↑ (P = 0.04)
PFS ↑ (P = 0.07)
Toxicity n/a
    Tumor genotyping of TS polymorphismsTS genotype as independent predictor of RR, PFS, and OS(b) High TS expression group (B)(b) High TS expression group (B)
OS ↓ (P = 0.03)
        Low-expression group = TSER 2R/2R; 2R/3RC; 3RC/3RCRR ↓ (P = 0.04)
        High-expression group = TSER 2R/3G; 3RC/3RG; 3RG/3RGPFS ↓ (P = 0.07)
Toxicity n/a
50 metastatic colorectal cancer patients received 5-FU–based chemotherapy(a) Patients with homozygous TS 3R polymorphisms had a 3.6-fold higher mRNA expressionn/a(a) TS 3R/3RPullarkat et al. (13)
RR ↓ (P = 0.041)
Toxicity ↓ (P = 0.008)
    Tumor genotyping of TS polymorphisms (TS 2R/3R repeat)(b) Patients homozygous for TS 3R had worse RRs than patients homozygous or heterozygous for TSER 2R(b) TS 2R/2R and TS 2R/3R
RR ↑ (P = 0.041)
Toxicity ↑ (P = 0.008)
(c) Inverse relationship of TS 3R and toxicity
103 metastatic colorectal cancer patients received 5-FU–based chemotherapy(a) TS activity was found to be highest in the 2R/3R genotype group (in both the primary tumor and metastases)n/a(a) TS 2R/2R, 2R/3R, and 3R/3R genotyped tumors had the same response rateEtienne et al. (44)
    Tumor genotyping of TS polymorphisms (TS 2R/3R repeat)(b) TS activity ↓
    RR ↑ (P = 0.047)
  • Abbreviations: n/a, not available; n.s., not significant; DFS, disease-free survival; TTR, time to tumor recurrence.