Public Release: 

Bisphosphonate treatment fails to improve outcomes for women with chemoresistant breast cancer

American Association for Cancer Research

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

Many patients with breast cancer are treated with chemotherapy prior to surgery. In some patients who receive this form of treatment, which is called neoadjuvant 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 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, 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.

"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."

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 detected in breast tissue samples and/or lymph nodes removed during surgery after having received neoadjuvant chemotherapy were enrolled in the study. After surgery, patients were randomly assigned to either zoledronate for five years or no investigational postsurgery treatment. Those with hormone receptor-positive disease also received antihormone treatment for five years. From 2007, patients with HER2-positive disease also received trastuzumab for one 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, 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.

He also explained that a large number of patients with hormone receptor-positive disease enrolled in the study, 82 percent 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 zoledronate improve outcomes," said von Minckwitz.


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

This research will be presented at the 2013 San Antonio Breast Cancer Symposium Friday, Dec. 13, 7:30 a.m. CT, during a press conference hosted by Peter Ravdin, M.D., Ph.D., clinical professor of oncology, San Antonio, Texas. Press conferences will be held in Room 217D of the Henry B. Gonzalez Convention Center, San Antonio, Texas.

Reporters who cannot attend in person can call into the press conferences using the following information:

  • United States/Canada (toll-free): 866-297-6395
  • International (toll): 847-944-7317

To interview Gunter von Minckwitz, contact Elvira Mosig at or +49-6102-7480-429. For other inquiries, contact Jeremy Moore at or 215-446-7109.

The mission of the 2013 San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR's scientific prestige in basic, translational, and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit

Publication Number: S5-05

Presenter: Gunter von Minckwitz, M.D., Ph.D.

Title: 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)

Authors: Gunter von Minckwitz1,19, Mahdi Rezai2, Holger Eidtmann3, Hans Tesch4, Jens Huober5, Bernd Gerber6, Dirk Michael Zahn7, Serban Costa8, Michael Gnant9, Jens Uwe Blohmer10, Carsten Denkert11, Claus Hanusch12, Christian Jackisch13, Sherko Kümmel14, Peter A Fasching15, Andreas Schneeweiss16, Stefan Paepke17, Michael Untch18, Valentina Nekljudova1, Keyur Mehta1 and Sibylle Loibl1. 1German Breast Group, Neu-Isenburg, Germany; 2Luisenkrankenhaus Düsseldorf, Germany; 3Universitäts Frauenklinik Kiel, Germany; 4Onkologische Gemeinschaftspraxis, Frankfurt, Germany; 5Frauenklinik Ulm, Germany; 6Universitäts-Frauenklinik Rostock, Germany; 7SRH Wald Klinikum Gera, Germany; 8Universitätsklinikum Magdeburg, Germany; 9Medical University of Vienna, Austria; 10Sankt Gertrauden Krankenhaus, Berlin, Germany; 11Charité University, Berlin, Germany; 12Rotkruezklinikum München, Germany; 13Klinikum Offenbach, Germany; 14Kliniken Essen Mitte, Germany; 15University Erlangen, Germany; 16University Heidelberg; 17Klinikum Rechts der Isar der TU München, Germany; 18Helios Kliniken Berlin, Germany and 19Frauenklinik Frankfurt, Germany.

Background: Patients with residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemoresistant breast cancer. Adjuvant treatment with bisphosphonates is considered to reduce the relapse risk predominantly in estrogen-deprivated patients.

Methods: Patients who had invasive tumor residuals (ypT1-4 or ypN+) after a minimum of 4 cycles of anthracycline-taxane-containing NACT were eligible to the NATAN study. Patients were randomized within 3 years after surgery to receive zoledronate 4 mg i.v. (plus 1000 mg Ca2+ and 880 I.U. vitamin D daily) for 5 years vs. observation. Zoledronate 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. Patients with hormone receptor (HR)-positive disease received letrozole for 5 years if postmenopausal, or tamoxifen, if premenopausal. Adjuvant trastuzumab for HER2-positive disease was allowed since an amendment in 2007. Stratification factors were HR, time since surgery, age, and center. Primary objective was event-free survival (EFS). 654 patients and 316 events were required to observe an increase of 5yr EFS from 58% to 67.2% (hazard ratio 0.73). Secondary objectives were to determine overall survival, EFS with respect to the interval between surgery and randomization, bone-metastasis-free-survival, toxicity of and compliance to zoledronate, the predictive value of breast tumor response to NACT on the effect of postoperative treatment and the prognostic impact of chemotherapy induced amenorrhea in premenopausal patients. An interim analysis for high efficacy at 158 observed events was planned in the protocol; in agreement with study IDMC a Bayesian analysis for futility with futility boundary of 15% will be performed at the same time.

Results: Between 2/2005 and 5/2009 693 patients were enrolled. Time between surgery and randomization was <4 months in 48.4%, 4-12 months in 34.5%, and 13-36 months in 17.1% of patients. The median age was 50.9 yrs (range 33.7-88.2), 72.3% of patients were postmenopausal. 82 % had HR-positive and 19% HER2-positive disease. During a median follow up of 48 months 154 events were observed so far.

Conclusion: This is the first post-neoadjuvant phase III study. Analysis of the primary endpoint will be presented in case the IDMC will release of the results of the futility analysis.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.