Zometa (chemical name: zoledronic acid) is a medicine used to strengthen bones in women diagnosed with breast cancer that has spread to the bone. Zometa can reduce bone pain and the risk of broken bones.
The small study reviewed here found that adding Zometa to chemotherapy given before early-stage breast cancer surgery may destroy breast cancer cells that have traveled to the bone marrow in some women. Chemotherapy given before surgery is called neoadjuvant chemotherapy. The results of this study confirm results from other small studies suggesting that Zometa may help treat breast cancer, rather than just improving bone health in women with breast cancer that has spread to the bone. Research in the lab also suggests that Zometa can weaken or destroy breast cancer cells.
In this study, 109 women diagnosed with stage II or stage III breast cancer were treated with the chemotherapy medicines Ellence (chemical name: epirubicin) and Taxotere (chemical name: docetaxel) before surgery. About half the women also randomly got Zometa, while the other half got a placebo.
Before treatment started, all of the women had a bone marrow sample taken to see if breast cancer cells had traveled there:
Three months after chemotherapy treatment, all the women had another bone marrow test:
So it seems that adding Zometa to chemotherapy before surgery lowered the likelihood of finding breast cancer cells in bone marrow 3 months later. Still, it's important to know that this lower likelihood wasn't statistically significant, which means it could have been due to chance and not because Zometa was added to the chemotherapy.
The researchers studied women who didn't have cancer cells in their bone marrow before treatment as a separate group:
So adding Zometa to chemotherapy before surgery seemed to reduce the risk of finding breast cancer cells in bone marrow 3 months later for women who didn't have cancer cells in bone marrow when diagnosed. This reduction in risk was statistically significant, which means it was probably because of the Zometa and not due to chance.
Zometa didn't seem to affect the risk of the breast cancer coming back (recurrence), survival without the breast cancer coming back, and overall survival (whether or not the breast cancer came back) 1 and 2 years after diagnosis.
As expected, the researchers found that women who got Zometa had better bone health 1 year after treatment.
The second small study mentioned here looked to see if Zometa could treat breast cancer effectively, but the results didn't show any benefits.
A treatment that fights breast cancer AND helps keep bones strong during treatment would be a good thing. But more research is needed so doctors can understand if and how Zometa can be used to treat breast cancer. In the meantime, Zometa will still be used to strengthen bones in women diagnosed with breast cancer that has spread to the bones. Studies like the one reviewed here may not offer immediate advances, but offer promise for future treatments.
Patients with invasive breast cancer had fewer disseminated tumor cells in bone marrow when zoledronic acid (Zometa) was added to neoadjuvant chemotherapy, suggesting antitumor activity, investigators in a randomized trial reported.
After three months, nine of 56 patients treated with zoledronic acid had no detectable cells in their marrow compared with three of 53 patients randomized to placebo. However, the difference did not meet the minimal requirement for statistical significance (P=0.054).
"Zoledronic acid appeared to decrease the rate at which disseminated tumor cell-negative breast-cancer patients developed subsequent micrometastatic disease at three months," Rebecca L. Aft, MD, PhD, of Washington University in St. Louis, and coauthors reported online in The Lancet Oncology.
"Further, zoledronic acid was effective in preventing treatment-related loss in bone-mineral density, irrespective of menopausal status or tumor biomarkers, adding to the growing literature on the possible benefit of zoledronic acid in the treatment of women with breast cancer."
Clinical studies have shown that bisphosphonate drugs can prevent bone loss during adjuvant therapy for breast cancer. Among currently available agents, zoledronic acid has been shown to prevent bone loss in preclinical models, in women with postmenopausal osteoporosis, in breast cancer patients with bone metastases, in postmenopausal breast cancer patients treated with aromatase inhibitors, and in premenopausal breast cancer patients who develop ovarian failure or undergo induced ovarian suppression, the authors wrote.
Studies involving preclinical models have provided evidence that bisphosphonates have direct antitumor and antiangiogenic activity (Cancer Treat Rev 2008; 35(suppl 1): 19). Moreover, two recent clinical trials showed that concomitant use of zoledronic acid with endocrine therapy improved disease-free survival in patients with breast cancer (N Engl J Med 2009; 369: 679-691, Cancer Res 2009; 70(suppl): 4082).
Given the background of such prior studies, Aft and colleagues hypothesized that zoledronic acid would improve the activity of neoadjuvant chemotherapy by increasing the clearance of disseminated tumor cells from bone marrow of patients with breast cancer.
To address the question, they enrolled 120 patients with newly diagnosed clinical stage II-III breast cancer.
The patients were randomized to placebo or to 4 mg intravenous zoledronic acid every three weeks for a year, beginning with the first dose of epuribicin-docetaxel (Taxotere) chemotherapy.
Investigators obtained bone marrow from the anterior iliac crest, and bone-mineral density was measured at the lumbar spine, proximal femur, and distal radius, using dual-x-ray absorptiometry.
The primary endpoint was the proportion of patients with detectable disseminated tumor cells in bone marrow at three months.
About half of the patients were premenopausal, and 56% were estrogen-receptor positive. Pretreatment tumor size was similar in the two groups.
Following completion of chemotherapy, three menopausal patients with ER-positive tumors received tamoxifen, 24 received an aromatase inhibitor, and three received no endocrine therapy. Two premenopausal patients with ER-positive tumors received no endocrine therapy, 11 received an aromatase inhibitor, and 24 received tamoxifen.
At diagnosis 26 of 60 patients in the zoledronic acid group and 28 of 58 in the control group had detectable disseminated tumor cells.
After three months, 17 of 56 patients in the zoledronic acid group had detectable tumor cells, compared with 25 of 53 in the control group. An analysis that included all patients in each group yielded similar results (P=0.058).
Of the patients with no detectable disseminated tumor cells at baseline, 27 of 31 in the zoledronic acid arm and 15 of 25 in control arm remained free of detectable cells at three months (P=0.030).
Of 79 patients evaluable at one year, a similar proportion of each group had detectable tumor cells (16 of 40 with zoledronic acid and 13 of 39 with placebo).
"Chemotherapy alone had little effect on the proportion of patients with disseminated tumor cells at three months," the authors wrote. "By contrast, treatment with zoledronic acid resulted in fewer patients with detectable disseminated tumor cells at three months than at diagnosis. Patients who had no detectable disseminated tumor cells in their bone marrow at the time of diagnosis were more likely to remain negative for disseminated tumor cells at three months if they received zoledronic acid."
After 12 months, patients in the control group had significant losses in bone density at the hip and spine (P=0.0054), whereas women in the zoledronic acid group had a significant gain in bone density at the hip (P=0.0275).
Comparison of the two treatment groups at 12 months showed significant differences in bone density at the hip and wrist (P<0.05).
Disease-free, recurrence-free, and overall survival did not differ significantly between treatment groups at 12 or 24 months.
A study reported at the European Breast Cancer Conference showed no evidence of antitumor activity when zoledronic acid was combined with neoadjuvant endocrine therapy.
In that study, Nigel Bundred, MD, of South Manchester University Hospitals Trust in Manchester, England, and colleagues randomized 109 postmenopausal patients with early-stage invasive breast cancer to placebo, letrozole (Femara), or letrozole plus zoledronic acid.
The primary endpoint was change in epithelial proliferation and apotosis after 14 days of treatment, as determined by Ki-67 and activated caspase 3 immunochemistry.
Both active treatment groups significantly reduced Ki-67 levels and the cell-turnover index compared with placebo (P<0.001), but the addition of zoledronic acid did not increase the anti-proliferative effects beyond those seen with letrozole alone.
The rate of apoptosis did not change significantly from baseline in any of the groups.
The study was supported by Novartis Pharmaceuticals and Pfizer.
Aft and coauthors Katherine Weilbaecher, Matthew Ellis, and Kathryn Diemer disclosed relationships with Novartis. Coauthor Michael Naughton disclosed relationships with Novartis, sanofi-aventis, and Pfizer.
Primary source: The Lancet Oncology Source reference: Aft R et al. "Effect of zoledronic acid on disseminated tumor cells in women with locally advanced breast cancer: an open label, randomnized, phase II trial" Lancet Oncol 2010; DOI: 10.1016/S1470-2045(10)70054-1.Additional source: European Breast Cancer ConferenceSource reference: Bundred N et al. "Randomized placebo controlled trial studying short term biological effects of the combination of letrozole and zoledronic acid on invasive breast cancer" EBCC 2010; Abstract 110.
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