Alternate VEGF Ligands Associated With Bevacizumab Resistance in Metastatic Colorectal Cancer


Key Points

  • Elevated levels of VEGF-D and placental growth factor were observed in patients receiving bevacizumab.
  • Elevations of placental growth factor and VEGF-D appeared to be transient and were not maintained following discontinuation of bevacizumab.
  • Although these ligands are associated with resistance to bevacizumab-containing regimens, causation was not established.

Results from a University of Colorado Cancer Center study indicated that bevacizumab (Avastin) resistance in patients with colorectal cancer may be due to increases in growth factors other than the targeted VEGF-A. The study, led by Christopher Lieu, MD, and published in the journal PLoS One, focused on the tendency of tumors targeted by bevacizumab to switch dependence from VEGF-A to other related growth factors such as VEGF-C, VEGF-D, and placental growth factor.

Study Details

Prior preclinical analyses suggested that alternate proangiogenic factors may modulate sensitivity to anti–VEGF-A therapy and allow regrowth of tumor-associated vasculature. In the current study, researchers analyzed paired plasma samples obtained from two cohorts of patients with metastatic colorectal cancer. The discovery cohort (n = 42) consisted of patients with metastatic colorectal cancer who were treated with FOLFIRI (leucovorin, fluorouracil, and irinotecan) and bevacizumab, and for the validation cohort (n = 403), the researchers utilized a cross-section of patients who underwent a one-time plasma collection between 2002 and 2008.

Patients were separated into three groups based on treatment history: no prior history of colorectal cancer chemotherapy (Group A), progression on chemotherapy without bevacizumab (Group B), and progression on chemotherapy with bevacizumab (Group C). Patient samples were matched for the number of metastatic disease sites (Groups A, B, and C), prior chemotherapy duration, and time from last chemotherapy dose (Groups B and C). Evaluable patients in Group A within the validation cohort were divided into two groups based on their median cytokine levels in order to evaluate the prognostic value of VEGF-A, VEGF-C, VEGF-D, or placental growth factor.

Study Results

This study was able to demonstrate an association between bevacizumab and alternate VEGF ligands in metastatic colorectal cancer. In the discovery cohort, VEGF-C was increased prior to disease progression (+49% from baseline, P =.045) and at the time of disease progression (+94%, P = .004). VEGF-D levels were increased at the time of disease progression (+23%, P = .04) but not prior to disease progression (-1%, P = .84), in contrast to VEGF-C levels. It should be noted that while there was an increase in VEGF-C levels in the discovery group, there was not a similar increase in the validation group; indeed, there were lower levels of VEGF-C (-36%, P < .0001) within the validation cohort in patients previously treated with chemotherapy plus bevacizumab.

Changes in placental growth factor levels may also have potential for predicting bevacizumab resistance. Significantly elevated levels of placental growth factor were observed in the chemotherapy plus bevacizumab group (+72%, P < .0001) compared with the chemotherapy without bevacizumab group. However, no difference in VEGF-C (+5%, P = .64) and VEGF-D (+7%, P = .18) levels was seen in patients receiving chemotherapy alone and patients receiving prior chemotherapy and bevacizumab.

The elevation in placental growth factor and VEGF-D levels were found to be transient and were not maintained after removal of bevacizumab-containing chemotherapy, nor was a similar correlation seen in patients treated with chemotherapy alone. Using a single-phase log decay curve, the half-life for placental growth factor was found to be 1.6 months (95% confidence interval [CI] = 1.4–1.9) and the half-life for VEGF-D was 1.5 months (95% CI = 1.2–2.0).

The researchers also evaluated cytokines that were associated with one or more of the VEGF ligand family members, and found that several several cytokines were highly correlated with VEGF-A, VEGF-C, and placental growth factor.

Dr. Lieu noted, “It’s too early to say with certainty that VEGF-C, VEGF-D, and placental growth factor are the cause of colorectal cancer resistance to bevacizumab, but the correlation we saw in this study is compelling.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.