Fast track — ArticlesEffect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial
Introduction
Early tumour-cell dissemination from the primary site is the first step in the development of distant metastases. Disseminated tumour cells (DTCs) have been found in the bone marrow of patients with breast cancer and are an independent prognostic indicator of increased risk of distant disease development and death.1 Moreover, patients with detectable DTCs after cytotoxic chemotherapy have a high risk of recurrence.2
The bone microenvironment seems to be a sanctuary site for DTCs, allowing the cells to adapt and disseminate to other organs.3 Preclinical models suggest that tumour growth in bone is enhanced when osteoclast activity is increased, possibly due to the release of bone-derived growth factors.4 Breast-cancer therapies can increase osteoclastic-mediated bone resorption through development of osteoporosis.5
Several clinical trials have examined the use of osteoclast-inhibiting bisphosphonates for the prevention of bone loss during adjuvant therapy for breast cancer. Bisphosphonates are analogues of pyrophosphates that bind to hydroxyapatite crystals in bone and inhibit bone resorption. Zoledronic acid, a third-generation bisphosphonate, inhibits osteoclastic resorptive activity partly through inhibition of farnesyl-diphosphate synthase and protein prenylation.6 Zoledronic acid prevents bone loss in preclinical models,7 in women with postmenopausal osteoporosis,8 in patients with breast cancer with bone metastases,9 in postmenopausal patients with breast cancer receiving adjuvant aromatase inhibitors,10 and in premenopausal patients with breast cancer who develop ovarian failure or in whom ovarian suppression has been induced.11 In preclinical models, bisphosphonates directly inhibit tumour growth and angiogenesis.12 Two recent clinical trials, ABCSG13 and Z/Zo-FAST,14 have shown a disease-free survival benefit with zoledronic acid in women receiving adjuvant endocrine therapy.
We postulated that zoledronic acid could improve the effect of neoadjuvant chemotherapy in women with breast cancer, by increasing the clearance of DTCs from bone marrow. We did a randomised phase 2 study to investigate the effects of zoledronic acid on DTCs, bone-turnover markers, and bone-mineral density, in women undergoing neoadjuvant chemotherapy for stage II–III breast cancer.
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Patients
120 women were enrolled between March 17, 2003, and May 19, 2006, at Siteman Cancer Center, Washington University, St Louis, MO, USA. Patients with clinical stage II–III (≥T2 and/or ≥N1) newly diagnosed breast cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and normal cardiac, renal, and liver function were eligible. Exclusion criteria included evidence of distant metastasis by CT scan of the chest, abdomen, pelvis, or bone scan. Other exclusion criteria were
Results
Between March 17, 2003, and May 19, 2006, 120 patients with locally advanced breast cancer were randomly assigned to receive zoledronic acid or no zoledronic acid, concurrent with neoadjuvant chemotherapy. Women in the two groups had similar baseline characteristics (table 1). About half the patients in each group were premenopausal and 56% of all patients were oestrogen-receptor positive. Mean pretreatment tumour size was similar in both groups. After chemotherapy, three of the postmenopausal
Discussion
We postulated that the decrease of osteoclast activity with bisphosphonates in patients with breast cancer undergoing chemotherapy would alter the bone microenvironment and result in a decrease in the development of micrometastatic disease. We noted that around 46% of patients with clinical stage II–III breast cancer had DTCs at the time of diagnosis. Chemotherapy alone had little effect on the proportion of patients with DTCs at 3 months. By contrast, treatment with zoledronic acid resulted in
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