Limits...
Combining bevacizumab and chemoradiation in rectal cancer. Translational results of the AXEBeam trial.

Verstraete M, Debucquoy A, Dekervel J, van Pelt J, Verslype C, Devos E, Chiritescu G, Dumon K, D'Hoore A, Gevaert O, Sagaert X, Van Cutsem E, Haustermans K - Br. J. Cancer (2015)

Bottom Line: One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia.Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response.Validation in larger patient groups is needed.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, Leuven, Belgium.

ABSTRACT

Background: This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT).

Methods: From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients.

Results: One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response.

Conclusions: We could not support the 'normalization hypothesis' and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed.

Show MeSH

Related in: MedlinePlus

Changes in tissue markers during bevacizumab treatment. Box plots of expression levels at T0 and T1 measured by IHC in responding vs non-responding patients. (A, B) Changes in percentage of pericyte-covered blood vessels (BV), (C, D) MVD and (E, F) tumour hypoxia (CA-IX). Each plot represents the 25th and 75th percentile. The square inside the box indicates the median, and the whiskers indicate the minimum and maximum values. Indicated P-values by Mann–Whitney U-test. Abbreviations: pCR=pathological complete response; T0=baseline; T1=after one dose bevacizumab.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4402460&req=5

fig3: Changes in tissue markers during bevacizumab treatment. Box plots of expression levels at T0 and T1 measured by IHC in responding vs non-responding patients. (A, B) Changes in percentage of pericyte-covered blood vessels (BV), (C, D) MVD and (E, F) tumour hypoxia (CA-IX). Each plot represents the 25th and 75th percentile. The square inside the box indicates the median, and the whiskers indicate the minimum and maximum values. Indicated P-values by Mann–Whitney U-test. Abbreviations: pCR=pathological complete response; T0=baseline; T1=after one dose bevacizumab.

Mentions: Histological data on all patients demonstrated that a single dose of bevacizumab induced a significant but small decrease in the MVD, more specifically in the proportion of vessels covered by α-SMA-positive pericytes. The MVD shifted from 74 blood vessels per mm2 (36–126 blood vessels per mm2) to 62 blood vessels per mm2 (22–151 blood vessels per mm2; P=0.02) and the proportion of mature vessels declined from 87% (20–98%) before treatment to 73% (35–91%) afterwards (T1; P<0.0001). The decrease in pericyte-covered blood vessels was similar in both groups (Figures 3A and B). However, the effect on the MVD was more pronounced in the responders (from 71 to 53 blood vessels per mm2; P=0.11) than in the non-responders (from 74 to 64 blood vessels per mm2; P=0.20) although not significantly (P=0.91; Figures 3C and D).


Combining bevacizumab and chemoradiation in rectal cancer. Translational results of the AXEBeam trial.

Verstraete M, Debucquoy A, Dekervel J, van Pelt J, Verslype C, Devos E, Chiritescu G, Dumon K, D'Hoore A, Gevaert O, Sagaert X, Van Cutsem E, Haustermans K - Br. J. Cancer (2015)

Changes in tissue markers during bevacizumab treatment. Box plots of expression levels at T0 and T1 measured by IHC in responding vs non-responding patients. (A, B) Changes in percentage of pericyte-covered blood vessels (BV), (C, D) MVD and (E, F) tumour hypoxia (CA-IX). Each plot represents the 25th and 75th percentile. The square inside the box indicates the median, and the whiskers indicate the minimum and maximum values. Indicated P-values by Mann–Whitney U-test. Abbreviations: pCR=pathological complete response; T0=baseline; T1=after one dose bevacizumab.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402460&req=5

fig3: Changes in tissue markers during bevacizumab treatment. Box plots of expression levels at T0 and T1 measured by IHC in responding vs non-responding patients. (A, B) Changes in percentage of pericyte-covered blood vessels (BV), (C, D) MVD and (E, F) tumour hypoxia (CA-IX). Each plot represents the 25th and 75th percentile. The square inside the box indicates the median, and the whiskers indicate the minimum and maximum values. Indicated P-values by Mann–Whitney U-test. Abbreviations: pCR=pathological complete response; T0=baseline; T1=after one dose bevacizumab.
Mentions: Histological data on all patients demonstrated that a single dose of bevacizumab induced a significant but small decrease in the MVD, more specifically in the proportion of vessels covered by α-SMA-positive pericytes. The MVD shifted from 74 blood vessels per mm2 (36–126 blood vessels per mm2) to 62 blood vessels per mm2 (22–151 blood vessels per mm2; P=0.02) and the proportion of mature vessels declined from 87% (20–98%) before treatment to 73% (35–91%) afterwards (T1; P<0.0001). The decrease in pericyte-covered blood vessels was similar in both groups (Figures 3A and B). However, the effect on the MVD was more pronounced in the responders (from 71 to 53 blood vessels per mm2; P=0.11) than in the non-responders (from 74 to 64 blood vessels per mm2; P=0.20) although not significantly (P=0.91; Figures 3C and D).

Bottom Line: One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia.Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response.Validation in larger patient groups is needed.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, Leuven, Belgium.

ABSTRACT

Background: This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT).

Methods: From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients.

Results: One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response.

Conclusions: We could not support the 'normalization hypothesis' and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed.

Show MeSH
Related in: MedlinePlus