Zoledronic Acid-Related Angiogenesis Modifications and Survival in Advanced Breast Cancer Patients

Abstract

The proven antiangiogenic activity of zoledronic acid, a third-generation bisphosphonate widely used in bone metastatic cancer patients, led us to investigate if the vascular endothelial growth factor (VEGF)-related zoledronic acid modifications are correlated with survival advantages in advanced breast cancer patients. Forty-two consecutive breast cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg zoledronic acid before anticancer chemotherapy. The patients were prospectively evaluated for circulating levels of VEGF and interferon-gamma (IFN-gamma) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. Afterward, clinical outcome was prospectively monitored. The basal serum VEGF median levels were significantly decreased at each time point, but the major reduction was recorded 21 days after the infusion. In particular, 25 patients of 42 (59.5%) experienced a reduction of at least 25% in the VEGF circulating levels. In contrast, no statistically significant modifications of the IFN-gamma serum levels were recorded. We stratified patients on the basis of this VEGF reduction 21 days after the infusion. No differences in patient features were recorded between those with or without the VEGF reduction. The analysis of survival showed that patients with a reduction in the VEGF circulating levels had a longer time to first skeletal-related event (p = 0.0002), time to bone progression disease (p = 0.0024), and time to performance status worsening (p = 0.0352) than those without the VEGF reduction. No statistically significant differences were recorded in terms of overall survival and time to visceral progression. This study confirms that zoledronic acid could have an in vivo antiangiogenic property and that the VEGF modifications may represent a surrogate marker able to predict time to first skeletal-related event, time to bone progression disease, and time to worsening of performance status.

The benefits of timely intervention with zoledronic acid in patients with metastatic prostate cancer to bones: a retrospective study of the US Veterans Affairs population

“…16,17 Results from the analysis of SRE outcomes confirm findings from other metastatic prostate cancer studies, and confirm the benefits of ZA in reducing skeletal morbidity. Consistent with the evidence of ZA anticancer activities from recent breast cancer studies, 19,[24][25][26] we found evidence of prolonged overall survival with ZA among patients with prostate cancer. While earlier studies of ZA in prostate cancer did not show significant overall survival benefit with this therapy, the present study found that timely ZA treatment significantly reduced mortality risk during the first 6 months after diagnosis of bone metastasis.…”

Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws

“…Bisphosphonates also have antiangiogenesis properties (8,9) and can activate ␥␦ T cells (10,11). The use of bisphosphonates in patients with multiple myeloma and metastatic cancer to the bones, such as breast, prostate, lung, and renal cell carcinomas, has resulted in a statistically significant reduction in skeletal complications, including pathologic fractures, spinal cord compression, hypercalcemia of malignant disease, and the need for subsequent radiotherapy or surgery to bone (12)(13)(14).…”

Zoledronic acid use in cancer patients

“…43 In a second ZOL study in patients with advanced BC who received 1 ZOL dose before chemotherapy (N ¼ 42), the majority had !25% lower circulating VEGF levels compared with baseline. 44 The reduction in VEGF levels was correlated significantly with prolonged time to first SRE (P ¼ .0002), delayed bone disease progression (P ¼ .0024), and maintained or improved performance status (P ¼ .0352) compared with VEGF levels that remained unchanged. 44 The VEGF pathway is important, because increased VEGF levels are associated with a poor prognosis in patients with advanced BC.…”

“…44 The reduction in VEGF levels was correlated significantly with prolonged time to first SRE (P ¼ .0002), delayed bone disease progression (P ¼ .0024), and maintained or improved performance status (P ¼ .0352) compared with VEGF levels that remained unchanged. 44 The VEGF pathway is important, because increased VEGF levels are associated with a poor prognosis in patients with advanced BC. 45 Moreover, bevacizumab, an anti-VEGF antibody, has demonstrated clinical benefits in this patient population.…”