Prognostic Value of Angiopoietin-2 for death risk stratification in Patients with Metastatic Colorectal Carcinoma (original) (raw)
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2023
Background: Baseline prognostic biomarkers stratifying treatment strategies in first-line metastatic colorectal cancer (mCRC) are lacking. Angiopoietin-2 (Ang-2) is proposed as a potential biomarker in several cancers. We therefore decided to establish the additional prognostic value of Ang-2 for overall survival (OS) in patients with first-line mCRC. Methods: We enrolled 177 patients treated with a bevacizumab containing chemotherapy in two prospective phase II clinical trials. Patient plasma samples were collected at baseline. ELISAs were used to measure Ang-2. Results: The multivariable Cox model identified increased lactate dehydrogenase [HR, 1.60; 95% confidence interval (CI), 1.04-2.45; P ¼ 0.03] and Ang-2 log-transformation level (HR, 1.59; 95% CI, 1.14-2.21; P ¼ 0.0065) as two significant independent OS prognostic factors. It exhibited good calibration (P ¼ 0.8) and discrimination (C-index: 0.64; 95% CI, 0.58-0.68). Ang-2 parameter inclusion in the GERCOR reference model significantly and strongly improved its discriminative ability because the C-statistic increased significantly from 0.61 to 0.63 (bootstrap mean difference ¼ 0.07; 95% CI, 0.069-0.077). Interestingly, the addition of Ang-2 binary information with a 5 ng/mL cutoff value to the GERCOR model allowed the reclassification of intermediate-risk profile patients (41%) into two subsets of low and high risks. Conclusions: Our study provides robust evidence in favor of baseline Ang-2 prognostic value for OS adding to the conventional factors. Its assessment appears to be useful for the improvement in risk stratification for patients with intermediate-risk profile. Impact: Ang-2 ability to predict OS at diagnosis could be of interest in the selection of patients eligible for intermittent or sequential therapeutic strategies dedicated to the optimization of patients' quality of life and chemotherapy cost-effectiveness.
Cancer Medicine, 2013
A novel combination of capecitabine, oxaliplatin, and bevacizumab was evaluated in colorectal cancer patients enrolled in a phase II clinical trial. In this retrospective analysis, plasma samples from patients receiving capecitabine, oxaliplatin, and bevacizumab were analyzed to investigate biomarkers of clinical benefit. Forty-one protein biomarkers were tested in 38 patients at baseline and after two cycles of drug administration. Correlations among analytes were evaluated by Spearman analysis. Analyte levels at baseline and changes on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) by univariate analysis. Multivariate analyses were determined using the Cox proportional hazard model. Time to event analyses were evaluated by Kaplan-Meier analysis and compared by log-rank test. Baseline levels of vWF and Ang-2 significantly correlated with PFS, while levels of VCAM-1, vWF, TSP-2, IL-8, MMP-2, and Ang-2 correlated with OS (P < 0.05). The fold change of IGF-1 levels from baseline to the end of cycle 2 was correlated with PFS, while fold changes of Ang-2, TSP-2, and TGF-b2 correlated with OS. A baseline signature of Ang-2, IGFBP-3, IL-6, and VCAM-1 identified a low-risk and high-risk group of patients (OS: 33.9 months vs. 18.1 months, respectively, P = 0.016). For treatment-related changes, a signature consisting of Ang-2, E-Cadherin, IL-6, MCP-1, OPN, and TGF-b1 was able to stratify patients into high-and lowrisk groups (PFS: 7.7 months vs. 15.5 months, P = 0.004). Multiplex analysis of patient plasma in this trial identified several baseline-and treatment-related biomarkers associated with clinical outcome. These findings merit further exploration in larger, controlled clinical trials.
2010
BACKGROUND: The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC. METHODS: Serum Ang-2 levels were measured in 33 healthy volunteers and 90 patients with CRC. Of these, 34 had metastatic disease and received bevacizumab-containing therapy. To determine the tissue of origin of Ang-2, quantitative real-time PCR was performed on microdissected cryosections of human CRC and in a murine xenograft model of CRC using species-specific amplification. RESULTS: Ang-2 originated from the stromal compartment of CRC tissues. Serum Ang-2 levels were significantly elevated in patients with metastatic CRC compared with healthy controls. Amongst patients receiving bevacizumab-containing treatment, low pre-therapeutic serum Ang-2 levels were associated with a significant better response rate (82 vs 31%; Po0.01), a prolonged median progression-free survival (14.1 vs 8.5 months; Po0.01) and a reduction of 91% in the hazard of death (Po0.05). CONCLUSION: Serum Ang-2 is a candidate biomarker for outcome of patients with metastatic CRC treated with bevacizumabcontaining therapy, and it should be further validated to customise combined chemotherapeutic and anti-angiogenic treatment.
European Journal of Cancer, 2009
Advanced colorectal cancer DPD TP TS ERCC1 OPRT Capecitabine Irinotecan Prognostic and predictive markers A B S T R A C T We have tested several biomarkers [dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), thymidylate synthase (TS) and excision cross-complementing gene (ERCC1)] for their prognostic and predictive value in relation to the outcome of chemotherapy in tumour tissues of 556 advanced colorectal cancer (ACC) patients who were randomised between sequential treatment and combination treatment in the CApecitabine, IRinotecan, Oxaliplatin (CAIRO) study. DPD expression showed a statistically significant predictive value for combination treatment with capecitabine plus irinotecan with low versus high values resulting in an improved median progression-free survival (PFS) and median overall survival (OS) of 8.9
Cancer Science, 2016
The identification of surrogate markers for long-term outcomes in patients with metastatic colorectal cancer (mCRC) may help in designing treatment regimens. The aim of this study was to assess whether two-dimensional response (2-DR) can serve as a new surrogate marker for overall survival (OS) in patients with mCRC. The study group consisted of 99 patients with mCRC from two independent cohorts who were treated with oxaliplatin-based chemotherapy plus bevacizumab. Two-dimensional response was defined as an area enclosed by coordinate points, including early tumor shrinkage at 8 weeks, depth of response at nadir, and 20% increase over nadir at progression. Each variable was weighted by its contribution rate to OS. The model was developed and internally validated in the learning cohort, and the performance of this model was externally verified in the validation cohort. Spearman correlation coefficients for 2-DR and OS in the learning and validation cohorts were 0.593 and 0.661, respectively. The C-indexes in predicting OS were 0.724 (95% confidence interval, 0.623-0.815) in the learning cohort and 0.762 (95% confidence interval, 0.651-0.873) in the validation cohort. Overall survival was significantly longer in patients with high 2-DR values than in patients with low 2-DR values in both the learning (37.0 vs. 24.1 months, P < 0.001) and validation (41.2 vs. 20.4 months, P < 0.001) cohorts. In contrast, differences in early tumor shrinkage and depth of response were not statistically significant. Multivariate analyses showed that 2-DR was an independent prognostic factor for OS.
2023
Purpose: Randomized ovarian cancer trials, including ICON7, have reported improved progression-free survival (PFS) when bevacizumab was added to conventional cytotoxic therapy. The improvement was modest prompting the search for predictive biomarkers for bevacizumab. Experimental Design: Pretreatment training (n ¼ 91) and validation (n ¼ 114) blood samples were provided by ICON7 patients. Plasma concentrations of 15 angio-associated factors were determined using validated multiplex ELISAs. Our statistical approach adopted PFS as the primary outcome measure and involved (i) searching for biomarkers with prognostic relevance or which related to between-individual variation in bevacizumab effect; (ii) unbiased determination of cutoffs for putative biomarker values; (iii) investigation of biologically meaningfully predictive combinations of putative biomarkers; and (iv) replicating the analysis on candidate biomarkers in the validation dataset. Results: The combined values of circulating Ang1 (angiopoietin 1) and Tie2 (Tunica internal endothelial cell kinase 2) concentrations predicted improved PFS in bevacizumab-treated patients in the training set. Using median concentrations as cutoffs, high Ang1/low Tie2 values were associated with significantly improved PFS for bevacizumab-treated patients in both datasets (median, 23.0 months vs. 16.2; P ¼ 0.003) for the interaction of Ang1-Tie2 treatment in Cox regression analysis. The prognostic indices derived from the training set also distinguished high and low probability for progression in the validation set (P ¼ 0.008), generating similar values for HR (0.21 vs. 0.27) between treatment and control arms for patients with high Ang1 and low Tie2 values. Conclusions: The combined values of Ang1 and Tie2 are predictive biomarkers for improved PFS in bevacizumab-treated patients with ovarian cancer. These findings need to be validated in larger trials due to the limitation of sample size in this study. Clin Cancer Res; 20(17); 4549-58. Ó2014 AACR.
Validation of prognostic scores for survival in cancer patients beyond first-line therapy
BMC Cancer, 2011
Background: We aimed to validate prognostic scores for survival in patients undergoing chemotherapy for advanced or metastatic cancer after first-line treatment. Methods: We previously described two models with good prognostic value based on a combination of Performance Status (PS) and either lactate dehydrogenase (LDH) level or lymphocyte count. These factors were evaluated for their ability to predict overall survival (OS) in a prospective cohort of 299 patients. Clinical and blood parameters were prospectively recorded. Candidate prognostic factors for OS with 0.05 significance level in univariate analysis were included in a multivariate Cox model. Results: Median age was 59 years (range: 26-85). Primary tumor sites were breast (45%), lung (15%), ovaries (11%) and others (29%). The number of metastatic sites was 1 (29%), 2 (48%), >2 (23%). Median follow-up and median OS were 12 and 6 months, respectively. Multiple regression analysis confirmed that PS >1, lymphocyte count ≤700/μL and LDH >600 UI/L were independent predictors of short OS, as well as interleukin 6 (IL-6) level, serum albumin concentration and platelet count. Conclusions: Prognostic scores using PS plus LDH level or PS plus lymphocyte count were validated for predicting survival in metastatic cancer patients in relapse beyond first-line treatment. A score combining PS, LDH, lymphocyte and platelet count, serum albumin and IL-6 level was superior in determining patients' prognosis.
Clinical colorectal …, 2005
Background: The objective of this study was to analyze prognostic factors for survival and to assess the applicability of Köhne's classification in patients treated with irinotecan-or oxaliplatin-based first-line chemotherapy. Patients and Methods: One hundred forty-two consecutive cases from a single center were retrospectively reviewed. Median patient age was 62 years. Sixty percent were men. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0/1 in 88%. Primary tumor resection (PTR) was performed in 80.6% of patients who initially had stage IV disease. Chemotherapy consisted of fluoropyrimidines or raltitrexed plus irinotecan (50.5%), oxaliplatin (38.5%), or both (11%).Univariate and multivariate analyses for survival were performed using pretreatment patient characteristics. Results: Median follow-up was 33.9 months and median overall survival was 15.9 months. Significantly unfavorable prognostic factors were PTR not being performed, disease involvement of > 1 organ, liver metastases, undifferentiated histology, EGOG PS > 1, increased serum carcinoembryonic antigen and cancer antigen 19.9 levels, hypoalbuminemia, leucocytosis, and elevated alkaline phosphatase and lactate dehydrogenase (LDH) levels. Only ECOG PS, PTR, increased LDH level, no hypoalbuminemia, and number of organs involved retained prognostic value in the multivariate analysis.The incidence and median survival for Köhne's prognostic groups were as follows: good (54.2%; 20 months), intermediate (26.8%; 15.7 months), and poor (19%; 6.8 months). For patients with stage IV disease at presentation, PTR was associated with a significantly longer survival, mainly in patients with an ECOG PS of 0/1. Conclusion: Eastern Cooperative Oncology Group PS, PTR, serum albumin, increased LDH levels, and organ involvement were the main prognostic indicators in our series. Köhne's prognostic groups, developed in the era of 5-fluorouracil treatment, also seem to be applicable to patients treated with combination chemotherapy. Primary tumor resection should always be considered, especially in patients with an ECOG PS of 0/1. However, the benefit of PTR and multiple-agent chemotherapy is questionable in patients with an ECOG PS of > 1.
Clinical Colorectal Cancer, 2005
Background: The objective of this study was to analyze prognostic factors for survival and to assess the applicability of Köhne's classification in patients treated with irinotecan-or oxaliplatin-based first-line chemotherapy. Patients and Methods: One hundred forty-two consecutive cases from a single center were retrospectively reviewed. Median patient age was 62 years. Sixty percent were men. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0/1 in 88%. Primary tumor resection (PTR) was performed in 80.6% of patients who initially had stage IV disease. Chemotherapy consisted of fluoropyrimidines or raltitrexed plus irinotecan (50.5%), oxaliplatin (38.5%), or both (11%).Univariate and multivariate analyses for survival were performed using pretreatment patient characteristics. Results: Median follow-up was 33.9 months and median overall survival was 15.9 months. Significantly unfavorable prognostic factors were PTR not being performed, disease involvement of > 1 organ, liver metastases, undifferentiated histology, EGOG PS > 1, increased serum carcinoembryonic antigen and cancer antigen 19.9 levels, hypoalbuminemia, leucocytosis, and elevated alkaline phosphatase and lactate dehydrogenase (LDH) levels. Only ECOG PS, PTR, increased LDH level, no hypoalbuminemia, and number of organs involved retained prognostic value in the multivariate analysis.The incidence and median survival for Köhne's prognostic groups were as follows: good (54.2%; 20 months), intermediate (26.8%; 15.7 months), and poor (19%; 6.8 months). For patients with stage IV disease at presentation, PTR was associated with a significantly longer survival, mainly in patients with an ECOG PS of 0/1. Conclusion: Eastern Cooperative Oncology Group PS, PTR, serum albumin, increased LDH levels, and organ involvement were the main prognostic indicators in our series. Köhne's prognostic groups, developed in the era of 5-fluorouracil treatment, also seem to be applicable to patients treated with combination chemotherapy. Primary tumor resection should always be considered, especially in patients with an ECOG PS of 0/1. However, the benefit of PTR and multiple-agent chemotherapy is questionable in patients with an ECOG PS of > 1.