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Predicting response to vascular endothelial growth factor inhibitor and chemotherapy in metastatic colorectal cancer.

Martin P, Noonan S, Mullen MP, Scaife C, Tosetto M, Nolan B, Wynne K, Hyland J, Sheahan K, Elia G, O'Donoghue D, Fennelly D, O'Sullivan J - BMC Cancer (2014)

Bottom Line: Three proteins (apolipoprotein E (APOE), angiotensinogen (AGT) and vitamin D binding protein (DBP)) were selected for validation studies.Increasing APOE expression in the epithelium was associated with a longer PFS and OS, and AGT epithelial expression was associated with a longer PFS (all p < .05).Increasing serum AGT concentration was associated with shorter OS (p = 0.009).

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Trinity Centre for Health Sciences, Institute of Molecular Medicine, St, James's Hospital, Dublin 8, Ireland. osullij4@tcd.ie.

ABSTRACT

Background: Bevacizumab improves progression free survival (PFS) and overall survival (OS) in metastatic colorectal cancer patients however currently there are no biomarkers that predict response to this treatment. The aim of this study was to assess if differential protein expression can differentiate patients who respond to chemotherapy and bevacizumab, and to assess if select proteins correlate with patient survival.

Methods: Pre-treatment serum from patients with metastatic colorectal cancer (mCRC) treated with chemotherapy and bevacizumab were divided into responders and nonresponders based on their progression free survival (PFS). Serum samples underwent immunoaffinity depletion and protein expression was analysed using two-dimensional difference gel electrophoresis (2D-DIGE), followed by LC-MS/MS for protein identification. Validation on selected proteins was performed on serum and tissue samples from a larger cohort of patients using ELISA and immunohistochemistry, respectively (n = 68 and n = 95, respectively).

Results: 68 proteins were identified following LC-MS/MS analysis to be differentially expressed between the groups. Three proteins (apolipoprotein E (APOE), angiotensinogen (AGT) and vitamin D binding protein (DBP)) were selected for validation studies. Increasing APOE expression in the stroma was associated with shorter progression free survival (PFS) (p = 0.0001) and overall survival (OS) (p = 0.01), DBP expression (stroma) was associated with shorter OS (p = 0.037). Increasing APOE expression in the epithelium was associated with a longer PFS and OS, and AGT epithelial expression was associated with a longer PFS (all p < .05). Increasing serum AGT concentration was associated with shorter OS (p = 0.009).

Conclusions: APOE, DBP and AGT identified were associated with survival outcomes in mCRC patients treated with chemotherapy and bevacizumab.

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Related in: MedlinePlus

Survival and APOE expression. Representative images of APOE expression demonstrating (A) low, (B) medium and (C) high expression, (D) PFS Kaplan meier curve of APOE stromal expression of high, medium and low expression, demonstrating significantly shorter PFS in patients with high expression, (E) OS Kaplan meier curve of APOE stromal expression of high, medium and low expression, demonstrating significantly shorter OS in patients with high expression, (F) PFS Kaplan meier curve of APOE epithelial expression of high, medium and low expression, demonstrating significantly longer PFS in patients with high expression, (G) OS Kaplan meier curve of APOE epithelial expression of high, medium and low expression, demonstrating no significance between between the groups.
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Fig3: Survival and APOE expression. Representative images of APOE expression demonstrating (A) low, (B) medium and (C) high expression, (D) PFS Kaplan meier curve of APOE stromal expression of high, medium and low expression, demonstrating significantly shorter PFS in patients with high expression, (E) OS Kaplan meier curve of APOE stromal expression of high, medium and low expression, demonstrating significantly shorter OS in patients with high expression, (F) PFS Kaplan meier curve of APOE epithelial expression of high, medium and low expression, demonstrating significantly longer PFS in patients with high expression, (G) OS Kaplan meier curve of APOE epithelial expression of high, medium and low expression, demonstrating no significance between between the groups.

Mentions: Proteins were divided into three subsets using the tertile points. These three subsets were classified as "Low", "Medium", and "High". For each subset, a product-limit survival estimate was obtained using the Kaplan-Meier method.‘High’ APOE stromal expression demonstrated a significantly shorter PFS and OS compared with medium and low expression. (Figure 3D,E). Conversely, ‘high’ APOE (epithelial) expression demonstrated a significantly longer PFS than medium and low expression (Figure 3F), however no significance was seen between the three groups for OS (Figure 3G).


Predicting response to vascular endothelial growth factor inhibitor and chemotherapy in metastatic colorectal cancer.

Martin P, Noonan S, Mullen MP, Scaife C, Tosetto M, Nolan B, Wynne K, Hyland J, Sheahan K, Elia G, O'Donoghue D, Fennelly D, O'Sullivan J - BMC Cancer (2014)

Survival and APOE expression. Representative images of APOE expression demonstrating (A) low, (B) medium and (C) high expression, (D) PFS Kaplan meier curve of APOE stromal expression of high, medium and low expression, demonstrating significantly shorter PFS in patients with high expression, (E) OS Kaplan meier curve of APOE stromal expression of high, medium and low expression, demonstrating significantly shorter OS in patients with high expression, (F) PFS Kaplan meier curve of APOE epithelial expression of high, medium and low expression, demonstrating significantly longer PFS in patients with high expression, (G) OS Kaplan meier curve of APOE epithelial expression of high, medium and low expression, demonstrating no significance between between the groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4289341&req=5

Fig3: Survival and APOE expression. Representative images of APOE expression demonstrating (A) low, (B) medium and (C) high expression, (D) PFS Kaplan meier curve of APOE stromal expression of high, medium and low expression, demonstrating significantly shorter PFS in patients with high expression, (E) OS Kaplan meier curve of APOE stromal expression of high, medium and low expression, demonstrating significantly shorter OS in patients with high expression, (F) PFS Kaplan meier curve of APOE epithelial expression of high, medium and low expression, demonstrating significantly longer PFS in patients with high expression, (G) OS Kaplan meier curve of APOE epithelial expression of high, medium and low expression, demonstrating no significance between between the groups.
Mentions: Proteins were divided into three subsets using the tertile points. These three subsets were classified as "Low", "Medium", and "High". For each subset, a product-limit survival estimate was obtained using the Kaplan-Meier method.‘High’ APOE stromal expression demonstrated a significantly shorter PFS and OS compared with medium and low expression. (Figure 3D,E). Conversely, ‘high’ APOE (epithelial) expression demonstrated a significantly longer PFS than medium and low expression (Figure 3F), however no significance was seen between the three groups for OS (Figure 3G).

Bottom Line: Three proteins (apolipoprotein E (APOE), angiotensinogen (AGT) and vitamin D binding protein (DBP)) were selected for validation studies.Increasing APOE expression in the epithelium was associated with a longer PFS and OS, and AGT epithelial expression was associated with a longer PFS (all p < .05).Increasing serum AGT concentration was associated with shorter OS (p = 0.009).

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Trinity Centre for Health Sciences, Institute of Molecular Medicine, St, James's Hospital, Dublin 8, Ireland. osullij4@tcd.ie.

ABSTRACT

Background: Bevacizumab improves progression free survival (PFS) and overall survival (OS) in metastatic colorectal cancer patients however currently there are no biomarkers that predict response to this treatment. The aim of this study was to assess if differential protein expression can differentiate patients who respond to chemotherapy and bevacizumab, and to assess if select proteins correlate with patient survival.

Methods: Pre-treatment serum from patients with metastatic colorectal cancer (mCRC) treated with chemotherapy and bevacizumab were divided into responders and nonresponders based on their progression free survival (PFS). Serum samples underwent immunoaffinity depletion and protein expression was analysed using two-dimensional difference gel electrophoresis (2D-DIGE), followed by LC-MS/MS for protein identification. Validation on selected proteins was performed on serum and tissue samples from a larger cohort of patients using ELISA and immunohistochemistry, respectively (n = 68 and n = 95, respectively).

Results: 68 proteins were identified following LC-MS/MS analysis to be differentially expressed between the groups. Three proteins (apolipoprotein E (APOE), angiotensinogen (AGT) and vitamin D binding protein (DBP)) were selected for validation studies. Increasing APOE expression in the stroma was associated with shorter progression free survival (PFS) (p = 0.0001) and overall survival (OS) (p = 0.01), DBP expression (stroma) was associated with shorter OS (p = 0.037). Increasing APOE expression in the epithelium was associated with a longer PFS and OS, and AGT epithelial expression was associated with a longer PFS (all p < .05). Increasing serum AGT concentration was associated with shorter OS (p = 0.009).

Conclusions: APOE, DBP and AGT identified were associated with survival outcomes in mCRC patients treated with chemotherapy and bevacizumab.

Show MeSH
Related in: MedlinePlus