Breast cancer patients with residual disease after neo-adjuvant chemotherapy (NACT) are considered to have chemo-resistant cancer and adjuvant treatment with bisphosphonates, such as zoledronic acid or zoledronate(Zometa?; Novartis) is considered to reduce the relapse risk predominantly in estrogen-deprivated patients. However, initial results of a phase III clinical trial presented at the 36th San Antonio Breast Cancer Symposium(SABCS), being held December 10?14, 2013 in San Antonio, Texas, seems to suggest that treatment with zoledronic acid does not improve outcomes for women with chemo-resistant breast cancer.[1][2]

Many patients with breast cancer are treated with chemotherapy prior to surgery. In some patients who receive this form of treatment, which is called neo-adjuvant therapy, no residual invasive cancer can be detected in breast tissue samples and lymph nodes removed during surgery. Patients with residual disease are considered to have breast cancer that is resistant to chemotherapy, and emerging data indicate that they experience poorer long-term outcomes compared with women who respond completely to neo-adjuvant therapy.

…patients with residual disease after neo-adjuvant chemotherapy are considered to have chemo-resistant breast cancer – and they have few post-surgery treatment options…

Few postsurgery treatment options
?Because patients with residual disease after neo-adjuvant chemotherapy are considered to have chemo-resistant breast cancer, they have few post-surgery treatment options,? noted Gunter von Minckwitz, M.D., Ph.D., chairman of the German Breast Group in Neu-Isenburg, Germany. ?We evaluated a new postsurgery treatment for these patients, the bisphosphonate zoledronate, in a phase III clinical trial.

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Disappointing results
?We are disappointed to report that zoledronate had no effect on event-free survival. That is, it had no effect on the number of patients who had disease relapse, developed a new cancer, or died.

Although the results are completely negative, we hope that our experience running the first phase III clinical trial to test a treatment in women who had not had a complete response to neoadjuvant therapy will inform future post-neoadjuvant phase III clinical trials,? added Von Minckwitz, who is also professor of gynecology at the University of Frankfurt.

?We experienced a number of challenges while conducting this study, and are sharing what we have learned with other researchers running, or thinking of running, these extremely complicated clinical trials.?

Study design
The phase III clinical trial conducted by Von Minckwitz and colleagues is referred to as the NATAN study, or NeoAdjuvant Trial Add-oN. From February 2005 to May 2009, 654 patients who had residual invasive disease (ypT1-4 or ypN+) detected in breast tissue samples and/or lymph nodes removed during surgery after having received neoadjuvant chemotherapy (a minimum of 4 cycles of anthracycline-taxane-containing NACT) were enrolled in the study.[1][2]

After surgery, patients were randomly assigned to either zoledronate 4 mg i.v. (plus 1000 mg Ca2+ and 880 I.U. vitamin D daily) for five years or no investigational – observational – postsurgery treatment. Zoledronate acid was given q 4 weeks for the first 6 months, q 3 months the following 2 years, and q 6 months for the last 2.5 years.

Those patients with hormone receptor-positive disease also received treatment withthe aromatase inhibitorletrozole (Femara?;Novartis)for five yearsif postmenopausal, or tamoxifen, if premenopausal.From 2007, patients with HER2-positive disease also received trastuzumab (Herceptin?; Roche/Genentech) for one year.

Follow up
During a median follow-up of 48 months, 154 events were reported, with no difference observed between the two groups in an interim analysis for futility. According to Von Minckwitz, they had expected twice the number of events at this stage of follow-up when planning the study, so the time to reporting results was twice as long as they had anticipated.

Von Minckwitz also explained that a large number of patients with hormone receptor-positive disease enrolled in the study, 82% of participants had this form of breast cancer, and that the effects of different treatments on outcome are often only detectable five or more years later for patients with this disease. As a result, the researchers will keep following participants in the NATAN study, ?But I am not hopeful of seeing zoledronic acid or zoledronateimprove outcomes,? Von Minckwitz said.

This study was funded by Novartis Pharmaceuticals Corporation. Von Minckwitz has received speaker honoraria and research funding from Novartis Pharmaceuticals Corporation.

For more information:
[1] Von Minckwitz G, Rezai M, Eidtmann H, Tesch H, Huober J, Gerber B, Zahn DM, et al. Postneoadjuvant treatment with zoledronate in patients with tumor residuals after anthracyclines-taxane-based chemotherapy for primary breast cancer ? The phase III NATAN study (GBG 36/ABCSG XX) Publication Number: S5-05. Presenter: Gunter von Minckwitz, M.D., Ph.D.
[2] NCT00512993 – Postoperative Use of Zoledronic Acid in Breast Cancer Patients After Neoadjuvant Chemotherapy (NATAN) [Study Record Details]

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