Zoledronate No Help After Neoadjuvant Failure, But...

Neil Osterweil

December 16, 2013

SAN ANTONIO — In women with residual breast cancer, a bisphosphonate after neoadjuvant therapy did not improve outcomes, although there was evidence that older women might benefit.

In the NaTan (Neoadjuvant Trial Add-On) study, zoledronate (Zometa, Novartis) did not improve outcomes in patients with primary breast cancer whose tumors did not have a pathologic complete response after they completed neoadjuvant chemotherapy, said Gunter von Minckwitz, MD, PhD, who is chair of the German Breast Group in Neu-Isenburg.

However, there was a trend, albeit nonsignificant, toward a benefit for women older than 55 years, he reported here at the 36th Annual San Antonio Breast Cancer Symposium (SABCS).

This finding was supported in a separate meta-analysis of bisphosphonates in the adjuvant setting, also presented at SABCS, as reported by Medscape Medical News.

In the meta-analysis, bisphosphonates were shown to decrease the absolute breast cancer mortality rate from 18.3% to 15.2% in postmenopausal women (P = .004), a relative risk reduction of 17.0%. In postmenopausal (but not premenopausal) women, there was also a significant reduction in bone recurrence with bisphosphonates.

Dr. von Minckwitz put a great deal of stock in the meta-analysis. "Because no new safety signal for zoledronate was observed in this specific situation, I believe we can use the findings of the meta-analysis in this [postneoadjuvant] setting, and maybe use zoledronate for postmenopausal patients," he said.

Jeffrey B. Smerage, MD, PhD, from the University of Michigan Comprehensive Cancer Center in Ann Arbor, who was not involved in the study, told Medscape Medical News that although the evidence for bisphosphonates in breast cancer is mixed, women of a certain age are the most likely to see benefits.

"There's a suggestion that for patients who have a low estrogen state, zoledronate or another bisphosphonate may be an important component of care," he said.

Dr. Smerage pointed out that a trial limited to women 55 years and older might reveal a stronger effect.

"One of the hints of a benefit is that the menopausal state — the level of estrogen that's in that particular patient's system — may impact the efficacy of that particular intervention. Maybe in this case that was an important factor," he said.

Slightly more than 100 patients in each treatment group were older than 55 at the time of treatment, but Dr. von Minckwitz did not present an analysis of response by age group.

Five Years of Therapy

The investigators evaluated women with residual disease after intensive neoadjuvant chemotherapy and surgery, and randomly assigned 350 patients to observation and 350 to treatment with intravenous zoledronate 4 mg every 4 weeks for the first 6 doses, every 3 months for the next 8 doses, and every 6 months for 5 more doses, for a total of 5 years.

Patients with hormone-receptor-positive disease also received tamoxifen or an aromatase inhibitor for 5 years.

The median ages were 49 years in the observation group and 50 years in the treatment group. Overall, 33.3% of patients in the observation group and 34.4% assigned to zoledronate were older than 55.

The trial began in 2005, but by mid-2013, when the observed event rate for the study was only half of what the trial designers had predicted, investigators determined that it would take another 6 to 8 years to reach the required 316 events. The trial was therefore halted and final results were released.

As noted, no significant difference in either disease-free survival (P = .7885) or overall survival (= .4082) was found.

In a media briefing prior to his presentation, Dr. von Minckwitz reported that nearly 80% of women in each study group had hormone-receptor-positive disease. In these women, it often takes more than 5 years before the effects of different treatments emerge, he noted. Although the investigators plan to follow the participants, they do not expect to see a long-term benefit with zoledronate.

In women older than 55 years, the hazard ratio for those who received zoledronate was 0.832, but this finding was only a trend; it was not statistically significant.

There were fewer serious adverse events in the observation group than in the zoledronate group (21 vs 60), but no treatment-related deaths in either group. It is possible that under-reporting of events occurred in the observation group because the trial was not placebo controlled, Dr. von Minckwitz pointed out.

He noted that there are currently at least 3 other "postneoadjuvant' trials underway: one looking at the PARP inhibitor rucaparib in triple-negative breast cancers (the BRE09-146 study), one looking at ado-trastuzumab emtansine in HER2-positive disease, and one looking at the oral cyclin-dependent kinases (CDK) 4 and 6 inhibitor palbociclib in hormone-receptor-positive HER2-negative disease.

The study was funded by Novartis Pharmaceuticals. Dr. von Minckwitz reports receiving speaker honoraria and research funding from Novartis. Dr. Smerage has disclosed no relevant financial relationships.

36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S5-05. Presented December 13, 2013.

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