Effect of adjuvant zoledronic acid (ZOL) on disseminated tumor cells (DTC) in the bone marrow (BM) of women with early-stage breast cancer (ESBC): Updated results.

Abstract

1002 Background: DTC are associated with increased risk of distant recurrence and death in patients (pts) with ESBC, especially if present after adjuvant chemotherapy (AT). Bisphosphonates (BP) including clodronate and ZOL have demonstrated anti-tumor activity in several clinical trials. We designed a pilot study to evaluate the effect of ZOL on DTC in pts with ESBC and DTC following AT. We hypothesized that ZOL would reduce DTC which could serve as a surrogate marker of anti-tumor effect. Methods: Pts with stage I-III BC were evaluated for DTC with a unilateral BM aspiration after neoadjuvant or AT. Eligibility was defined as > 4 DTC/mL w/in 12 wks of study entry, defined as > 2.5 standard deviations above that found in 50 normal BMs (Park, Proc ASCO 2002). Pts received 4 mg of ZOL IV monthly for 24 months (mos). Concomitant hormonal therapy was allowed. Serum creatinine (Cr) and toxicity were evaluated monthly, urinary n-telopeptide (nTX) was measured at 0, 2, 4, 6, 12, and 24 mos, peripheral blood circulating tumor cells (pbCTC) were measured every 6 mos. Repeat BM aspirations were performed at 12 and 24 mos. DTCs were detected by immunomagnetic enrichment + flow cytometry (FC): 4 mL of BM aspirate was subjected to anti-EpCAM-conjugated iron particles, followed by FC for EpCAM, CD45, and nucleic acid content for quantitative analysis of DTC/mL. Results: 45 pts were enrolled. Median FU is 49 mos (5-81 mo). Median DTC at baseline were 13.3 DTC/mL (range 4-333). DTC increased with tumor size up to 5 cm (p < 0.001). There was a significant reduction in DTC from baseline to 12 mos (mean reduction 9.3, range: 23.6 to 57.2, p > 0.0001), and from baseline to 24 mos (p < 0.001). Baseline DTC predicted recurrence (p > 0.0002); there was a trend towards greater risk of recurrence in pts with higher baseline pbCTC (p > 0.09). ZOL was well tolerated; 1 pt withdrew due to minor toxicity and there was 1 dose delay for elevated Cr. Conclusions: Adjuvant ZOL results in a reduction in DTC at 12 and 24 mos in pts with high risk ESBC; treatment was well tolerated. Elevated DTC following AT was predictive of recurrence. DTC may be a surrogate marker of the antitumor effect of ZOL. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Foundation Novartis Novartis