Dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients

BACKGROUND: To determine the dose-limiting toxicity (DLT), maximum tolerated dose, recommended dose (RD) and preliminary evidence of activity of escalating doses of irinotecan (CPT-11) fixed-dose-rate infusional gemcitabine (FDR-GMB) and bevacizumab in pretreated metastatic colorectal cancer (mCRC) patients. Pharmacogenomic analysis was performed to investigate the association between VEGF single-nucleotide polymorphisms and clinical outcome. PATIENTS AND METHODS: A total of 89 mCRC patients were recruited in a two-step study design; 28 were included in the dose-finding study and 59 in the pharmacogenomic analysis. The FDR-GMB of 1000 mg m⁻², bevacizumab 5 mg kg⁻¹ and CPT-11 doses ranging from 100 to 160 mg m⁻² were explored. The VEGF protein serum levels were quantified by EIA. Allelic discrimination was performed to genotype polymorphisms in the VEGF gene. RESULTS: CPT-11 RD was 150 mg m⁻². Diarrhoea and neutropenia were the DLT. After a median follow-up of 42 months, the median time to progression (TTP) and overall survival were 5.2 and 19.9 months, respectively. VEGF levels were significantly correlated with VEGF-2578AA and VEGF-460CC genotypes, and a trend was observed with VEGF+405GG genotype. The presence of any of these genotypes correlated with a longer median TTP (8.8 vs 4.5 months, P=0.04). CONCLUSION: The triplet combination tested in this study is effective and well tolerated. A possible predictive role for VEGF gene polymorphisms and baseline VEGF circulating levels is suggested

Tumor surveillance by circulating microRNAs: a hypothesis

A growing body of experimental evidence supports the diagnostic relevance of circulating microRNAs in various diseases including cancer. The biological relevance of circulating microRNAs is, however, largely unknown, particularly in healthy individuals. Here, we propose a hypothesis based on the relative abundance of microRNAs with predominant tumor suppressor activity in the blood of healthy individuals. According to our hypothesis, certain sets of circulating microRNAs might function as a tumor surveillance mechanism exerting continuous inhibition on tumor formation. The microRNA-mediated tumor surveillance might complement cancer immune surveillance

Identification of predictive circulating biomarkers of bevacizumab-containing regimen efficacy in pre-treated metastatic colorectal cancer patients

BACKGROUND: To identify whether circulating levels of angiogenesis-related factors may be predictive of bevacizumab efficacy in pre-treated metastatic colorectal cancer (mCRC) patients. METHODS: Pre-treatment serum levels of 24 cytokines were measured using a multiplex bead assay (MBA) in 32 pre-treated mCRC patients treated with irinotecan plus bevacizumab-based salvage therapy. Macrophage-derived chemokine (MDC), interleukins (ILs) 8 and 6 levels were also validated by enzyme-linked immunosorbent assay (ELISA) at different time points during therapy. RESULTS: Higher epidermal growth factor (EGF) and MDC baseline levels (2.2- and 1.4-fold, respectively) and lower IL-10, IL-6 and IL-8 levels (0.2-, 0.6-, and 0.6-fold, respectively, P<0.05) were observed in patients responding to therapy. Baseline levels of these five serum factors compose a risk signature that may define the subset of patients most likely to benefit from bevacizumab-based therapy in terms of response rate and survival times. A positive correlation was found between MBA and ELISA results (P<0.01). Treatment exposure increased MDC and had opposite effects on IL-8 levels, which were decreased (P<0.05). CONCLUSION: This study suggests that a set of inflammatory and angiogenesis-related serum markers may be associated with the efficacy of bevacizumab-containing regimen

Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis

A dose-finding study was performed to evaluate the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and the recommended dose (RD) of escalating the doses of capecitabine and fixed doses of irinotecan and oxaliplatin on a biweekly schedule for metastatic colorectal cancer patients (mCRC). A pharmacogenomic analysis was performed to investigate the association between SNPs and treatment outcome. METHODS: Eighty-seven chemotherapy-naive mCRC patients were recruited through a two-step study design; 27 were included in the dose-finding study and 60 in the pharmacogenomic analysis. Oxaliplatin (85 mg m(-2)) and CPT-11 (150 mg m(-2)), both on day 1, and capecitabine doses ranging from 850 to 1500 mg m(-2) bid on days 1-7 were explored. Peripheral blood samples were used to genotype 13 SNPs in 10 genes related to drug metabolism or efficacy. Univariate and multivariate Cox analysis was performed to examine associations between SNPs, ORR and PFS. RESULTS: The capecitabine RD was 1000 mg m(-2) bid. Diarrhoea and neutropenia were the DLTs. After a median follow-up of 52.5 months, the median PFS and OS were 12 (95% CI; 10.6-13.4) and 27 months (95% CI; 17.2-36.8), respectively.The GSTP1-G genotype, the Kohne low-risk category and use of a consolidation approach strongly correlated with decreased risk of progression. Patients with all favourable variables showed a median PFS of 42 months vs 3.4 months in the group with all adverse factors. A superior clinical response was obtained in patients with one GSTP1-G allele as compared with GSTP1-AA carriers (P=0.004). CONCLUSION: First-line therapy with oxaliplatin, irinotecan and capecitabine is efficient and well-tolerated. The GSTP1 polymorphism A>G status was significantly associated with ORR and PFS in mCRC treated with this triplet therapy

Base Pairing Interaction between 5'- and 3'-UTRs Controls icaR mRNA Translation in Staphylococcus aureus.

The presence of regulatory sequences in the 3' untranslated region (3'-UTR) of eukaryotic mRNAs controlling RNA stability and translation efficiency is widely recognized. In contrast, the relevance of 3'-UTRs in bacterial mRNA functionality has been disregarded. Here, we report evidences showing that around one-third of the mapped mRNAs of the major human pathogen Staphylococcus aureus carry 3'-UTRs longer than 100-nt and thus, potential regulatory functions. We selected the long 3'-UTR of icaR, which codes for the repressor of the main exopolysaccharidic compound of the S. aureus biofilm matrix, to evaluate the role that 3'-UTRs may play in controlling mRNA expression. We showed that base pairing between the 3'-UTR and the Shine-Dalgarno (SD) region of icaR mRNA interferes with the translation initiation complex and generates a double-stranded substrate for RNase III. Deletion or substitution of the motif (UCCCCUG) within icaR 3'-UTR was sufficient to abolish this interaction and resulted in the accumulation of IcaR repressor and inhibition of biofilm development. Our findings provide a singular example of a new potential post-transcriptional regulatory mechanism to modulate bacterial gene expression through the interaction of a 3'-UTR with the 5'-UTR of the same mRNA

Predictive value of Ile105Val polymorphism of the gluthatione-S-transferase P1 in patients with metastatic colorectal cancer (m CRC) treated with the triplet combination of irinotecan, oxaliplatin, and capecitabine

2544 Background: Several phase I/II trials have shown that the triplet combination of oxaliplatin, irinotecan and capecitabine is a feasible and active in solid tumors. We aimed to investigate whether germline polymorphisms may be predictors of clinical outcome in mCRC pts treated with this combination. Methods: The following genetic polymorphisms were analysed: glutathione S-transferase (GSTP1-Ile105Val, GSTT1 and GSTM1 deletion), TYMS (TS-5´UTR 2R/3R; TS-5´G/C; TS-3´UTR 6-bp deletion), MTHFR 1298A&gt;C, UGT1A1, ERCC1, XPD. Polymorphisms from peripheral lymphocytes were detected using the TaqMan genotyping assays (Applied Biosystems, CA). Univariate analysis (Fisher´s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: Blood samples for 63 out of 72 prospectively enrolled pts were tested for genomic analysis. Median age was 57 (32–78), median ECOG 1(0–2), median number of cycles administered 6 (1–13), median number of metastatic sites was 1 (1–4). M/F: 50/22. Risk according to Köhne classification was low (52.8% of pts), intermediate (26.4%) and high (8.3%). Overall response rate (ORR) was 62.5%. Median progression-free survival (PFS) was 9.87 months (95% CI; 7.6–12) and median overall survival was 24.6 months (95% CI; 19.5–29.7). A significant association was observed between MTHFR 1298A&gt;C and haematological toxicity, with C/C genotype pts being at higher risk of grade 3–4 neutropenia (50% vs. 28%, p = 0.035) and leucopenia (50% vs. 15%, p = 0.04). Heterozygous and homozygous GSTP-105Val showed a significant superior response rate (80%) compared to only 40% in pts harbouring the GSTP1–105Ile/Ile genotype (p = 0.008, Fisher´s exact test). PFS was also adversely affected in pts with GSTP1–105Ile/Ile (5.2 months vs. 12.3 months in those pts with at least one GSTP1–105Val allele, p = 0.001). In the multivariate analysis, the relative risk for progression was 3.4 (95% CI; 1.3–9.1) for the GSTP1–105Ile/Ile genotype (p = 0.01). Conclusions: The GSTP1-Ile105Val polymorphism is a strong predictor of clinical outcome for XELOXIRI therapy in mCRC pts. No significant financial relationships to disclose. </jats:p

Pharmacogenomic analysis of the triplet combination of gemcitabine, oxaliplatin, and cetuximab as salvage therapy for metastatic colorectal cancer (mCRC) patients

e14531 Background: We have previously reported that biweekly gemcitabine-based therapy was active in pretreated mCRC pts (De la Cruz et al, ASCO GI 2008, abstr 377). We aimed to investigate whether germ line polymorphisms may be predictors of clinical outcome in mCRC pts treated with this combination. Methods: We evaluated SNPs of genes involved in gemcitabine metabolism (CDA, dCDK, RRM1, DCTD, SLC28A1), DNA repair (XRCC1, XRCC 3, ERCC1, XPD) and two IgG Fcγ R polymorphisms (Fcγ RIIa- H131R and Fcγ RIIIa-V158F), reported to be predictive of cetuximab-based therapy, even in K-ras mutated pts. Whole blood was collected and DNA extracted from peripheral lymphocytes using a DNA isolation Kit (Qiagen, CA). Polymorphisms were detected using the TaqMan genotyping assays (Applied Biosystems, CA). Clinical response was evaluated according to RECIST criteria. Univariate analysis (Fisher´s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: Blood samples of 35 out of 39 enrolled pts were tested for genomic analysis. Patient‘s characteristics are as follows; M/F: 26/13, median age: 59 years, median number of prior chemotherapy lines: 2 (1–4), Köhne risk groups; low: 8 pts, intermediate: 18 pts, high: 13 pts. After a median follow-up of 20 months, median progression-free survival (PFS) is 6.7 months (95% CI; 5.2–8.3) and median overall survival 15.4 m (95% CI; 14.7–16.1). Overall response rate (ORR) was 53.8%. RRM1 R284R SNPs (p=0.06), T741T (p=0.02) and RRM1–524CT (p=0.04) were linked to clinical responsiveness. All pts possessing 2 or 3 favourable RRM1 SNPs responded. ORR was 53.3% for pts with no favourable SNPs versus 85% for pts with any favourable SNP (p=0.04). ORR was also significantly higher in pts with any histidine allele in the Fcγ RIIa polymorphism (93% vs. 60%, p=0.034). Median PFS was adversely affected in pts harbouring no favourable RRM1 SNPs (4.2m versus 6.7 months, p=0.019) and in those pts with homozygous Fcγ RIIa-131R allele (4.4 vs. 7.5 months, p=0.007). Conclusions: Polymorphic variants of RRM1 and Fcγ RIIa may play a key role in the efficacy of gemcitabine and cetuximab-based therapy for mCRC pts. No significant financial relationships to disclose. </jats:p