Biomarkers of Anti-Angiogenic Therapy in Metastatic Colorectal Cancer (mCRC): Original Data and Review of the Literature

Zusammenfassung

Einleitung: Das kolorektale Karzinom (KRK) ist die zweithäufigste krebsbedingte Todesursache in der westlichen Industriewelt. Der monoklonale anti-VEGF-Antikörper Bevacizumab gegen die „Vascular Endothelial Growth Factor” (VEGF) vermittelte Tumorangiogenese verbessert das progressionsfreie Überleben von Patienten mit metastasiertem kolorektalen Karzinom (mCRC). Eine Subpopulation der mononukleären Blutzellen, die Endothelialen-Progenitor-Zellen (EPC), sind an der Tumorangiogenese beteiligt. In dieser Pilotstudie wurden mögliche Biomarker bei Patienten der randomisierten, multizentrischen Phase-II-Studie AIO KRK 0604 und deren Vorhersagewert für das Therapieansprechen einer antiangiogenetischen Therapie evaluiert. Material und Methoden: Es wurden 23 Patienten aus der AIO KRK 0604, die Bevacizumab in Kombination mit Capecitabin/Irinotecan oder Capecitabin/Oxaliplatin in der Erstlinientherapie erhielten, analysiert. Aus Patientenblutproben wurden durchflusszytometrisch die EPC (CD34 + , CD 133 + , KDR + ), der Serum-VEGF-Spiegel mittels ELISA und die VEGF-Expression im Tumor bestimmt. Ergebnisse: Patienten mit mKRK, die nach 6 Monaten Behandlung mit Bevacizumab eine partielle Remission (PR) der Tumorerkrankung zeigten, wiesen nach 21 Therapietagen eine deutliche Reduktion der CD 34-negativen KDR-positiven Zellen auf, im Gegensatz zu keiner wesentlichen Änderung der CD 34 /KDR-positiven Zellen. Die Behandlung mit dem humanisierten mAk Bevacizumab führte zu einer Reduktion des Serum-VEGF-Spiegels bei Patienten mit metastasiertem Kolonkarzinom. Diese war unabhängig und nicht prädiktiv für ein Therapieansprechen mit dem antiangiogenetischen Antikörper. Die VEGF-Expression im Primärtumor korrelierte nicht mit dem Therapieansprechen. Diskussion: Wir haben die EPC, den Serum-VEGF-Spiegel in Blutproben und die VEGF-Expression im Tumorgewebe als Biomarker für ein Therapieansprechen evaluiert. Patienten, die nach 6 Monaten Behandlung mit Bevacizumab eine partielle Remission (PR) zeigten, wiesen nach 21 Therapietagen eine Reduktion der CD 34-negativen KDR-positiven Zellen auf. Die Daten werden vor dem Hintergrund der derzeit aktuellen Diskussion über prädiktiven Biomarker für antiangiogenetische Therapien kritisch durchleuchtet.

Abstract

Introduction: Tumour angiogenesis via vascular endothelial growth factor (VEGF) is essential for promoting tumour progression and is overexpressed in colorectal cancer. The humanised monoclonal anti-VEGF antibody bevacizumab (Avastin®, Genentech Inc., South San Francisco, CA) has shown activity in metastatic colorectal cancer (mCRC) combined with conventional chemotherapy. The search for biomarkers to predict response to anti-angiogenic therapy in mCRC is of great interest. We investigated several potential predictive anti-angiogenic markers including circulating endothelial progenitor cells (EPC) in patients with mCRC receiving bevacizumab containing treatment within a randomised multicenter phase 2 study of the German AIO GI tumour study group. Methods: We collected sequential blood samples and tumour tissues from patients participating in a clinical trial for patients with mCRC. We performed flow cytometry of mononuclear cells isolated from peripheral blood to assess CD 133 + or CD 34 + /KDR +  EPC before the first bevacizumab containing chemotherapy and after 21 days. Circulating VEGF blood levels before a bevacizumab containing chemotherapy regimen and after 21 days and VEGF expression in tumour tissue were examined. Results: Patients with mCRC and a partial remission after six months of immuno-chemotherapy containing bevacizumab showed a reduction of CD 34 negative KDR positive cells as early as 3 weeks after start of therapy. In contrast, no remarkable change in the number of CD 34 /KDR positive or CD 34 /CD133 positive cells was seen. Furthermore, there was no correlation between treatment response and VEGF expression within the tumour tissue. The mAb bevacizumab reduced serum-VEGF levels in patients independent of their treatment response to bevacizumab. Discussion: We examined circulating endothelial progenitor cells (EPC), serum-VEGF levels and the tumour tissue VEGF expression of patients with mCRC under a bevacizumab containing chemotherapy. The patients with a partial remission after six months of immuno-chemotherapy showed a reduction of CD 34 negative KDR positive cells as early as 3 weeks after start of therapy. Neither serum nor tissue markers were of significant predictive value in our pilot study. Furthermore, we review the current data on biomarkers for anti-angiogenic therapy of mCRC.

Schlüsselwörter

antiangiogenetische Therapie - Bevacizumab - Biomarker - endotheliale Progenitor-Zellen - VEGF - metastasiertes kolorektales Karzinom

Key words

anti-angiogenic therapy - bevacizumab - biomarker - endothelial progenitor cells - VEGF - metastatic colorectal cancer

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