Clinical cancer research : an official journal of the American Association for Cancer Research 20160202 13
<h4>Purpose</h4>The IL6/STAT3 axis promotes inflammation, angiogenesis, and cancer. The effect of genetic variants within this pathway on benefit from antiangiogenic cancer therapy is unknown. We tested whether SNPs in genes involved in IL6/STAT3 signaling can predict efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer (mCRC) patients.<h4>Experimental design</h4>Associations between potentially functional IL6 (rs2069837 and rs1800795) and STAT3 (rs744166 and rs4796793) SNP ...[more]
Project description:BackgroundAdenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy.Patients and methodsWe analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in FIRE-3 (ClinicalTrials.gov identifier, NCT00433927); a validation cohort of 215 patients with FOLFIRI plus bevacizumab in TRIBE (ClinicalTrials.gov identifier, NCT00719797); and a control cohort of 129 patients treated with FOLFIRI plus cetuximab in FIRE-3. The relationship between the selected SNPs and clinical outcomes was analyzed.ResultsIn the discovery cohort, patients with any C allele in CD39 rs11188513 had significantly shorter median progression-free survival compared with those with the T/T variant (11.3 vs. 13.1 months; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.04-2.77; P = .022) on univariate analysis. Also, their overall survival (OS) was shorter (27.4 vs. 49.9 months; HR, 2.10; 95% CI, 1.07-4.10; P = .031) on univariate and multivariable analyses. The significant association between CD39 rs11188513 and OS was confirmed in the validation cohort (25.8 vs. 31.6 months; HR, 1.53; 95% CI, 1.09-2.15; P = .013). CD73 rs2229523 and A2BR rs2015353 in the discovery cohort and CD39 rs2226163 in the validation cohort showed significant correlations with OS on univariate and multivariable analyses. None of SNPs were significant in the cetuximab control cohort.ConclusionSelected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.
Project description:Colorectal cancer (CRC) ranks as second most common cause of cancer-related deaths. The CRC management considerably improved in recent years, especially due to biological therapies such as bevacizumab. The lack of predictive or prognostic biomarkers remains one of the major disadvantages of using bevacizumab in the CRC management. We performed a prospective study to analyze the prognostic and predictive roles of three potential serum biomarkers (Cyclophilin A (CypA), copeptin and Tie2) investigated by ELISA in 56 patients with metastatic CRC undergoing bevacizumab and chemotherapy between May 2019 and September 2021 at baseline and after one and six months of therapy. We showed that low levels of CypA at baseline and after one month of treatment were associated with better overall survival (OS) (42 versus 24 months, p = 0.029 at baseline; 42 versus 25 months, p = 0.039 after one month). For copeptin and Tie2, Kaplan-Meier curves showed no correlation between these biomarkers and OS or progression-free survival. When adjusting for baseline and post-treatment factors, a multivariate Cox analysis showed that low values of CypA at baseline and after one month of treatment were independent prognostic factors for OS and correlated with a better prognosis in metastatic CRC patients.
Project description:High tumor expression of epidermal growth factor-like domain 7 (EGFL7) has been associated with a poor prognosis in colorectal cancer. The aim of the current study was to investigate the possible prognostic impact of circulating EGFL7 (cir-EGFL7), combined with single nucleotide polymorphism (SNP) analyses, in patients with metastatic colorectal cancer (mCRC) treated with first line chemotherapy and bevacizumab. A total of 88 patients were included. Serum was collected prior to treatment initiation, at first evaluation after 3 weeks, and at progression. Cir-EGFL7 was analysed by the enzyme-linked immunosorbent assay (ELISA) technique. The SNPs were analysed by real-time qPCR based on DNA from whole blood. Endpoints were response rate (RR), progression free survival (PFS), and overall survival (OS). Cir-EGFL7 decreases after administration of chemotherapy plus bevacizumab. Baseline levels of cir-EGFL7 were significantly related to PFS and OS, p = 0.0431 and p = 0.0017, respectively, with increasing cir-EGFL7 levels associated with a worse prognosis. Circulating EGFL7 was not associated with RR. The SNP analyses revealed a significant relationship between rs1051851 and OS, p = 0.030. This study demonstrates that cir-EGFL7 changes during treatment with chemotherapy plus bevacizumab and that baseline levels and genetic variations may influence the overall prognosis of patients with mCRC. The findings call for further validation.
Project description:BACKGROUND: Hypertension (HTN) is a common toxicity of anti-VEGF (vascular endothelial growth factor) antibody treatment. It may be a marker of VEGF signalling pathway inhibition and therefore represent a cancer biomarker in metastatic colorectal cancer (mCRC) patients treated with chemotherapy and bevacizumab. METHODS: A total of 101 consecutive patients with mCRC were treated with standard chemotherapy combined with bevacizumab at dose of 2.5 mg kg(-1) per week in a single centre. The median follow-up time of the patients alive was 64 months. Blood pressure was measured before each bevacizumab infusion, and HTN was graded according to common toxicity criteria for adverse events version 3.0. RESULTS: Overall, 57 patients (56%) developed ≥grade 1 HTN (median blood pressure 168/97 mm Hg), whereas 44 (44%) remained normotensive when treated with bevacizumab-containing chemotherapy regimen. Overall response rate was higher among patients with HTN (30 vs 20%; P=0.025). Hypertension was associated with improved progression-free survival (10.5 vs 5.3 months; P=0.008) and overall survival (25.8 vs 11.7 months; P<0.001), and development of HTN within 3 months had an independent, prognostic influence in a multivariate landmark survival analysis together with other known mCRC prognostic factors (P=0.007). There was no association between HTN and development of thromboembolic complications. CONCLUSION: Hypertension may predict outcome of bevacizumab-containing chemotherapy in mCRC. These data require confirmation in prospective studies including pharmacodynamic and pharmacokinetic analyses.
Project description:Angiogenesis pathway genes show substantial genetic variability causing inter-individual differences in responses to anti-angiogenic drugs. We examined 20 single nucleotide polymorphisms (SNPs) in 13 of these genes to predict tumour response and clinical outcome measured as progression free survival (PFS) and overall survival (OS) in 57 patients with metastatic colorectal cancer (mCRC) given bevacizumab plus chemotherapy. SNPs were detected (iPLEX® Assay) in genomic DNA extracted from formalin-fixed paraffin-embedded tumour specimens. The variant allele CD39 rs11188513 was associated with a good tumour response (p = 0.024). Patients homozygous for the wild-type allele FGF2 rs1960669 showed a median PFS of 10.95 months versus 5.44 months for those with at least one variant allele-A (HR 3.30; 95% CI: 1.52-7.14; p = 0.001). Patients homozygous for wild-type MMP9 rs2236416 and rs2274755 showed a median PFS of 9.48 months versus 6 and 6.62 months, respectively, for those with at least one variant allele (p = 0.022, p = 0.043, respectively). OS was also lengthened to 30.92 months (p = 0.034) in carriers of wild-type ANGPT1 rs2445365 versus 22.07 months for those carrying at least one variant allele-A. These gene variants were able to predict clinical outcome and tumour response in mCRC patients given bevacizumab-based therapy.
Project description:BackgroundAMP-activated protein kinase (AMPK) has a central role in cellular energy sensing and is activated in preclinical tumour models following anti-vascular endothelial growth factor (VEGF) therapy. The possible predictive or prognostic role of AMPK status in cancer patients treated with anti-VEGF drugs has not been investigated so far.MethodsExpression of components of the AMPK pathway including phosphorylated AMPK (pAMPK), phosphorylated acetyl-Coa carboxylase (pACC) and liver kinase B1 (LKB1) was investigated by immunohistochemistry in 48 colorectal cancers treated with FOLFIRI plus bevacizumab. Correlation between pAMPK and pACC and associations between the AMPK pathway scores and clinico-pathological characteristics were assessed. Overall survival (OS) was estimated through Kaplan-Meier method, whereas hazard ratios were computed to identify prognostic factors.ResultsFourteen patients (29.2%) were included in the pAMPK-negative group (score ≤5), whereas 34 patients (70.8%) were included in the pAMPK-positive group (score >5). The Spearman's coefficient for the correlation between pAMPK and pACC scores in primary tumour samples was 0.514 (P=0.0002). Low pAMPK levels were associated with worse OS (P-value 0.0002) but not with PFS, whereas low pACC levels were associated both with worse OS and PFS (P-value 0.0007 and 0.01, respectively).ConclusionsOur findings suggest that high tissue AMPK activation is a prognostic biomarker in this cohort of metastatic colorectal cancer patients.
Project description:Bevacizumab plus chemotherapy is a well-established first-line treatment for metastatic colorectal cancer (mCRC). We investigated whether polymorphisms of genes involved in immune regulation signaling are related to the clinical outcome of mCRC patients treated with bevacizumab-based chemotherapy. In this study, we genotyped 14 single-nucleotide polymorphisms (SNP) in IFN-γ/IFNGRs/JAKs/STATs/PD-L1 pathway by using DNA from blood samples of 141 mCRC patients treated with first-line bevacizumab-based chemotherapy. In the univariate and multivariate analysis, patients with AA genotype of CD274:rs2297136 had a significantly better PFS and OS than patients with AG or GG genotype (10.8 versus 9.8, log-rank P=0.0031; 31.4 versus 20.9, log-rank P=0.0233). Patients with AG/GG genotype of IFNGR1:rs2234711, CT/TT genotype of IFNGR1:rs9376267 also showed longer OS than patients with AA or CC genotype, however, the statistic did not reach significant after adjusted by clinical factors in the multivariate analysis. A nomogram based on the genetic variants and clinic characteristics was developed with a good accuracy to predict patients' survival. Our result indicates that CD274:rs2297136 is one of the most important predictors for the prognosis of mCRC patients treated with bevacizumab-based chemotherapy, if further validated in larger population.
Project description:A desmoplastic colorectal cancer stroma, characterized by excess turnover of the cancer-associated fibroblast derived collagens type III and VI, can lead to reduced drug-uptake and poor treatment response. We investigated the association between biomarkers of collagen type III and VI and overall survival (OS) in patients with metastatic colorectal cancer (mCRC). Serum samples were collected from 252 patients with mCRC prior to treatment with bevacizumab and chemotherapy. Serum concentrations of biomarkers reflecting formation of collagen type III (PRO-C3) and VI (PRO-C6) and degradation of collagen type VI (C6M and C6Mα3) were determined by ELISA. The biomarkers were evaluated for associations with OS, individually, combined, and after adjusting for carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH) and performance status (PS). High baseline levels (> median) of each collagen biomarker were significantly associated with shorter OS (PRO-C3: HR = 2.0, 95%CI = 1.54-2.63; PRO-C6: HR = 1.6, 95%CI = 1.24-2.11; C6M: HR = 1.4, 95%CI = 1.05-1.78; C6Mα3: HR = 1.6, 95%CI = 1.16-2.07). PRO-C3 and PRO-C6 remained significant after adjustment for CEA, LDH and PS. Weak correlations were seen between the collagen biomarkers (r = 0.03-0.59) and combining all improved prognostic capacity (HR = 3.6, 95%CI = 2.30-5.76). Collagen biomarkers were predictive of shorter OS in patients with mCRC. This supports that collagen- and CAF biology is important in CRC.
Project description:We analyzed associations between CXCR4/CXCL12 single-nucleotide polymorphisms and outcomes in metastatic colorectal cancer (mCRC) patients who underwent first-line bevacizumab-based chemotherapy. A total of 874 patients were included in this study: 144 treated with bevacizumab and FOLFOX or XELOX (training cohort), 653 treated with bevacizumab and FOLFIRI or FOLFOXIRI (validation cohort A or B) and 77 treated with cetuximab- and oxaliplatin-based regimens (control cohort). One CXCR4 polymorphism (rs2228014) and two CXCL12 polymorphisms (rs1801157 and rs3740085) were analyzed by PCR-based direct sequencing. Patients with a C/C genotype had a prolonged progression-free survival (PFS) compared with those with any T allele (P=0.030) in the training cohort. Similarly, patients with the C/C genotype had a superior PFS in the validation cohorts, but not in the control cohort. Our findings suggest that a common genetic variant, CXCR4 rs2228014, could predict PFS and may guide therapeutic decisions in mCRC patients receiving first-line bevacizumab-based chemotherapy.
Project description:Panitumumab and bevacizumab have been widely used in combination with chemotherapy for patients with wild type RAS metastatic colorectal cancer (mCRC). Whether panitumumab or bevacizumab was the optimal option remained controversial. Thus, we conducted a meta-anaylsis to evaluate chemotherapy plus panitumumab (C?+?P) versus chemotherapy plus bevacizumab (C?+?B) in wild type RAS mCRC. Electronic databases including PubMed, Embase, and Web of Science, Cochrane Library, ClinicalTrials.gov, were searched. This meta-analysis estimated the progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and adverse events (AEs). Three randomized controlled trials with a total number of 577 patients were included. In wild type RAS population, PFS [hazard ratio (HR)?=?0.96; 95% confidence interval (CI), 0.76 to 1.15] and OS (HR?=?0.90; 95% CI, 0.54 to 1.27) and ORR [relative ratio (RR)?=?2.06; 95% CI, 0.86 to 4.90] appeared similar between the two treatments, the incidence of AEs slightly increased (RR?=?1.16; 95% CI 1.08 to 1.26). In conclusion, there was insufficient evidence to precisely conclude that combination treatment of C?+?P had an improved efficacy compared with C?+?B. Further large-scale and better-designed clinical trials are still needed to evaluate the combination treatment of C?+?P in patients with wild type RAS mCRC.