Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients.

Abstract

#2048 Background: The presence of disseminated tumor cells (DTC) in the bone marrow is associated with an increased risk for subsequent bone metastases. Bisphosphonates reduce the occurence of bone metastases in patients (pts) with primary breast cancer (BC) with DTC. The aim of this trial was to evaluate the effect of adjuvant zoledronic acid (ZOL) on DTC in the bone marrow and the Patients and methods: Eligibilty criteria for this prospective, randomized multicenter trial were primary BC pts (pT1-4, N1-2, M0) with positive bone marrow status as determined by a standardized immunocytochemistry staining procedure. Ninety-eight pts were enrolled between April 2002 and January 2006. Randomization and medication had to be started within 28 days of primary surgery. Consenting pts were randomized to the treatment arm (ZOL 4mg i.v. q 4 weekly) or control arm. During the study, all pts received adjuvant treatment in the form of chemotherapy ± hormonal therapy or hormonal therapy alone. Bone marrow aspirations were performed to analyze the presence of DTC at surgery (baseline) and 12 months later. Efficacy and tolerability of intravenous ZOL in pts with primary Result: Bone marrow status was available for 76 patients both at baseline and 12 months after surgery. At baseline a median of 2.0 / range 1-6 (mean 2.1±1.1) DTC were detected in the ZOL group and a median of 2.0 / range 1-35 (mean 2.9±5.5) DTC in the control group. In both groups the number of detected tumor cells decreased during the 12 months follow-up with 0.5±0.8 (median 0.0; 0-2) DTC in the ZOL group and 0.9±0.8 (median 1.0; 0-2) DTC in the control group. By ANCOVA analysis a trend was seen towards a reduction of the number of DTC in the ZOL group compared with the control group (p=0.066). In addition, bone marrow-positive pts treated with ZOL were more likely to become bone marrow negative after 12 months (66.7% versus 35.1%, (p=0.009) compared to the control group. Most frequently reported AEs were musculoskeletal,arthralgia and myalgia in Conclusions: In this first prospective, randomized, multicenter trial we were able to show, that both treatment groups have a reduction in the number of DTC after 12 months as compared to baseline. There is a tendency to more reduction of DTC in the ZOL group. More pts under ZOL achieved a change from positive to negative bone marrow status than controls (p=0.009). Treatment with ZOL was safe and well tolerated. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2048.

Zoledronic acid use in cancer patients

“…52 In a subsequent randomized study among patients with early BC and DTCs in the bone marrow (N ¼ 96), adding ZOL (4 mg per month iv for up to 2 years) to adjuvant therapy resulted in a higher proportion of patients with negative bone marrow assessments compared with patients who received endocrine therapy alone (66.7% vs 35.1%, respectively; P ¼ .009). 54 In a larger, matched-pair study (N ¼ 172) among patients with DTCs in bone marrow, patients who received adjuvant chemotherapy plus ZOL (4 mg per month iv) for 6 months were more likely to be free of DTCs at subsequent assessment compared with patients who received chemotherapy alone (P ¼ .099 for between-group comparison). 53 However, the science of DTC research still is evolving, and it is unclear whether DTC numbers or specific types of DTCs (which may have different sensitivities to therapy) are important for disease recurrence.…”

“…50 In 4 small trials in patients with BC, adjuvant ZOL reduced the numbers of disseminated tumor cells (DTCs) in the bone marrow compared with baseline. [51][52][53][54][55] Patients with early BC and DTCs in the bone marrow (N ¼ 45) who received endocrine therapy plus ZOL (4 mg per month iv for up to 2 years) had significant decreases in bone marrow DTCs at the 1-year follow-up (P ¼ .0006) and the 2-year followup (P ¼ .0026) compared with baseline. 52 In a subsequent randomized study among patients with early BC and DTCs in the bone marrow (N ¼ 96), adding ZOL (4 mg per month iv for up to 2 years) to adjuvant therapy resulted in a higher proportion of patients with negative bone marrow assessments compared with patients who received endocrine therapy alone (66.7% vs 35.1%, respectively; P ¼ .009).…”

Final 5‐year results of Z‐FAST trial

“…2,3,[13][14][15][16][17] Recently, preclinical and clinical data have also demonstrated anticancer effects of bisphosphonates in breast and other cancer types. [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] The prevention and treatment of bone loss with upfront (initiated simultaneously with letrozole) versus delayed (initiated with a decrease in T score to <À2 or occurrence of clinical nontraumatic fracture) zoledronic acid in early breast cancer patients receiving letrozole was evaluated in 3 similarly designed, geographically diverse studies (Z-FAST; ZO-FAST; E-ZO-FAST) and in the similarly-designed N03CC study. 15 Interim (<36 months follow-up) results from the former 3 studies indicate that upfront rather than delayed-start zoledronic acid is significantly more effective in preventing bone loss.…”

Bones, breasts, and bisphosphonates: rationale for the use of zoledronic acid in advanced and early breast cancer

“…Data from translational clinical trials suggest that ZOL may affect the viability of cancer cells via its effects on bone metabolism. [51][52][53][54] Indeed, ZOL may modify the bone microenvironment surrounding cancer cells through indirect effects on the ability of disseminated tumor cells (DTCs) to survive and/or reactivate to initiate tumor recurrence. 36 This concept has been supported by studies of the effects of ZOL on DTCs.…”