Dataset Information

Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy.

ABSTRACT: BACKGROUND:Adenosine 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 METHODS:We 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. RESULTS:In 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. CONCLUSION:Selected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.

SUBMITTER: Tokunaga R

PROVIDER: S-EPMC6416082 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy.

Tokunaga Ryuma R Cao Shu S Naseem Madiha M Lo Jae Ho JH Battaglin Francesca F Puccini Alberto A Berger Martin D MD Soni Shivani S Millstein Joshua J Zhang Wu W Stintzing Sebastian S Loupakis Fotios F Cremolini Chiara C Heinemann Volker V Falcone Alfredo A Lenz Heinz-Josef HJ

Clinical colorectal cancer 20180913 1

<h4>Background</h4>Adenosine 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.<h4>Patients and methods</h4>We analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leuc ...[more]

PMID: 30293873

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Project description:BACKGROUND:No biomarkers exist to predict benefit from antiangiogenic therapy in metastatic colorectal cancer patients. ACVRL1 (activin receptor like-protein 1) encodes for ALK1, a member of the transforming growth factor-? receptor family, which directs pathologic angiogenesis. We examined the intratumoral expression of ACVRL1 and other angiogenesis pathway-related genes to identify molecular markers in the TRIBE study. MATERIALS AND METHODS:Of 503 randomized patients, 228 had sufficient tissue for analysis. Formalin-fixed paraffin-embedded specimens were examined for expression of VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, ACVRL1, EphB4, and EGFL7 using reverse transcription polymerase chain reaction. A maximal ?2 approach was used to determine the messenger RNA levels associated with progression-free survival (PFS), overall survival (OS), response rate, early tumor shrinkage, and depth of response. Recursive partitioning trees were constructed to identify composite prognostic biomarker profiles. External validation was conducted in silico using the Oncomine database. RESULTS:High ACVRL1 expression was associated with superior OS in both treatment arms (FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]-bevacizumab, 32.7 vs. 13.5 months, hazard ratio [HR], 0.38, P = .023; FOLFIRI [5-fluorouracil, leucovorin, irinotecan]-bevacizumab, 35.1 vs. 22.0 months, HR, 0.36, P = .006) and prolonged PFS (11.7 vs. 5.9 months, multivariate HR, 0.17; P = .001) for patients receiving FOLFOXIRI-bevacizumab on univariate and multivariate analyses. In recursive partitioning analysis, ACVRL1 was the strongest discriminator of the response rate, PFS, and OS in patients receiving FOLFOXIRI-bevacizumab and of OS in patients receiving FOLFIRI-bevacizumab. In silico validation revealed significant associations between ACVRL1 expression, disease recurrence, and 1-year survival (P < .05) among all colorectal cancer stages. CONCLUSION:ACVRL1 expression could serve as a prognostic biomarker in metastatic colorectal cancer patients receiving chemotherapy and bevacizumab and warrants further evaluation in prospective studies.

Project description:BACKGROUND:In spite of demonstrating prognostic and possibly predictive benefit in retrospective cohorts and meta-analyses of cancer populations, including colorectal cancer (CRC), prospective evaluation of the relationship between neutrophil to lymphocyte ratio (NLR) and treatment outcomes in previously untreated mCRC patients receiving bevacizumab-based therapy has not yet been performed. METHODS:An open-label, single arm, multi-centre study. Patients received first-line bevacizumab plus XELOX or mFOLFOX6 (Phase-A) and continued bevacizumab plus FOLFIRI beyond first progression (Phase-B). Analyses included the association of NLR with phase A progression free survival (PFS) and overall survival (OS). A sub-study investigated the safety in patients with the primary in situ tumor. An exploratory sub-study examined relationships of circulating proteomic markers with PFS. RESULTS:Phase-A enrolled 128 patients; median age was 64 years (range: 26-84), 70 (55%) were female, 71 (56%) were PS-0 and 51 (40%) had primary in situ tumor. Fifty-three (41%) patients entered Phase-B. The median baseline (b) NLR was 3.2 (range: 1.5-20.4) with 32 (25%) patients having bNLR > 5. The PFS hazard ratio (HR) by bNLR > 5 versus ? 5 was 1.4 (95% CI: 0.9-2.2; p = 0.101). The median PFS was 9.2 months (95% CI: 7.9-10.8) for Phase-A and 6.7 months (95% CI: 3.0-8.2) for Phase-B. The HR for OS based on bNLR > 5 versus ? 5 was 1.6 (95% CI: 1.0-2.7; p = 0.052). The median OS was 25 months (95% CI: 19.2-29.7) for the full analysis set and 14.9 months for Phase-B. Baseline levels of nine proteomic markers showed a relationship with PFS. Treatment related toxicities were consistent with what has previously been published. There were 4 (3%) instances of GI perforation, of which, 3 (6%) occurred in the primary in situ tumor group. CONCLUSIONS:Results from this study are aligned with the previously reported trend towards worse PFS and OS in patients with higher bNLR. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01588990; posted May 1, 2012.

Dataset Information

Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy.

Publications

Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy.

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