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The significance of combining VEGFA, FLT1, and KDR expressions in colon cancer patient prognosis and predicting response to bevacizumab.

Zhang SD, McCrudden CM, Meng C, Lin Y, Kwok HF - Onco Targets Ther (2015)

Bottom Line: Targeting angiogenesis through inhibition of the vascular endothelial growth factor (VEGF) pathway has been successful in the treatment of late stage colorectal cancer.However, not all patients benefit from inhibition of VEGF.Most importantly, this signature also predicted tumor response to bevacizumab, an antibody targeting VEGFA, in a cohort of bevacizumab-treated patients.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau, Special Administrative Region of the People's Republic of China ; Center for Cancer Research and Cell Biology, Queen's University Belfast, United Kingdom.

ABSTRACT
Targeting angiogenesis through inhibition of the vascular endothelial growth factor (VEGF) pathway has been successful in the treatment of late stage colorectal cancer. However, not all patients benefit from inhibition of VEGF. Ras status is a powerful biomarker for response to anti-epidermal growth factor receptor therapy; however, an appropriate biomarker for response to anti-VEGF therapy is yet to be identified. VEGF and its receptors, FLT1 and KDR, play a crucial role in colon cancer progression; individually, these factors have been shown to be prognostic in colon cancer; however, expression of none of these factors alone was predictive of tumor response to anti-VEGF therapy. In the present study, we analyzed the expression levels of VEGFA, FLT1, and KDR in two independent colon cancer datasets and found that high expression levels of all three factors afforded a very poor prognosis. The observation was further confirmed in another independent colon cancer dataset, wherein high levels of expression of this three-gene signature was predictive of poor prognosis in patients with proficient mismatch repair a wild-type KRas status, or mutant p53 status. Most importantly, this signature also predicted tumor response to bevacizumab, an antibody targeting VEGFA, in a cohort of bevacizumab-treated patients. Since bevacizumab has been proven to be an important drug in the treatment of advanced stage colon cancer, our results suggest that the three-gene signature approach is valuable in terms of its prognostic value, and that it should be further evaluated in a prospective clinical trial to investigate its predictive value to anti-VEGF treatment.

No MeSH data available.


Related in: MedlinePlus

The association between the combination of VEGFA/FLT1/KDR mRNA expression and colon cancer patient survival.Notes: Kaplan–Meier analyses for VEGFA, FLT1, and KDR mRNA expression in combination in (A) GSE14333 and (B) GSE17538.Abbreviation:VEGFA, vascular endothelial growth factor a.
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f3-ott-8-835: The association between the combination of VEGFA/FLT1/KDR mRNA expression and colon cancer patient survival.Notes: Kaplan–Meier analyses for VEGFA, FLT1, and KDR mRNA expression in combination in (A) GSE14333 and (B) GSE17538.Abbreviation:VEGFA, vascular endothelial growth factor a.

Mentions: Since the combinations of VEGFA-FLT1 and VEGFA-KDR were shown to be more consistent in terms of prognostication than when these genes were considered individually, we further investigated whether combination assessment of expression of the three genes, VEGFA-FLT1-KDR, could be a better prognostic indicator. In GSE14333, patients whose tumors expressed all three genes at a low level had a mean disease-free survival of 101 months (95% confidence interval [CI] =86–116 months), which is significantly longer than patients whose tumors expressed all three genes at a high level (mean disease-free survival =72 months, 95% CI =54–90 months). As shown in Figure 3A, the VEGFA-FLT1-KDR gene signature was significantly associated with disease-free survival in colon cancer patients (P=0.014). Similar results were obtained using the GSE17538 dataset. Patients whose tumors expressed all three genes at a low level had a mean disease-free survival of 104 months (95% CI = 95–113 months), while those who expressed all three genes at a high level had a mean disease-free survival of 71 months (95% CI =57–86 months). As shown in Figure 3B, the VEGFA-FLT1-KDR gene signature was again significantly associated with disease-free survival in this patient cohort (P=0.024).


The significance of combining VEGFA, FLT1, and KDR expressions in colon cancer patient prognosis and predicting response to bevacizumab.

Zhang SD, McCrudden CM, Meng C, Lin Y, Kwok HF - Onco Targets Ther (2015)

The association between the combination of VEGFA/FLT1/KDR mRNA expression and colon cancer patient survival.Notes: Kaplan–Meier analyses for VEGFA, FLT1, and KDR mRNA expression in combination in (A) GSE14333 and (B) GSE17538.Abbreviation:VEGFA, vascular endothelial growth factor a.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403689&req=5

f3-ott-8-835: The association between the combination of VEGFA/FLT1/KDR mRNA expression and colon cancer patient survival.Notes: Kaplan–Meier analyses for VEGFA, FLT1, and KDR mRNA expression in combination in (A) GSE14333 and (B) GSE17538.Abbreviation:VEGFA, vascular endothelial growth factor a.
Mentions: Since the combinations of VEGFA-FLT1 and VEGFA-KDR were shown to be more consistent in terms of prognostication than when these genes were considered individually, we further investigated whether combination assessment of expression of the three genes, VEGFA-FLT1-KDR, could be a better prognostic indicator. In GSE14333, patients whose tumors expressed all three genes at a low level had a mean disease-free survival of 101 months (95% confidence interval [CI] =86–116 months), which is significantly longer than patients whose tumors expressed all three genes at a high level (mean disease-free survival =72 months, 95% CI =54–90 months). As shown in Figure 3A, the VEGFA-FLT1-KDR gene signature was significantly associated with disease-free survival in colon cancer patients (P=0.014). Similar results were obtained using the GSE17538 dataset. Patients whose tumors expressed all three genes at a low level had a mean disease-free survival of 104 months (95% CI = 95–113 months), while those who expressed all three genes at a high level had a mean disease-free survival of 71 months (95% CI =57–86 months). As shown in Figure 3B, the VEGFA-FLT1-KDR gene signature was again significantly associated with disease-free survival in this patient cohort (P=0.024).

Bottom Line: Targeting angiogenesis through inhibition of the vascular endothelial growth factor (VEGF) pathway has been successful in the treatment of late stage colorectal cancer.However, not all patients benefit from inhibition of VEGF.Most importantly, this signature also predicted tumor response to bevacizumab, an antibody targeting VEGFA, in a cohort of bevacizumab-treated patients.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau, Special Administrative Region of the People's Republic of China ; Center for Cancer Research and Cell Biology, Queen's University Belfast, United Kingdom.

ABSTRACT
Targeting angiogenesis through inhibition of the vascular endothelial growth factor (VEGF) pathway has been successful in the treatment of late stage colorectal cancer. However, not all patients benefit from inhibition of VEGF. Ras status is a powerful biomarker for response to anti-epidermal growth factor receptor therapy; however, an appropriate biomarker for response to anti-VEGF therapy is yet to be identified. VEGF and its receptors, FLT1 and KDR, play a crucial role in colon cancer progression; individually, these factors have been shown to be prognostic in colon cancer; however, expression of none of these factors alone was predictive of tumor response to anti-VEGF therapy. In the present study, we analyzed the expression levels of VEGFA, FLT1, and KDR in two independent colon cancer datasets and found that high expression levels of all three factors afforded a very poor prognosis. The observation was further confirmed in another independent colon cancer dataset, wherein high levels of expression of this three-gene signature was predictive of poor prognosis in patients with proficient mismatch repair a wild-type KRas status, or mutant p53 status. Most importantly, this signature also predicted tumor response to bevacizumab, an antibody targeting VEGFA, in a cohort of bevacizumab-treated patients. Since bevacizumab has been proven to be an important drug in the treatment of advanced stage colon cancer, our results suggest that the three-gene signature approach is valuable in terms of its prognostic value, and that it should be further evaluated in a prospective clinical trial to investigate its predictive value to anti-VEGF treatment.

No MeSH data available.


Related in: MedlinePlus