Treatment with zoledronate, a bisphosphonate, did not improve outcomes for women with chemoresistant breast cancer, according to initial results of a phase 3 clinical trial presented at the 2013 San Antonio Breast Cancer Symposium, December 10-14, 2013.

Many patients with breast cancer are treated with chemotherapy prior to surgery. In patients who receive this neoadjuvant therapy, no residual invasive cancer can be detected in their breast tissue samples, and lymph nodes are 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 neoadjuvant therapy.

“Because patients with residual disease after neoadjuvant chemotherapy are considered to have chemoresistant breast cancer, they have few postsurgery treatment options,” said Gunter von Minckwitz, MD, PhD, chairman of the German Breast Group in Neu-Isenburg, Germany.

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“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 3 clinical trial to test a treatment in women who had not had a complete response to neoadjuvant therapy will inform future postneoadjuvant phase 3 clinical trials,” said von Minckwitz. “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.”

The phase 3 clinical trial conducted by von Minckwitz and colleagues is referred to as the NATAN study, or NeoAdjuvant Trial Add-oN. From February 2005 through May 2009, 654 patients who had residual invasive disease detected in breast tissue samples, and/or who had lymph nodes removed during surgery after having received neoadjuvant chemotherapy, were enrolled in the study. After surgery, patients were randomly assigned to receive either zoledronate for 5 years or no investigational postsurgery treatment. Those with hormone receptor (HR)-positive disease also received antihormone treatment for 5 years. Beginning in 2007, patients with human epidermal growth factor receptor 2 (HER2)-positive disease also received trastuzumab for 1 year.

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, during the study planning they had expected twice the number of events at this stage of follow-up, so the time to reporting results was twice as long as had been anticipated.

He also explained that a large number of patients with HR-positive disease had been enrolled in the study—82% of participants—and that the effects of different treatments on outcome are often only detectable 5 or more years later for patients with this form of the disease. As a result, the researchers will keep following these participants in the NATAN study, “but I am not hopeful of seeing zoledronate improve outcomes,” said von Minckwitz.