Older patients with melanoma may have poorer response to anti-VEGF therapy
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Angiogenesis appeared to be driven by an increase in the protein sFRP2 in the aged tumor microenvironment as VEGF decreased among older patients with melanoma, according to results of a study published in Clinical Cancer Research.
The results reflect the importance of considering age as a factor when designing targeted therapies, researchers noted, as older patients studied tended to have poorer response to the anti-VEGF antibody bevacizumab (Avastin, Genentech) than younger patients.
“Over the years, it has become increasingly clear that we cannot rely on a one-size-fits-all approach when selecting treatments for patients with cancer,” Ashani T. Weeraratna, MD, Bloomberg distinguished professor of cancer biology and E.V. McCollum professor and chair in the department of biochemistry and molecular biology at Johns Hopkins School of Public Health, as well as professor in the department of oncology at Johns Hopkins School of Medicine, said in a press release. “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.”
Progression of melanoma to distant metastatic sites increases as patients get older. Age is a critical prognostic factor for patient survival, with older patients at an increased risk for the development of often incurable visceral metastases.
Angiogenesis may be critical for tumor metastasis. However, inhibiting angiogenesis using drugs such as bevacizumab has had little impact on melanoma survival.
Previous studies have shown increased angiogenesis and metastases in older individuals. This prompted Weeraratna and colleagues to investigate whether there is an age-related difference in response to bevacizumab, as well as the potential mechanism for such a difference.
The researchers evaluated data from the randomized, phase 3 AVAST-M trial, in which 1,343 patients with resected melanoma received bevacizumab or underwent observation for 1 year .
The investigators looked for interactions between age and response to the agent. They also examined the age-dependent expression of VEGF and its cognate receptors in patients with melanoma while using syngeneic melanoma animal models to target VEGF in young vs. old mice. Further, they studied whether age-related proangiogenic factor sFRP2 could modulate response to anti-VEGF therapy.
Results showed bevacizumab had no impact on DFS among patients aged older than 65 years (HR = 1; 95% CI, 0.72-1.38) but significantly prolonged DFS among patients aged younger than 45 years (HR = 0.71; 95% CI, 0.53-0.96) compared with observation. Researchers also observed a 25% decreased risk for overall mortality among the younger patients who received bevacizumab vs. observation, although this did not reach statistical significance, compared with no OS impact among older patients.
Targeting VEGF did not remove angiogenesis in an aged mouse model, whereas sFRP2 promoted angiogenesis in vitro and in young mice, according to researchers.
Additionally, targeting sFRP2 in aged mice successfully removed angiogenesis, and in young mice, the effects of targeting VEGF could be overcome by increasing sFRP2.
“Our results underscore the importance of considering age in designing preclinical studies, in clinical trial enrollment and when interpreting trial results,” Weeraratna said in the press release.
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