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A plasma cytokine and angiogenic factor (CAF) analysis for selection of bevacizumab therapy in patients with metastatic colorectal cancer.

Bai L, Wang F, Zhang DS, Li C, Jin Y, Wang DS, Chen DL, Qiu MZ, Luo HY, Wang ZQ, Li YH, Wang FH, Xu RH - Sci Rep (2015)

Bottom Line: Patients with lower pretreatment levels of hepatocyte growth factor (HGF) or VEGF-A(121) gain much more benefit from bevacizumab treatment as measured by progression-free survival (PFS) and overall survival (OS), while angiopoietin-like 4 (ANGPTL4) levels negatively correlated with PFS and response rate following bevacizumab (all adjusted interaction P < 0.05).Signature-negative patients showed impaired survival following bevacizumab treatment (PFS, 7.3 vs 7.0 months; hazard ratio [HR] 1.03; OS, 29.9 vs 21.1 months, HR 1.33) compared with signature-positive patients (PFS, 6.5 vs 11.9 months, HR 0.52; OS, 28.0 vs 55.3 months, HR 0.67).These promising results warrant further prospective studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China.

ABSTRACT
This study intends to identify biomarkers that could refine the selection of patients with metastatic colorectal cancer (mCRC) for bevacizumab treatment. Pretreatment 36 plasma cytokines and angiogenic factors (CAFs) were first measured by protein microarray analysis in patients who received first-line bevacizumab-containing therapies (discovery cohort, n = 64), and further evaluated by enzyme-linked immunosorbent assay in patients treated on regimens with or without bevacizumab (validation cohort, n = 186). Factor levels were correlated with clinical outcomes, predictive values were assessed using a treatment by marker interaction term in the Cox model. Patients with lower pretreatment levels of hepatocyte growth factor (HGF) or VEGF-A(121) gain much more benefit from bevacizumab treatment as measured by progression-free survival (PFS) and overall survival (OS), while angiopoietin-like 4 (ANGPTL4) levels negatively correlated with PFS and response rate following bevacizumab (all adjusted interaction P < 0.05). A baseline CAF signature combining these three markers has greater predictive ability than individual markers. Signature-negative patients showed impaired survival following bevacizumab treatment (PFS, 7.3 vs 7.0 months; hazard ratio [HR] 1.03; OS, 29.9 vs 21.1 months, HR 1.33) compared with signature-positive patients (PFS, 6.5 vs 11.9 months, HR 0.52; OS, 28.0 vs 55.3 months, HR 0.67). These promising results warrant further prospective studies.

No MeSH data available.


Related in: MedlinePlus

The predictive value of candidate markers for progression-free survival (A, C, E) and overall survival (B, D, F) in ELISA test were presented by Kaplan–Meier curves stratified according to baseline marker levels (using corresponding optimal binary split) and treatment arms.BEV, bevacizumab; chemo, chemotherapy.
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f3: The predictive value of candidate markers for progression-free survival (A, C, E) and overall survival (B, D, F) in ELISA test were presented by Kaplan–Meier curves stratified according to baseline marker levels (using corresponding optimal binary split) and treatment arms.BEV, bevacizumab; chemo, chemotherapy.

Mentions: As a result, patients with lower baseline plasma levels of ANGPTL4 (i.e. lower than the median 1.97 ng/ml), HGF (0.88 ng/ml) or VEGF121 (0.59 ng/ml) were more sensitive to bevacizumab treatment as measured by PFS (for ANGPTL4, HR 0.58; 95% CI 0.36–0.94; for HGF, HR 0.52, 95% CI 0.35–0.76; for VEGF121, HR 0.52; 95% CI 0.36–0.76) than those with higher analytes levels (for ANGPTL4, HR 0.73; 95% CI 0.49–1.08, unadjusted P = 0.048 from interaction Cox Wald tests; for HGF, HR 0.79, 95% CI 0.49–1.27, unadjusted interaction P = 0.020; for VEGF121, HR 0.90; 95% CI 0.53–1.53, unadjusted interaction P = 0.023). Similarly, patients with lower baseline HGF or VEGF-A121 levels experienced remarkably larger benefit from bevacizumab in terms of OS than patients with higher analytes levels (for HGF, HR 0.42 versus 1.19, lower versus higher levels, unadjusted interaction P = 0.010; for HGF, HR 0.42 versus 1.25, lower versus higher levels, unadjusted interaction P = 0.034) (Table 3 and Fig. 3). With the addition of bevacizumab, response rates were only increased in patients with lower ANGPTL4 levels (48.8% vs 10.7%) rather than those with higher ANGPTL4 levels (34.1% vs 41.1%; unadjusted interaction P = 0.003). Likewise, patients who had lower HGF or VEGF121 levels also showed a trend toward improved ORR versus patients with higher levels, though the interaction test did not show enough power (Table 3). The P-values for treatment-marker interaction remained significant in multivariate models after adjusted for known clinical prognostic variables (gender, age, performance status, primary tumor site, tumor grade, prior adjuvant chemotherapy, number of metastasis site, and curative-intent metastasis resection) (Table 3). To identify trends that may not have been apparent at the binary split, analytes were further categorized and analyzed by quartile. The forest plots provided a clear trend indicating that the outcomes became poorer as the concentrations of these markers increased, patients with baseline VEGF121 or HGF concentrations in the lowest quartile obtained the most survival benefit from bevacizumab (Fig. 4).


A plasma cytokine and angiogenic factor (CAF) analysis for selection of bevacizumab therapy in patients with metastatic colorectal cancer.

Bai L, Wang F, Zhang DS, Li C, Jin Y, Wang DS, Chen DL, Qiu MZ, Luo HY, Wang ZQ, Li YH, Wang FH, Xu RH - Sci Rep (2015)

The predictive value of candidate markers for progression-free survival (A, C, E) and overall survival (B, D, F) in ELISA test were presented by Kaplan–Meier curves stratified according to baseline marker levels (using corresponding optimal binary split) and treatment arms.BEV, bevacizumab; chemo, chemotherapy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664961&req=5

f3: The predictive value of candidate markers for progression-free survival (A, C, E) and overall survival (B, D, F) in ELISA test were presented by Kaplan–Meier curves stratified according to baseline marker levels (using corresponding optimal binary split) and treatment arms.BEV, bevacizumab; chemo, chemotherapy.
Mentions: As a result, patients with lower baseline plasma levels of ANGPTL4 (i.e. lower than the median 1.97 ng/ml), HGF (0.88 ng/ml) or VEGF121 (0.59 ng/ml) were more sensitive to bevacizumab treatment as measured by PFS (for ANGPTL4, HR 0.58; 95% CI 0.36–0.94; for HGF, HR 0.52, 95% CI 0.35–0.76; for VEGF121, HR 0.52; 95% CI 0.36–0.76) than those with higher analytes levels (for ANGPTL4, HR 0.73; 95% CI 0.49–1.08, unadjusted P = 0.048 from interaction Cox Wald tests; for HGF, HR 0.79, 95% CI 0.49–1.27, unadjusted interaction P = 0.020; for VEGF121, HR 0.90; 95% CI 0.53–1.53, unadjusted interaction P = 0.023). Similarly, patients with lower baseline HGF or VEGF-A121 levels experienced remarkably larger benefit from bevacizumab in terms of OS than patients with higher analytes levels (for HGF, HR 0.42 versus 1.19, lower versus higher levels, unadjusted interaction P = 0.010; for HGF, HR 0.42 versus 1.25, lower versus higher levels, unadjusted interaction P = 0.034) (Table 3 and Fig. 3). With the addition of bevacizumab, response rates were only increased in patients with lower ANGPTL4 levels (48.8% vs 10.7%) rather than those with higher ANGPTL4 levels (34.1% vs 41.1%; unadjusted interaction P = 0.003). Likewise, patients who had lower HGF or VEGF121 levels also showed a trend toward improved ORR versus patients with higher levels, though the interaction test did not show enough power (Table 3). The P-values for treatment-marker interaction remained significant in multivariate models after adjusted for known clinical prognostic variables (gender, age, performance status, primary tumor site, tumor grade, prior adjuvant chemotherapy, number of metastasis site, and curative-intent metastasis resection) (Table 3). To identify trends that may not have been apparent at the binary split, analytes were further categorized and analyzed by quartile. The forest plots provided a clear trend indicating that the outcomes became poorer as the concentrations of these markers increased, patients with baseline VEGF121 or HGF concentrations in the lowest quartile obtained the most survival benefit from bevacizumab (Fig. 4).

Bottom Line: Patients with lower pretreatment levels of hepatocyte growth factor (HGF) or VEGF-A(121) gain much more benefit from bevacizumab treatment as measured by progression-free survival (PFS) and overall survival (OS), while angiopoietin-like 4 (ANGPTL4) levels negatively correlated with PFS and response rate following bevacizumab (all adjusted interaction P < 0.05).Signature-negative patients showed impaired survival following bevacizumab treatment (PFS, 7.3 vs 7.0 months; hazard ratio [HR] 1.03; OS, 29.9 vs 21.1 months, HR 1.33) compared with signature-positive patients (PFS, 6.5 vs 11.9 months, HR 0.52; OS, 28.0 vs 55.3 months, HR 0.67).These promising results warrant further prospective studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China.

ABSTRACT
This study intends to identify biomarkers that could refine the selection of patients with metastatic colorectal cancer (mCRC) for bevacizumab treatment. Pretreatment 36 plasma cytokines and angiogenic factors (CAFs) were first measured by protein microarray analysis in patients who received first-line bevacizumab-containing therapies (discovery cohort, n = 64), and further evaluated by enzyme-linked immunosorbent assay in patients treated on regimens with or without bevacizumab (validation cohort, n = 186). Factor levels were correlated with clinical outcomes, predictive values were assessed using a treatment by marker interaction term in the Cox model. Patients with lower pretreatment levels of hepatocyte growth factor (HGF) or VEGF-A(121) gain much more benefit from bevacizumab treatment as measured by progression-free survival (PFS) and overall survival (OS), while angiopoietin-like 4 (ANGPTL4) levels negatively correlated with PFS and response rate following bevacizumab (all adjusted interaction P < 0.05). A baseline CAF signature combining these three markers has greater predictive ability than individual markers. Signature-negative patients showed impaired survival following bevacizumab treatment (PFS, 7.3 vs 7.0 months; hazard ratio [HR] 1.03; OS, 29.9 vs 21.1 months, HR 1.33) compared with signature-positive patients (PFS, 6.5 vs 11.9 months, HR 0.52; OS, 28.0 vs 55.3 months, HR 0.67). These promising results warrant further prospective studies.

No MeSH data available.


Related in: MedlinePlus