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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 in cohorts stratified based on genetic aberration.Notes: Kaplan–Meier analyses for VEGFA, FLT1, and KDR mRNA expression in combination in GSE40967 in (A) the whole cohort, (B) patients with proficient mismatch repair, (C) patients with wild-type KRas status, and (D) patients with mutant p53 status.Abbreviations:VEGFA, vascular endothelial growth factor a; mRNA, messenger ribonucleic acid; pMMR, proficient mismatch repair.
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f4-ott-8-835: The association between the combination of VEGFA-FLT1-KDR mRNA expression and colon cancer patient survival in cohorts stratified based on genetic aberration.Notes: Kaplan–Meier analyses for VEGFA, FLT1, and KDR mRNA expression in combination in GSE40967 in (A) the whole cohort, (B) patients with proficient mismatch repair, (C) patients with wild-type KRas status, and (D) patients with mutant p53 status.Abbreviations:VEGFA, vascular endothelial growth factor a; mRNA, messenger ribonucleic acid; pMMR, proficient mismatch repair.

Mentions: In another independent dataset, GSE40967, which has available clinicopathological parameters, we sought to investigate whether the association between the three-gene signature and disease-free survival retained relevance in patients with specific genetic alterations. The clinical characteristics for patients in this cohort are listed in Table 1. In the GSE40967 colon cancer patient cohort, patients whose tumors had a high level of expression of the three-gene signature again had a significantly shorter disease-free survival than those patients whose tumors had a low level of expression of the three-gene signature (P=0.048; Figure 4A). Interestingly, this VEGFA-FLT1-KDR signature and survival association was only significant in patients with proficient mismatch repair (MMR) status (P=0.031; Figure 4B), but not in those with deficient MMR status (P=0.657; data not shown). Likewise, the three-gene signature was a potent prognostic indicator in patients with wild-type KRas status (P=0.001; Figure 4C), but not in those with mutant KRas status (P=0.848; data not shown). Similarly, the three-gene signature was also significantly associated with survival in patients with mutant p53 status (P=0.038; Figure 4D), but not in those with wild-type p53 status (P=0.501; data not shown).


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 in cohorts stratified based on genetic aberration.Notes: Kaplan–Meier analyses for VEGFA, FLT1, and KDR mRNA expression in combination in GSE40967 in (A) the whole cohort, (B) patients with proficient mismatch repair, (C) patients with wild-type KRas status, and (D) patients with mutant p53 status.Abbreviations:VEGFA, vascular endothelial growth factor a; mRNA, messenger ribonucleic acid; pMMR, proficient mismatch repair.
© Copyright Policy
Related In: Results  -  Collection

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

f4-ott-8-835: The association between the combination of VEGFA-FLT1-KDR mRNA expression and colon cancer patient survival in cohorts stratified based on genetic aberration.Notes: Kaplan–Meier analyses for VEGFA, FLT1, and KDR mRNA expression in combination in GSE40967 in (A) the whole cohort, (B) patients with proficient mismatch repair, (C) patients with wild-type KRas status, and (D) patients with mutant p53 status.Abbreviations:VEGFA, vascular endothelial growth factor a; mRNA, messenger ribonucleic acid; pMMR, proficient mismatch repair.
Mentions: In another independent dataset, GSE40967, which has available clinicopathological parameters, we sought to investigate whether the association between the three-gene signature and disease-free survival retained relevance in patients with specific genetic alterations. The clinical characteristics for patients in this cohort are listed in Table 1. In the GSE40967 colon cancer patient cohort, patients whose tumors had a high level of expression of the three-gene signature again had a significantly shorter disease-free survival than those patients whose tumors had a low level of expression of the three-gene signature (P=0.048; Figure 4A). Interestingly, this VEGFA-FLT1-KDR signature and survival association was only significant in patients with proficient mismatch repair (MMR) status (P=0.031; Figure 4B), but not in those with deficient MMR status (P=0.657; data not shown). Likewise, the three-gene signature was a potent prognostic indicator in patients with wild-type KRas status (P=0.001; Figure 4C), but not in those with mutant KRas status (P=0.848; data not shown). Similarly, the three-gene signature was also significantly associated with survival in patients with mutant p53 status (P=0.038; Figure 4D), but not in those with wild-type p53 status (P=0.501; data not shown).

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