Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer.
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ABSTRACT:
SUBMITTER: Gusella M
PROVIDER: S-EPMC2696766 | biostudies-other | 2009 May
REPOSITORIES: biostudies-other
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Project description:BackgroundGolgi phosphoprotein 3 (GOLPH3) has been validated as a potent oncogene involved in the progression of many types of solid tumors, and its overexpression is associated with poor clinical outcome in many cancers. However, it is still unknown the association of GOLPH3 expression with the prognosis of colorectal cancer (CRC) patients who received 5-fluorouracil (5-FU)-based adjuvant chemotherapy.MethodsThe expression of GOLPH3 was determined by qRT-PCR and immunohistochemistry in colorectal tissues from CRC patients treated with 5-FU based adjuvant chemotherapy after surgery. The association of GOLPH3 with clinicopathologic features and prognosis was analysed. The effects of GOLPH3 on 5-FU sensitivity were examined in CRC cell lines.ResultsGOLPH3 expression was elevated in CRC tissues compared with matched adjacent noncancerous tissues. Kaplan-Meier survival curves indicated that high GOLPH3 expression was significantly associated with prolonged disease-free survival (DFS, P = 0.002) and overall survival (OS, P = 0.011) in patients who received 5-FU-based adjuvant chemotherapy. Moreover, multivariate analysis showed that GOLPH3 expression was an independent prognostic factor for DFS in CRC patients treated with 5-FU-based chemotherapy (HR, 0.468; 95%CI, 0.222-0.987; P = 0.046). In vitro, overexpression of GOLPH3 facilitated the 5-FU chemosensitivity in CRC cells; while siRNA-mediated knockdown of GOLPH3 reduced the sensitivity of CRC cells to 5-FU-induced apoptosis.ConclusionsOur results suggest that GOLPH3 is associated with prognosis in CRC patients treated with postoperative 5-FU-based adjuvant chemotherapy, and may serve as a potential indicator to predict 5-FU chemosensitivity.
| S-EPMC4029222 | biostudies-literature
Project description:Previous studies have suggested the potential importance of three DPYD variants (DPYD*2A, D949V, and I560S) with increased 5-FU toxicity. Their individual associations, however, in 5-FU-based combination therapies, remain controversial and require further systematic study in a large patient population receiving comparable treatment regimens with uniform clinical data. We genotyped 2886 stage III colon cancer patients treated adjuvantly in a randomized phase III trial with FOLFOX or FOLFIRI, alone or combined with cetuximab, and tested the individual associations between functionally deleterious DPYD variants and toxicity. Logistic regressions were used to assess univariate and multivariable associations. All statistical tests were two-sided. In 2594 patients with complete adverse event (AE) data, the incidence of grade 3 or greater 5FU-AEs in DPYD*2A, I560S, and D949V carriers were 22/25 (88.0%), 2/4 (50.0%), and 22/27 (81.5%), respectively. Statistically significant associations were identified between grade 3 or greater 5FU-AEs and both DPYD*2A (odds ratio [OR] = 15.21, 95% confidence interval [CI] = 4.54 to 50.96, P < .001) and D949V (OR = 9.10, 95% CI = 3.43 to 24.10, P < .001) variants. Statistical significance remained after adjusting for multiple variables. The DPYD*2A variant statistically significantly associated with the specific AEs nausea/vomiting (P = .007) and neutropenia (P < .001), whereas D949V statistically significantly associated with dehydration (P = .02), diarrhea (P = .003), leukopenia (P = .002), neutropenia (P < .001), and thrombocytopenia (P < .001). Although two patients with I560S had grade≥3 5FU-AEs; a statistically significant association could not be demonstrated because of its low frequency (P = .48). In the largest study to date, statistically significant associations were found between DPYD variants (DPYD*2A and D949V) and increased incidence of grade 3 or greater 5FU-AEs in patients treated with adjuvant 5-FU-based combination chemotherapy.
| S-EPMC4271081 | biostudies-literature
Project description:Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) is a genetic signature found in up to 60% of colorectal cancers (CRCs) that is caused by somatic dysfunction of the DNA mismatch repair (MMR) protein hMSH3. We have previously shown in vitro that recognition of 5-fluorouracil (5-FU) within DNA and subsequent cytotoxicity was most effective when both hMutS? (hMSH2-hMSH6 heterodimer) and hMutS? (hMSH2-hMSH3 heterodimer) MMR complexes were present, compared to hMutS? > hMutS? alone. We tested if patients with EMAST CRCs (hMutS? defective) had diminished response to adjuvant 5-FU chemotherapy, paralleling in vitro findings. We analyzed 230 patients with stage II/III sporadic colorectal cancers for which we had 5-FU treatment and survival data. Archival DNA was analyzed for EMAST (>2 of 5 markers mutated among UT5037, D8S321, D9S242, D20S82, D20S85 tetranucleotide loci). Kaplan-Meier survival curves were generated and multivariate analysis was used to determine contribution to risk. We identified 102 (44%) EMAST cancers. Ninety-four patients (41%) received adjuvant 5-FU chemotherapy, and median follow-up for all patients was 51 months. Patients with EMAST CRCs demonstrated improved survival with adjuvant 5FU to the same extent as patients with non-EMAST CRCs (P<0.05). We observed no difference in survival between patients with stage II/III EMAST and non-EMAST cancers (P = 0.36). There is improved survival for stage II/III CRC patients after adjuvant 5-FU-based chemotherapy regardless of EMAST status. The loss of contribution of hMSH3 for 5-FU cytotoxicity may not adversely affect patient outcome, contrasting patients whose tumors completely lack DNA MMR function (MSI-H).
| S-EPMC4440728 | biostudies-literature
Project description:Tumor-associated macrophages (TAMs) play a role in tumor development and progression. We hypothesized that abundance of TAMs might modify efficacy of 5-fluorouracil chemotherapy in colorectal cancer. We measured the density of CD68+ TAMs at the invasive front of primary tumor of colorectal carcinoma (PT-TAMs; n = 208), at available matched metastatic lymph node (LN-TAMs; n = 149), and in an independent set of primary colorectal cancers (PT-TAMs, n = 111). The hazard ratios for disease-free survival were computed by Cox proportional-hazards model. In exploratory analysis, the interaction between TAMs and 5-fluorouracil adjuvant therapy was significant (PT-TAMs, p = 0.02; LN-TAMs, p = 0.005). High TAMs were independently associated with better disease-free survival only in 5-fluorouracil-treated patients (PT-TAMs, HR 0.23; 95%CI, 0.08-0.65; p = 0.005; LN-TAMs, HR 0.13; 95%CI, 0.04-0.43; p = 0.001). The independent predictive value of PT-TAMs was replicated in the external set (HR, 0.14; 95%CI 0.02-1.00; p = 0.05). In an in vitro experiment, 5-fluorouracil and macrophages showed a synergistic effect and increased colorectal cancer cell death. High densities of TAMs, particularly in metastatic lymph-nodes, identify stage III colorectal cancer patients benefitting from 5-fluorouracil adjuvant therapy.
| S-EPMC5706531 | biostudies-other
Project description:5-fluorouracil (5-FU) is widely used to treat patients with gastric cancer (GC). However, the response rate is quite heterogeneous. The single nucleotide polymorphisms (SNPs) and their interactions of genes in the one-carbon metabolism (OCM) pathway, including Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), Methionine synthase (MTR), and Thymidylate synthase (TS), significantly affect 5-FU metabolism. In this study, 650 stage II-III patients were recruited from 1998 to 2006. Among them, 251 received 5-FU treatment and other 399 patients were untreated. The Cox regression analysis, log-rank tests and Kaplan-Meier plots were adopted. In the chemotherapy cohort, MTRR 66 GA + GG genotypes decreased death risk, however, the protect effect of MTRR 66 GA + GG disappeared when GC patients simultaneously had MTHFR 677TT + TC or MTR 2756GG + GA genotypes. TS 5'-UTR 2R3R + 3R3R genotypes also prolonged overall survival of patients treated with 5-FU. And this favorable prognosis obviously enhanced when GC patients simultaneously had TS 3'-UTR DD + DI and TS 5'-UTR 2R3R + 3R3R genotypes. Our findings showed that the polymorphisms of MTRR 66 A > G and TS 5'-UTR 3R > 2R may be potential prognostic factors for GC patients receiving 5-FU.
| S-EPMC4960563 | biostudies-literature
Project description:Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).
| S-EPMC3036798 | biostudies-literature
Project description:BackgroundThe impact of thymidylate synthase (TYMS) and UDP-glucoronosyltransferase 1A (UGT1A) germline polymorphisms on the outcome of colorectal cancer (CRC) patients treated with irinotecan plus 5-fluorouracil (irinotecan/5FU) is still controversial. Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU.MethodsGenotyping of TYMS (5'TRP and 3'UTR), UGT1A1(*)28, UGT1A9(*)22 and UGT1A7(*)3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a randomised phase 3 study. Their association with response, toxicity and survival was investigated by univariate and multivariate statistical analysis.ResultsTYMS 3TRP/3TRP genotype was the only independent predictor of tumour response (OR=5.87, 95% confidence interval (CI)=1.68-20.45; P=0.005). UGT1A1(*)28/(*)28 was predictive for haematologic toxicity (OR=6.27, 95% CI=1.09-36.12; P=0.04), specifically for neutropenia alone (OR=6.40, 95% CI=1.11-37.03; P=0.038) or together with diarrhoea (OR=18.87, 95% CI=2.14-166.67; P=0.008). UGT1A9(*)1/(*)1 was associated with non-haematologic toxicity (OR=2.70, 95% CI=1.07-6.82; P=0.035). Haplotype VII (all non-favourable alleles) was associated with non-haematologic toxicity (OR=2.11, 95% CI=1.12-3.98; P=0.02).ConclusionTYMS and UGT1A polymorphisms influence on tumour response and toxicities derived from irinotecan/5FU treatment in CRC patients. A genetic-based algorithm to optimise treatment individualisation is proposed.
| S-EPMC2939780 | biostudies-literature
Project description:Background: Aflibercept and fluorouracil, leucovorin, irinotecan (FOLFIRI) is commonly used as a second-line treatment for metastatic colorectal cancer (CRC). However, the biomarkers to guide the choice of this regimen from among treatment options remain unclear. Patients and Methods: We performed exploratory analyses to validate potential prognostic factors for patients receiving aflibercept plus FOLFIRI as a second-line systemic treatment for metastatic CRC between January 2015 and July 2019. Patient characteristics, histopathologic data, laboratory and radiologic data, and treatment outcomes were collected and reviewed. Results: Included were 52 patients: 50 (96.2%) received bevacizumab plus fluorouracil, leucovorin, oxaliplatin (FOLFOX) as prior first-line treatment. Among the 52 patients receiving aflibercept and FOLFIRI, four complete responses and 21 partial responses were observed in analyzed patients for an overall response rate of 48.1%. Median progression-free survival (PFS) was 7.0 months and overall survival (OS) was 16.8 months. Response to first-line treatment (median PFS, 8.0 versus 4.2 months), left-side location of primary tumor (7.9 versus 4.9 months), low baseline CEA level (8.0 versus 5.9 months), and no RAS/RAF mutation (9.9 versus 6.4 months) were remained significant prognostic factors for PFS in the multivariate backward stepwise Cox regression model, and the latter three factors were also significantly related to OS. Conclusions: Significant prognostic factors for PFS with aflibercept plus FOLFIRI as second-line therapy were extracted and validated in the multivariate OS model. These findings could provide useful information for selecting patients for aflibercept plus FOLFIRI as second-line therapy.
| S-EPMC7739009 | biostudies-literature
Project description:BACKGROUND: Identifying various pretreatment factors that predict chemotherapy-induced toxicity in colorectal cancer (CRC) patients undergoing treatment for their disease is crucial to optimising patient care. METHODS: Seventy-three patients received adjuvant 5-fluorouracil (5FU)/leucovorin using either the Mayo Clinic (n=42) or a weekly schedule (n=31) and evaluated for clinical toxicity. Pretreatment blood analysis included measures of plasma uracil and dihydrouracil, peripheral blood mononuclear cell (PBMNC) telomere length (TL), standard biochemistry and cell differential analysis. On the first day of treatment 5FU-pharmacokinetic variables of area under the curve, half life and clearance were also measured. These variables together with age and gender were used in univariate and multivariate analysis as predictors of clinical toxicity. RESULTS: For the Mayo schedule the primary toxicities were neutropenia (69%), mucositis (58%) and leukopenia (46%), with 70% of patients presenting with haematological toxicity ≥grade 1 (neutropenia and/or leukopenia). Multivariate analysis showed that haematological toxicity was predicted by short TL, high platelet lymphocyte ratio (PLR) and low neutrophil count (R(2)=0.38, P<0.0006), whereas mucositis was predicted by age, TL and PLR (R(2)=0.34, P<0.001). For the weekly schedule diarrhoea predominated (16%), with female gender as the only predictive factor. Although measures of uracil metabolism correlated well with 5FU metabolism (r=0.45-0.49), they did not indicate abnormal pyrimidine metabolism in this cohort and not surprisingly failed to predict for 5FU toxicity. CONCLUSION: Short TL of PBMNC and an increased PLR were strong predictors of mucositis and haematological toxicity in CRC patients undergoing 5FU treatment in the adjuvant setting.
| S-EPMC3493765 | biostudies-other
Project description:There is limited data on the clinical and biological parameters that enable the prediction of the benefits derived from additional chemotherapy after disease progression compared with standard chemotherapy in patients with metastatic colorectal cancer (mCRC). The present study evaluated the role of tumor response as a clinical parameter and single nucleotide polymorphisms (SNPs) as a biomarker to predict the benefit of additional 5-fluorouracil (5-FU) rechallenge chemotherapy in patients with refractory mCRC. Tumor responses were retrospectively reviewed based on the Response Evaluation Criteria in Solid Tumors, early tumor shrinkage (ETS) and depth of response (DoR) following first-line chemotherapy in patients with stage IV CRC. Together with these parameters, SNPs known to be associated with the response to chemotherapy were analyzed with survival outcomes. In total, the tumor responses of 242 patients with mCRC were evaluated. Overall response and ETS were identified in 110 (45.4%) and 103 patients (42.6%), respectively, and the median DoR was 38.5±30.08%. ETS and DoR were significantly associated with survival outcomes, including progression-free survival, post-progression survival and overall survival. Among these patients, SNPs were analyzed in 171 patients. X-ray repair cross complementing 1 (XRCC1) (AG/AA) with a DoR >60%, good performance status and the absence of bone lesions were associated with improved overall survival. In patients receiving third-line chemotherapy with 5-FU rechallenge therapy, the methylenetretrahydrofolate reductase (MTHFR) (C677T) CC genotype and a DoR >60% were significantly associated with a good prognosis in multivariate analysis. XRCC1 (AG/AA) was also associated with a good prognosis in patients with mCRC. Patients with a DoR >60% following first-line chemotherapy and a MTHFR (C677T) CC genotype exhibited a survival benefit from 5-FU retreatment. Therefore, the DoR and MTHFR genotype are potential markers for selecting patients with refractory mCRC that would benefit from 5-FU rechallenge therapy.
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