Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific <it>VEGF </it>polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.</p> <p>Methods</p> <p>Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. <it>VEGF </it>-2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of <it>VEGF </it>polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of <it>VEGF </it>-1498 C/T polymorphism between bevacizumab-and control group.</p> <p>Results</p> <p>In the bevacizumab-group median PFS and OS of patients carrying <it>VEGF </it>-1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). <it>VEGF </it>-1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of <it>VEGF </it>-1498 C/T allelic variants and PFS or OS was found. Interaction between <it>VEGF </it>-1498 C/T variants and treatment effect suggested that the relation of <it>VEGF </it>-1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.</p> <p>Conclusions</p> <p>These data suggest a possible role for <it>VEGF </it>-1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.</p

Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific <it>VEGF </it>polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.</p> <p>Methods</p> <p>Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. <it>VEGF </it>-2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of <it>VEGF </it>polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of <it>VEGF </it>-1498 C/T polymorphism between bevacizumab-and control group.</p> <p>Results</p> <p>In the bevacizumab-group median PFS and OS of patients carrying <it>VEGF </it>-1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). <it>VEGF </it>-1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of <it>VEGF </it>-1498 C/T allelic variants and PFS or OS was found. Interaction between <it>VEGF </it>-1498 C/T variants and treatment effect suggested that the relation of <it>VEGF </it>-1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.</p> <p>Conclusions</p> <p>These data suggest a possible role for <it>VEGF </it>-1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.</p

Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer

The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5′UTR and 3′UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3–4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome

Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients

Background: Dihydropyrimidine dehydrogenase (DPD) catabolizes approximately 85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomized trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, ten 49 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, rs75017182 C>G), were retrospectively tested for associations with > grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used. 55 Results: FAEs occurred in 194/508 assessable patients (38.2%). In the association analysis, FAEs 56 occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT 57 analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), 58 *2A rs3918290 A allele carriers (FDR <0.0001), rs2297595 GG genotype carriers (FDR=0.0014). 59 Neutropenia was the commonest FAEs (28.5%). *6 rs1801160 (FDR <.0001), and *2A 60 rs3918290 (FDR =0.0004) variant alleles were significantly associated with time to neutropenia. 61 Conclusions: This study adds evidence on the role of DPYD pharmacogenetics for safety of 62 patients undergoing fluoropyrimidine-based chemotherapy