Role of bisphosphonates in breast cancer treatment not yet clearly defined

The role of bisphosphonates in breast cancer is still evolving, and recent data add more evidence to both sides of the argument about whether the drugs actually can help prevent recurrence in women with the disease.

“There is a mix of studies with no clear answer on the role of bisphosphonates in breast cancer recurrence,” Julie R. Gralow, MD, professor of medical oncology and director of breast medical oncology at the University of Washington, told HemOnc Today. “Many of us think that there is evidence that there is potentially a benefit, but we just have to work harder to figure out which tumors and which patients would benefit.”

About 20 years ago, bisphosphonates started to be integrated into breast cancer treatment to help treat the hypercalcemia associated with the disease. Physicians subsequently realized that when patients took the drugs, they did not seem to get as many fractures. A few years later, trials of the bisphosphonate pamidronate (Aredia, Novartis) demonstrated that the drug actually helped prevent bone complications related to metastatic breast cancer.

Then a more powerful bisphosphonate, zoledronic acid (Zometa, Novartis), made its way to the market. Zoledronic acid also prevented the bone complications related to breast cancer treatment. At roughly the same time, physicians who treated osteoporosis were discovering that oral bisphosphonates also seemed to prevent bone loss.

“About 10 years ago, a lot of us became interested in trying to figure out whether bisphosphonates could prevent the bone loss associated with aromatase inhibitors,” Adam M. Brufsky, MD, PhD, professor of medicine at the University of Pittsburgh School of Medicine and a HemOnc Today Editorial Board member, said in an interview. “As a sideline to these trials, a lot of us knew from some of the data that when pamidronate was given to women with breast cancer, it actually reduced the risk of recurrence.”

Additional research with oral bisphosphonates showed that the drugs reduced the incidence of bone metastases in women with breast cancer who received them as adjuvant treatment, Brufsky said. However, the data were conflicting. As a result, more trials — with DFS as an endpoint — have been designed.

Conflicting data

Michael Gnant, MD, professor of surgery at the Medical University of Vienna, presented updated data from the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) during the 2011 San Antonio Breast Cancer Symposium. The study included a limited population of premenopausal women with ER-positive breast cancer who had not received chemotherapy.

Gnant and colleagues randomly assigned 1,803 women to goserelin (Zoladex, AstraZeneca) with tamoxifen or anastrozole, with or without zoledronic acid. At a median follow-up of 76 months, patients who received zoledronic acid had a 27% reduction in the risk for DFS events (P=.022). The patients also had a 41% reduction in the risk for death (P=.027).

Long-term follow-up data from the Zometa-Femara Adjuvant Synergy Trial (ZO-FAST) also were presented at the 2011 San Antonio Breast Cancer Symposium. Postmenopausal women who received letrozole and who had a bone mineral density T-score of –2 or higher were randomly assigned to immediate zoledronic acid (4 mg every 6 months) or delayed zoledronic acid given when the post-baseline T-score was less than –2. The 1,065 patients were followed for disease recurrence and OS for 5 years. After 60 months of follow-up, immediate zoledronic acid reduced the risk for a DFS event by 34% (P=.034).

However, there have been negative studies as well. In the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, presented at the 2010 San Antonio Breast Cancer Symposium, there was no evidence that bisphosphonates influenced breast cancer recurrence. According to Gralow, the AZURE trial consisted of a mix of women: ER-positive, ER-negative, premenopausal and postmenopausal. Most patients also received chemotherapy.

Gralow also referenced the German Adjuvant Intergroup Node Positive (GAIN) trial, which tested the bisphosphonate ibandronate (Boniva, Genentech). This study included a mix of patients: ER-positive and ER-negative patients and premenopausal and postmenopausal patients. All patients received chemotherapy. This trial did not show a benefit of adding adjuvant ibandronate.

Similarly, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34 trial — which tested the bisphosphonate clodronate — did not show a benefit. This trial also included a mix of patients: stage I, II and II patients, ER-positive and ER-negative patients, and premenopausal and postmenopausal patients.

“In the AZURE trial and the NSAPB-34 trials, the researchers took a look at subsets based on menopausal status and age,” Gralow said. “Retrospectively, they saw that there was a benefit for the postmenopausal population. This hypothesized that maybe a benefit exists in a truly non-estrogen state. However, it’s not clear that this is the answer.”

The data are clear that adjuvant bisphosphonates prevent recurrence, especially in the subset of patients who are postmenopausal, Brufsky said.

“We now have many trials, including the ABSCG-12 trial and the ZO-FAST trial, and the subset analyses of the AZURE and the NSAPB-34 trials that clearly show that bisphosphonates have a role to play,” Brufsky said. “The bottom line is that they have a role to play in the women with overactive bone, which are the postmenopausal patients.”

Ongoing studies

Gralow said physicians are waiting for data from the Southwest Oncology Group (SWOG)-S0307 trial, which is comparing three bisphosphonates — zoledronic acid, clodronate and ibandronate — to see if there are differences. Gralow, who is the primary investigator of the trial, said there are hints that zoledronic acid is more beneficial than the others.

There also are two trials examining whether a newly approved bisphosphonate, denosumab (Prolia, Xgeva; Amgen), reduces breast cancer recurrence.

For now, Gralow said she is not assigning bisphosphonates to patients who are ER-negative or who have received chemotherapy unless they are enrolled in a study; however, she considers them for those who are ER-positive and not receiving chemotherapy.

“It’s tough because we try to be evidence-based, but we don’t always have a trial that is capable of giving us the evidence,” Gralow said. “What I do matches the evidence from the ABCSG-12 trial and the ZO-FAST trials. It’s important to do what’s best for my patients while considering the evidence.” – by Emily Shafer

For more information:

De Boer R. Abstract #S1-3 and Gnant M. Abstract #S1-2. Presented at: 2011 CTRC-AACR San Antonio Breast Cancer Symposium; Dec. 6-11, 2011; San Antonio.

Disclosure: Dr. Brufsky receives consulting fees and speaking honoraria from Novartis and Amgen. Dr. Gralow receives research funding from Amgen, Novartis and Roche.