Postneoadjuvant Bisphosphonate Benefits in Breast Cancer Linked to Age, Menopausal Status

Wayne Kuznar
Published: Monday, Dec 16, 2013

Dr.  Gunter von Minckwitz

Photo Courtesy © SABCS/Todd Buchanan 2013

Gunter von Minckwitz, MD, PhD
Postneoadjuvant bisphosphonate therapy in women with residual invasive disease following chemotherapy for primary breast cancer does not improve clinical outcomes, according to an interim analysis of a large phase III clinical trial presented at the 2013 San Antonio Breast Cancer Symposium. However, there was a trend toward beneficial outcomes for women over age 55 that were supported by a separate meta-analysis of postmenopausal patients reported at the conference.

The Neo-Adjuvant Trial Add-On (NATAN) trial, the first randomized postneoadjuvant study investigating zoledronate in this setting, failed to demonstrate a benefit with this bisphosphonate after a median follow-up of 48 months on the endpoints of disease-free survival (DFS) and overall survival (OS), said Gunter von Minckwitz, MD, PhD, at the 2013 San Antonio Breast Cancer Symposium (SABCS). Emerging data indicate that a lack of pathologic complete response (pCR) after chemotherapy is associated with poorer long-term outcomes and is dependent on biological subtype, compared with women with a pCR to neoadjuvant therapy.

When NATAN was designed in 2004, “we were looking for a noncytotoxic agent [to study], and at that time bisphosphonates had already established efficacy in the treatment of bone metastases, and there were also a couple of adjuvant studies with clodronate available showing survival benefit, so it was reasonable to go into this high-risk population with this agent,” said Minckwitz, chairman of the German Breast Group in Neu-Isenburg, Germany, and professor of gynecology at the University of Frankfurt.

Patients with invasive tumor residuals (ypT1-4 or ypN+) after a minimum of four cycles of anthracycline-taxane-containing neoadjuvant chemotherapy were eligible for enrollment in NATAN. The 693 patients were randomized within 3 years after surgery to zoledronate, 4 mg IV, for 5 years or observation. Zoledronate was administered every 4 weeks for the first 6 months, every 3 months the following 2 years, and every 6 months for the last 2.5 years, for a total of 19 injections.

Women with hormone receptor-positive disease, who constituted 82% of the study population, received letrozole for 5 years if they were postmenopausal, or tamoxifen, if premenopausal. An amendment to the protocol in 2007 allowed adjuvant trastuzumab to be given for 1 year in women with HER2-positive disease (19% of the study population).

“The population, despite having no pathologic complete response, is probably not as unfavorable as we thought when we did our sample size calculation,” said Minckwitz.

For this reason, the observed event rate was 154 at 48 months, only half of expected events, which supported a Bayesian futility analysis of a protocol-planned interim analysis. “We would have needed to wait an additional 6 to 8 years to reach the required 316 events,” he said.

In this interim analysis, there was no difference observed between the two groups on DFS, the primary endpoint, with a hazard ratio of 0.96 (P = .7885). Nor was there a difference in OS (P = .4082).

On subgroup analysis, a nonsignificant trend toward longer DFS (HR = 0.83) was observed in women older than 55 years at the time of enrollment. The 17% risk reduction is identical to one found in estrogen-deprived women in a meta-analysis of individual patient data from 36 randomized controlled clinical trials of bisphosphonate therapy of women with early breast cancer. The results from this meta-analysis, from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), were reported by Rob Coleman, MD, Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, United Kingdom.

EBCTCG included data from 17,709 women, and the 17% reduction in the risk of breast cancer mortality found in estrogen-deprived women randomized to a bisphosphonate relative to placebo or open control was highly significant (P = .004).

Minckwitz said that the results of the EBCTCG meta-analysis could be used to support the use of a bisphosphonate as postneoadjuvant therapy in postmenopausal women with primary breast cancer who do not experience a pCR to adjuvant chemotherapy.


Von Minckwitz G, Rezai M, Eidtmann H, et al. Postneoadjuvant treatment with zoledronate in patients with tumor residuals after anthracycline-taxane-based chemotherapy for primary breast cancer-the phase III NATAN study (GBG 36/ABCSG 29). Presented at: 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S5-05.

Coleman R, Gnant M, Paterson A, et al. Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: a meta-analysis of individual patient data from randomised trials. Presented at: 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S4-07.

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