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    • To date no biomarker analyses of response to VEGFR

    2019-05-16

    To date, no biomarker analyses of response to VEGFR targeting agents in breast cancer patients with bone predominant metastatic disease has occurred. Although the bone turnover markers serum c-telopeptide (sCTx), and urinary N-telopeptide (uNTx) were measured at baseline, and uNTX measured every 8 weeks on patients accrued to the Zamboney study, no statistically significant association of these markers with response to vandetanib were observed in the main Zamboney study. Circulating angiogenic factors such as VEGF, bFGF, SDF-1α or soluble (s)VEGFR2 or sVEGFR3 have been previously suggested to associate with response following administration of the VEGF/VEGFR targeting agents bevacizumab, sunitinib (SU11248), BAY 57-9352, vatalinib (PTK787/ZK222584) and cediranib (AZD2171) [16–22]. Thus, we measured markers of tumor angiogenesis previously suggested to associate with response to VEGF-targeting drugs, namely VEGF, sVEGFR2 or sVEGFR3, and additionally evaluated putative markers of bone glucose transport proteins burden, namely transforming growth factor (TGF)-β and its related family member activinA, at baseline in patients enrolled in Zamboney to assess their prognostic or predictive abilities.
    Materials and methods
    Results
    Discussion A subgroup of 101 of patients consented to participate in a correlative marker sub-study, evaluating a number of angiogenic (VEGF-A, sVEGFR2, and sVEGFR3) and bone turnover (TGF-β, activinA) markers. In this subgroup of patients, higher baseline sVEGFR2 was statistically significant as a prognostic marker of improved OS, with trends towards significance as a prognostic marker for improved PFS and time to first SRE. sVEGFR2 has been shown to be prognostic in a number of other cancer types [24,25]. Our findings are similar to those recently reported from the AVADO trial which randomized HER2-negative locally recurrent and metastatic breast cancer patients to receive docetaxel with the anti-angiogenic agent bevacizumab [26]. In this study, higher plasma concentrations of sVEGFR2 were associated with better PFS response (HR=0.46, 95% C.I. (0.28–0.74), p=0.03) in bevacizumab treated patients compared to placebo; association of sVEGFR2 with OS was not reported. In contrast, low baseline sVEGFR2 levels were associated with longer PFS for patients on cediranib in hepatocellular carcinoma [24], and with greater benefit from cediranib treatment in colorectal cancer patients [25]. Median biomarker levels used to determine associations in these studies are similar to that used in our study (median sVEGFR2 of 5.9ng/ml [24] in the hepatocellular carcinoma study and 11.6ng/ml in the colorectal cancer study [25] compared to 8ng/ml in our study). However, as neither hepatocellular nor colorectal cancers commonly metastasize to bone while it is the predominant site of breast cancer metastases, it is perhaps not surprising that different associations are observed and the role of sVEGFR2 in progression of metastatic breast cancer remains unclear. It should also be noted that vandetanib targets alternative kinases compared to cediranib which primarily targets VEGFR1, 2 and 3, which may also contribute to the different observations in sVEGFR2 associations. The role of sVEGFR2 in specifically regulating bone metastases is not well established. The VEGF ligand plays an important role in establishment of a vascular bed in the bone in addition to promoting survival and differentiation of resident bone cells [27]. Cell surface expression of VEGFR2 has been shown to increase during osteoclast differentiation from mononuclear precursor cells where it is the predominant receptor mediating VEGF signaling in osteoclasts [28,29]. As one of the prime mediators of bone destruction in metastatic breast cancer, it is likely that patients with high circulating sVEGFR2 may have reduced osteoclastogenic activity as a result of binding and sequestration of VEGF ligand from cell surface receptors on osteoclasts. As patients with increased osteolytic activity and bone turnover tend to have worse prognosis [30], higher levels of sVEGFR2 may inhibit VEGF-induced osteoclastogenic activity and osteolysis and hence contribute to better survival outcomes in bone metastatic breast cancer patients.