Zoledronic acid as adjuvant therapy for women with early stage breast cancer and disseminated tumor cells in bone marrow

Abstract

559 Background: DTC in BM is associated with an increased risk of distant recurrence (DR) and death in patients (pts) with ESBC, particularly when these cells are detected after adjuvant therapy. Bisphosphonates can act as antitumor agents by various mechanisms including induction of tumor cell apoptosis. Clodronate in pts with DTC at BC diagnosis reduced the incidence of metastases and improved survival. ZA is significantly more potent than clodronate in inhibiting bone resorption. We designed a pilot study to evaluate ZA in pts with ESBC with DTC. Decrease in DTC could serve as a surrogate marker of antitumor effect. Methods: DTCs are detected by immunomagnetic enrichment + flow cytometry (FC): BM is enriched with anti-EpCAM-conjugated iron particles, DTC are detected with EpCAM, CD45, and nucleic acid content. Pts with stage I-III BC are evaluated for DTC with a unilateral BM aspiration following neoadjuvant or adjuvant CTX; eligibility was defined as >4 DTC/ml, which is 2.5 SD > than 50 normal BM (Park, Proc ASCO 2002). Pts receive 4 mg of ZA IV monthly x 2 years (yrs). Concomitant hormone therapy is allowed. Serum creatinine and toxicity are evaluated monthly, urinary n-telopeptide is measured at 0, 2, 4, 6, 12, 24 mo, and peripheral blood (PB) DTC q 6 mo for 2 yrs. Repeat BM is performed at 1 & 2 yrs. Results: 45 pts are enrolled. We report an interim analysis of baseline, one & 2 yr BM results. The mean DTC at baseline is 25.6 DTC/ml (range 4.9–332 DTC/ml), mean FU is 19.8 mo (range: 2 to 38 mo). Baseline DTC >30 DTC/ml predicts DR (p=0.007). 35 pts have received >12 mo ZA. 32 had BM at 1 yr, 25/32 pts (66%) had a decrease in DTC (p=0.0018). 17 pts had BM at 2 yrs, 12/17 pts (71%) had a decrease in DTC (p=0.01). 26/45 pts had positive DTC in PB at baseline (mean 0.4 DTC/ml, range 0–8.6 DTC/ml). Five BC recurrences occurred in the first yr (ave TTR 5.2 mo); all pts were node+, and negative for ER, PR, HER2/neu. ZA was well tolerated with 1 pt stopping ZA with side effects. Conclusions: Serial detection of DTC in BM is feasible in pts with early stage BC. High baseline BM DTCs predicted early DR, and DTCs decreased over the treatment period. This preliminary data suggests that ZA decreases the number of DTC in ESBC. The study is ongoing, updated data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis, Novartis Oncology