sFRP2 Drives Tumor Growth, Bevacizumab Ineffectiveness in Older Patients With Melanoma

Ashani Weeraratna, PhD

sFRP2-mediated angiogenesis offset decreased VEGF-mediated angiogenesis in older patients with cutaneous melanoma compared with younger patients, leading to poorer disease-free survival (DFS) and overall survival (OS) with adjuvant bevacizumab (Avastin), according to findings from a study published in Clinical Cancer Research.¹

Younger patients under the age of 45 years who received adjuvant bevacizumab had a significantly longer disease-free interval (HR, 0.71; 95% CI, 0.53-0.96) compared with older patients over the age of 65 years (HR, 1.00, 95% CI, 0.72-1.38). Similar trends were found with regard to OS.

“Our work highlights the fact that younger patients can have very different responses to a given therapy compared with older patients. Understanding that the age of a patient can affect response to treatment is critical to providing the best care for all patients,” said study author Ashani Weeraratna, PhD, Bloomberg Distinguished Professor of Cancer Biology and an E.V. McCollum professor and chair in the Department of Biochemistry and Molecular Biology at the Johns Hopkins School of Public Health.²

Although angiogenesis drives tumor growth and is increased in older patients, antiangiogenic agents, such as bevacizumab, have demonstrated modest antitumor activity in melanoma.

In order to better understand the mechanisms that are responsible for driving tumor growth in melanoma, investigators compiled data from the phase 3 AVAST-M trial, which evaluated 1343 patients with melanoma who received treatment with bevacizumab.

The 5-year results from the trial failed to show a significant difference in distant metastasis-free survival or OS in patients who received 1 year of bevacizumab versus observation. However, the analysis did not evaluate age as a potential predictive factor.

To determine the relationship between age and angiogenesis, investigators stained whole tumor samples from younger and older patients with melanoma for CD31 to evaluate blood vessel density in the tumor. The percentage of CD31 expression within tumors was significantly increased in patients older than 65 years versus patients younger than 65 years (P = .0174).

In addition to the negative correlation that was found between age and DFS benefit in younger and older patients, investigators demonstrated that increased age correlated with decreased VEGFA (n = 465; P = .0348), VEGFR1 (n = 465; P = .0002), VEGFR2 (n = 465; P = .0159) expression.

Investigators also evaluated syngeneic melanoma animal models in young and old mice within the context of VEGF and sFRP2 expression, the latter of which is another proangiogenic gene. Serial sections of primary Yumm1.7 allografts from untreated young oraged C57/BL6 mice were tested for their VEGF and sFRP2 status. Similar to the analysis from the AVAST-M trial, increasing age was associated with a decrease in VEGF expression, but also an increase in sFRP2 expression.

“This finding was really surprising to us, as we assumed that an increase in angiogenesis would correspond with an increase in VEGF expression among aged melanoma patients,” said Weeraratna, who is also a professor in the Department of Oncology at Johns Hopkins School of Medicine.

To determine whether increased sFRP2 expression had any bearing on response to VEGF inhibition, the mice were treated with an anti-VEGF antibody. The anti-VEGF antibody reduced angiogenesis in young mice but lost its effect in the presence of sFRP2. Moreover, blood vessel density was increased.

“While sFRP2 levels increase in the aged tumor microenvironment, accounting for the increase in angiogenesis, VEGF levels decrease, which explains why anti-VEGF treatment is no longer effective in older patients with melanoma,” said lead study author, Mitchell Fane, PhD, a postdoctoral fellow at The Wistar Institute.

“Our results underscore the importance of considering age in designing preclinical studies, in clinical trial enrollment, and when interpreting trial results,” Weeraratna concluded.

References

1. Response to adjuvant bevacizumab among patients with resected melanoma may vary by age. News release. AACR. October 23, 2020. Accessed October 25, 2020. https://bit.ly/3dThp9e​
2. Fane ME. Ecker sBL, Kaur A, et al. sFRP2 supersedes VEGF as an age-related driver of angiogenesis in melanoma, affecting response to anti-VEGF therapy in older patients. Clin Can Res. Published October 23, 2020. doi:10.1158/1078-0432.CCR-20-0046