Neoadjuvant Chemotherapy with or without Zoledronic Acid in Early Breast Cancer—A Randomized Biomarker Pilot Study

Abstract

Purpose: To investigate the short-term biologic effects of neoadjuvant chemotherapy þ/À zoledronic acid (ZOL) in invasive breast cancer.Experimental Design: Forty patients were randomized to receive a single 4 mg infusion of ZOL 24 hours after the first cycle of FE 100 C chemotherapy, or chemotherapy alone. Randomization was stratified for tumor stage, ER, HER2, and menopausal status. All patients had repeat breast core biopsy at day 5 (D5) AE day 21 (D21). Effects on apoptotic index, proliferation (Ki67), growth index, surrogate serum markers of angiogenesis (VEGF), and serum reproductive hormones within the TGFb family (activin-A, TGFb1, inhibin-A, and follistatin) were evaluated and compared.Results: Baseline clinicopathologic characteristics were well balanced. Cell growth index (increased apoptosis and reduced proliferation) fell at D5 in both groups but recovered more rapidly with chemotherapy þ ZOL compared with chemotherapy alone by D21 (P ¼ 0.006). At D5, a greater reduction in serum VEGF occurred with chemotherapy þ ZOL compared with chemotherapy: median percentage change À23.8% [interquartile range (IQR): À32.9 to À15.8] versus À8.4% (IQR: À27.3 to þ8.9; P ¼ 0.02), but these effects were lost by D21. Postmenopausal women showed a decrease in follistatin levels from baseline in the chemotherapy þ ZOL group at D5 and D21, compared with chemotherapy alone (P interaction ¼ 0.051).Conclusions: In this pilot study, short-term changes in biomarkers suggest potentially relevant interactions between tumor biology, chemotherapy, modification of the bone microenvironment, and the endocrine status of the host. Larger studies with more frequent dosing of zoledronic acid are needed to assess these complex interactions more thoroughly.

Blood‐based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic

“…likelihood of stabilized or improved cognition or lack of worsening in cognition in that specific individual) such a marker could conceivably be introduced as a surrogate biomarker for the primary outcome rather than change in cognition after appropriate validation work and ongoing discussions with regulators. Recent work suggests that early change in plasma S100β and neuron specific enolase (NSE) may predict six month clinical outcomes in stroke patients[63] and this area has been studied extensively in cancer[64–66]. The ideal situation would be the identification of such a response biomarker that changes within six months (given a specific profile of study subjects included in the cohort at the beginning), thereby significantly decreasing the time of the clinical trials.…”

Psychological states, serum markers and survival: associations and predictors of survival in patients with renal cell carcinoma

“…Patients completed assessments of psychosocial and quality-of-life variables and blood samples were drawn to measure serum markers of disease. Blood serum has been shown to undergo changes after chemotherapy treatment (Winter et al 2013), so patients who had undergone chemotherapy were excluded from our analysis because of the potential impact of the medications on serum markers. The present study was a part of a larger study investigating the association between psychological factors and survival (Cohen et al 2012).…”

Bone-Targeted Therapies in Cancer-Induced Bone Disease

“…A recent meta-analysis of individual patient data from randomised trials of adjuvant BP use in early breast cancer has further proved a reduction in the risk of bone and other metastases and breast cancer mortality only in older or oestrogen-deprived patients [35]. Two prospective clinical studies [36,37] explored the anti-tumour potential of ZOL in the neoadjuvant setting. The first study by Winter and colleagues [36] showed a synergistic effect of ZOL treatment followed by chemotherapy possibly due to an increased apoptosis and reduced proliferation and a reduction of the VEGF levels.…”

“…Two prospective clinical studies [36,37] explored the anti-tumour potential of ZOL in the neoadjuvant setting. The first study by Winter and colleagues [36] showed a synergistic effect of ZOL treatment followed by chemotherapy possibly due to an increased apoptosis and reduced proliferation and a reduction of the VEGF levels. The second study [37], enrolling fifty-three breast cancer patients (thirty-three with locally advanced and twenty with a first bone-only relapse) demonstrated that a single 4mg dose of ZOL 14 days prior to any further treatment increased the number of apoptotic CTCs and primary tumour cells, reduced tumour and endothelial cell proliferation.…”