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A polymorphism within the R-spondin 2 gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab: data from FIRE-3 and TRIBE trials.

ABSTRACT: BACKGROUND:Through enhancement of the Wnt signalling pathway, R-spondins are oncogenic drivers in colorectal cancer. Experimental data suggest that the R-spondin/Wnt axis stimulates vascular endothelial growth factor (VEGF)-dependent angiogenesis. We therefore hypothesise that variations within R-spondin genes predict outcome in patients with metastatic colorectal cancer (mCRC) treated with upfront FOLFIRI and bevacizumab. PATIENTS AND METHODS:773 patients with mCRC enrolled in the randomised phase III FIRE-3 and TRIBE trials and receiving either FOLFIRI/bevacizumab (training and validation cohorts) or FOLFIRI/cetuximab (control group) were involved in this study. The impact of six functional single-nucleotide polymorphisms (SNPs) within the R-spondin 1-3 genes on outcome was evaluated. RESULTS:RAS and KRAS wild-type patients harbouring any G allele of the RSPO2 rs555008 SNP had a longer overall survival compared with those having a TT genotype in both the training (FIRE-3) and validation (TRIBE) cohorts (29.0 vs 23.6 months, P = 0.009 and 37.8 vs 19.4 months, P = 0.021 for RAS wild-type patients and 28.4 vs 22.3 months, P = 0.011 and 36.0 vs 23.3 months, P = 0.046 for KRAS wild-type patients). Conversely, any G allele carriers with KRAS and RAS mutant tumours exhibited a shorter progression-free survival compared with TT genotype carriers, whereas the results were clinically more evident for KRAS mutant patients in both the training and validation cohorts (8.1 vs 11.2 months, P = 0.023 and 8.7 vs 10.3 months, P = 0.009). CONCLUSION:Genotyping of the RSPO2 rs555008 polymorphism may help to select patients who will derive the most benefit from FOLFIRI/bevacizumab dependent on (K)RAS mutational status.

SUBMITTER: Berger MD

PROVIDER: S-EPMC7513926 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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A polymorphism within the R-spondin 2 gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab: data from FIRE-3 and TRIBE trials.

Berger Martin D MD Ning Yan Y Stintzing Sebastian S Heinemann Volker V Cao Shu S Zhang Wu W Yang Dongyun D Miyamoto Yuji Y Suenaga Mitsukuni M Schirripa Marta M Hanna Diana L DL Soni Shivani S Puccini Alberto A Tokunaga Ryuma R Naseem Madiha M Battaglin Francesca F Cremolini Chiara C Falcone Alfredo A Loupakis Fotios F Lenz Heinz-Josef HJ

European journal of cancer (Oxford, England : 1990) 20200416

<h4>Background</h4>Through enhancement of the Wnt signalling pathway, R-spondins are oncogenic drivers in colorectal cancer. Experimental data suggest that the R-spondin/Wnt axis stimulates vascular endothelial growth factor (VEGF)-dependent angiogenesis. We therefore hypothesise that variations within R-spondin genes predict outcome in patients with metastatic colorectal cancer (mCRC) treated with upfront FOLFIRI and bevacizumab.<h4>Patients and methods</h4>773 patients with mCRC enrolled in th ...[more]

PMID: 32305727

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Project description:BackgroundThe MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev).Patients and methodsA total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed.ResultsAA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3 months, Hazard ratio (HR) 1.73, P = 0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0 months, HR 3.04, P = 0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25% versus 66%, P = 0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5 months) in univariable (HR 1.74, P = 0.015) and multivariable analysis (HR 1.76, P = 0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36% versus 65%, P = 0.005).ConclusionMKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.

Project description:BackgroundThe Avastin Registry: Investigation of Effectiveness and Safety (ARIES) study is a prospective, community-based observational cohort study that evaluated the effectiveness and safety of first-line treatment patterns, assessing the impact of chemotherapy choice and treatment duration.MethodsThe ARIES study enrolled patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy with bevacizumab and followed them longitudinally. The protocol did not specify treatment regimens or assessments. Analyses included all patients who initiated bevacizumab in combination with either first-line oxaliplatin with infusional 5-fluorouracil and leucovorin (FOLFOX) or irinotecan with infusional 5-fluorouracil and leucovorin (FOLFIRI). Progression-free survival (PFS) and overall survival (OS) times were estimated using Kaplan-Meier methods. Hazard ratios (HRs) were estimated with multivariate Cox regression analysis, adjusting for potential confounding factors.ResultsIn total, 1,550 patients with first-line mCRC were enrolled (median follow-up, 21 months) and most received FOLFOX-bevacizumab (n = 968) or FOLFIRI-bevacizumab (n = 243) as first-line therapy. The baseline characteristics and median treatment duration were generally similar between subgroups. There were no significant differences in the median PFS (10.3 months vs. 10.2 months) or OS (23.7 months vs. 25.5 months) time between the FOLFOX-bevacizumab and FOLFIRI-bevacizumab subgroups, respectively, by unadjusted analyses. Multivariate analyses showed FOLFIRI-bevacizumab resulted in a similar PFS (HR, 1.03; 95% confidence interval [CI], 0.88-1.21) and OS (HR, 0.95; 95% CI, 0.78-1.16) outcome as with FOLFOX-bevacizumab. The incidence proportions of bevacizumab-associated adverse events were similar for FOLFOX- and FOLFIRI-based therapies.ConclusionsIn first-line mCRC patients, the FOLFOX-bevacizumab and FOLFIRI-bevacizumab regimens were associated with similar treatment patterns and clinical outcomes.

Project description:BackgroundThe evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients' age and sidedness of primary tumour.MethodsThe study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan-Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS.ResultsOverall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31).ConclusionsIn FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC.Clinical trialFIRE-3 (NCT00433927).

Project description:Background: The prognosis of patients with metastatic colorectal cancer (mCRC) is poor, especially after failure of initial systemic therapy. The VELOUR study showed modestly prolonged overall survival (OS) with ziv-aflibercept plus 5-fluorouracil, leucovorin, and irinotecan (zFOLFIRI) vs. placebo+FOLFIRI after progression on 5-fluoruracil, leucovorin, and oxaliplatin (FOLFOX) ± bevacizumab. The utility of zFOLFIRI after bevacizumab+FOLFIRI is unknown and not recommended in NCCN guidelines. We explored whether zFOLFIRI may be active beyond progression on bevacizumab+FOLFIRI. Methods: We undertook a retrospective analysis of patients treated in routine clinical practice. A chart review was conducted for a cohort (N = 19) of advanced cancer patients (18 mCRC) who received zFOLFIRI from 2014 to 2018 at Fox Chase Cancer Center (FCCC). Analysis included time on zFOLFIRI, PFS, OS, CEA trends and adverse events. A second mCRC cohort (N = 26) from the Flatiron Health EHR-derived database treated with zFOLFIRI after prior bevacizumab+FOLFOX and bevacizumab+FOLFIRI was analyzed for time-on-treatment and overall survival. Results: Median age of mCRC cohort at zFOLFIRI treatment was 54 (FCCC; N = 18) and 62 (Flatiron Health-cohort; N = 26). Of 18 FCCC mCRC patients, 1 patient had prior bevacizumab+FOLFOX and ramucirumab+irinotecan prior to zFOLFIRI for 8.5 months. Of 17 FCCC mCRC patients with prior bevacizumab+FOLFIRI who received zFOLFIRI, 13 had mutant-KRAS, 3 WT-KRAS, and one BRAF-V600E. The patient with BRAF-V600E mutation achieved stable disease on zFOLFIRI after multiple BRAF-targeted therapies. One patient (WT-KRAS mCRC) remained on zFOLFIRI for 14 months. Of 14 patients with mutated-KRAS, 8 remained on zFOLFIRI for >5 months including 3 for >15 months. The rate-of-change in CEA measures on zFOLFIRI was significantly different (p = 0.004) between rapid progressors and those with PFS>4 months. For mCRC patients treated with zFOLFIRI in the 3rd line or greater (N = 18), median PFS was 7.1 months (214 days) and median OS was 13.8 months (416 days). Median time-on-treatment with zFOLFIRI in the Flatiron Health cohort was 4.4 months, median OS was 7.8 months, and longest time-on-treatment with zFOLFIRI was 266 days. Conclusions: In these small real-world cohorts, clinical meaningful stable disease and overall survival on zFOLFIRI beyond progression on bevacizumab+FOLFIRI was observed in patients with mCRC. Further exploration of this approach is warranted.

Dataset Information

A polymorphism within the R-spondin 2 gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab: data from FIRE-3 and TRIBE trials.

Publications

A polymorphism within the R-spondin 2 gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab: data from FIRE-3 and TRIBE trials.

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