SAN ANTONIO—Bisphosphonate zoledronate does not improve event-free survival rates among women with chemotherapy-resistant breast cancer, according to results of the phase 3 NeoAdjuvant Trial Add-oN (NATAN) trial, which were presented at the 2013 San Antonio Breast Cancer Symposium. The trial was the first randomized study of postneoadjuvant treatment with zoledronate, the authors reported.

“We are disappointed to report that zoledronate had no effect on event-free survival,” said Gunter von Minckwitz, MD, PhD, chairman of the German Breast Group in Neu-Isenburg, Germany. “That is, it had no effect on the number of patients who had disease relapse, developed a new cancer, or died.”

Patients with residual breast cancer following neoadjuvant chemotherapy are believed to have poor prognosis compared to women whose cancer responds completely to chemotherapy.

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Between 2005 and 2009, the NATAN trial enrolled 693 patients with tumor residuals in tissue in breast or lymph node tissue following anthracycline-taxane–containing neoadjuvant chemotherapy. Participants were randomized to receive no investigational treatment, or postsurgical intravenous (IV) zoledronate (4 mg every 4 weeks for the first 6 months, and then every 3 months for the following 2 years, and every 6 months for the next 2.5 years) plus 1,000 mg calcium and 880 IU vitamin D daily, for a total of 5 years. Women with hormone receptor–positive tumors were also administered anti-hormone therapy for 5 years, and starting in 2007, patients with HER2-positive tumors were administered trastuzumab for 1 year.

At a median follow-up of 48 months, an interim analysis found no difference in outcomes among women in the zoledronate and control arms of the study (P = 0.408).

“The observed event rate was only 50% of expected … so we used preplanned interim analysis,” noted Dr. von Minckwitz.

Many of the participants (82%) had hormone receptor (HR)–positive breast cancer, which might mean that benefits could still emerge more than 5 years after initiation of treatment, Dr. von Minckwitz noted. But “I am not hopeful of seeing zoledronate improve outcomes,” he emphasized.

“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 post-neoadjuvant phase 3 clinical trials,” Dr. von Minckwitz said.

Other options currently under investigation for this patient population include rucaparib, trastuzumab emtansine in HER2-positive disease, and palbociclib in HR-positive/HER2-negative disease, Dr. von Minckwitz said.

The study was funded by Novartis.


  1. von Minckwitz G et al. S5-05. Presented at: San Antonio Breast Cancer Symposium 2013. Dec. 10-14, 2013; San Antonio.