Osteoclast Inhibitors May Prevent Recurrences in Early-Stage Disease

Julie R. Gralow, MD

Professor, Medical Oncology

University of Washington

School of Medicine

Member of the Clinical Division

Fred Hutchinson Cancer Research Center Director, Breast Medical Oncology

Seattle Cancer Care Alliance

Seattle, WA

While osteoclast-targeting agents are proven treatments for bone metastases and the preservation of bone-mineral density in patients with breast cancer, their use in preventing recurrences in early-stage disease is not as well established.

In a presentation during the 11th International Congress on the Future of Breast Cancer in July, Julie R. Gralow, MD, gave an overview of studies looking at the potential of osteoclast inhibitors in the prevention of breast cancer recurrences in the adjuvant setting, and discussed which patients might reap the greatest benefits.

“The area of preventing recurrences is where the newest data are—and the most confusion and controversy,” Gralow said.

She also addressed the possibility that osteoclast inhibitors may help prevent breast cancer in healthy women, as well as the idea that the drugs might have a direct antitumor effect, which could make them useful as a supplement, or a less-toxic alternative, to chemotherapy for breast cancer patients.

In explaining how osteoclast inhibitors work, Gralow outlined the “vicious cycle” in the interaction between metastatic breast cancer and the bone microenvironment (Figure). The tumor cells secrete a peptide—parathyroid hormone-related protein (PTHrP)—and other osteoclast-stimulating factors, such as interleukins and prostaglandins, and, downstream, RANK ligand (RANK-L).

Figure. Breast Cancer and the Bone Microenvironment

Osteoclast inhibition, “X” at right, is aimed at breaking the “vicious cycle.”

Gralow J. Osteoclast inhibition: when and for whom in early stage breast cancer? Presented at: 11th International Congress on the Future of Breast Cancer; July 26-28, 2012; Coronado, CA.

Tumor cell activity releases growth factors, such as IGF, PDGF, and TGF-β, which promote tumor growth in the bone. Osteoclast inhibitors may interfere with this process, possibly preventing bone from becoming the first site of recurrence—which could lead, in turn, to fewer recurrences in the liver and lungs, Gralow said.

The drugs may work particularly well in patients whose ovarian function is suppressed, Gralow said. Other predictors of success with osteoclast inhibitors might be tied to menopausal status, excessive bone resorption, a lack of treatment with chemotherapy, a presence or history of estrogen receptor (ER)-positive tumors, tumors with biomarkers such as PTHrP or RANK-L, and/or involvement of bone marrow at diagnosis—yet those remain “unanswered questions,” the doctor said.

Gralow is involved in some of the latest research into adjuvant therapy with osteoclast-targeted agents in breast cancer; she is serving as principal investigator for the phase III SWOG 0307 study comparing zoledronic acid versus clodronate versus ibandronate in primary breast cancer. Three other phase III trials are evaluating zoledronic acid adjuvant therapy with various regimens, and two additional phase III trials are studying denosumab, which targets RANK-L.

Body of Data Available

Investigators have also gleaned information from nearly 10 completed clinical trials of adjuvant bisphosphonate therapy aimed at reducing cancer recurrence, Gralow said.

That body of work includes four randomized trials in early-stage breast cancer of oral clodronate, which is not approved in the United States but is marketed elsewhere for the treatment of bone metastases, as well as for the treatment and prevention of osteoporosis. Two of the placebo-controlled studies showed that clodronate resulted in a survival benefit for patients, while the other two did not.

Another bisphosphonate, ibandronate, is approved in the US for the treatment of osteoporosis and in Europe for the treatment of both osteoporosis and bone metastases. The GAIN trial, with 3023 patients, compared adjuvant oral ibandronate plus aggressive chemotherapy with aggressive chemotherapy alone. Disappointingly, Gralow said, ibandronate had no effect on either disease-free survival or overall survival.

Gralow said it is possible that chemotherapy may prevent the same recurrences that bisphosphonates do, negating the benefit of the osteoclast inhibitors.

Three primary trials of adjuvant zoledronic acid versus controls (hormonal therapy) saw variable results when it came to meeting their endpoints of reducing the recurrence of breast cancer—in most cases, ER-positive disease—and improving overall survival, Gralow said. A trial titled ABCSG-12 demonstrated a 28% reduction in breast cancer recurrences (P = .014) and a 37% reduction in deaths (P = .048), Gralow reported, and the combined ZO-FAST/Z-FAST trial found a reduction in recurrences with upfront versus delayed zoledronic acid.

Conversely, AZURE demonstrated no differences in disease-free or overall survival, the doctor said. However, she said, in all three studies, there appeared to be an association between a favorable response to adjuvant zoledronic acid and ovarian suppression, whether postmenopausal or induced by goserelin.

Looking at a subgroup of patients in the AZURE trial, it appears that patients who received chemotherapy plus zoledronic acid, and then underwent surgery, experienced an antitumor effect; their residual invasive tumors were 28 mm after treatment, as compared with 42 mm for the chemotherapy-alone group (P = .002), and the complete pathologic response rate in the breast and axilla was 10.9% for the experimental group versus 5.8% for the control arm (P = .033), Gralow said.

Evidence of an antitumor effect also came out in the ABCSG-12 trial, she said, since the reduction in recurrences demonstrated with zoledronic acid in that study affected not only distant but also local/ regional tumor sites.

Finally, the doctor said, data supporting the idea that bisphosphonates can help prevent breast cancer in healthy women came out of a Women’s Health Initiative (WHI) trial, a set of studies of postmenopausal women whose results were reported in 2010. In the trial, 2816 out of more than 150,000 participants were taking bisphosphonates (mainly alendronate, for osteoporosis). After a mean of 7.8 years’ follow-up, the incidence of invasive breast cancer was 32% lower among those who used oral bisphosphonates (P <.01).

As investigators consider whether to continue studying osteoclast inhibitors for the prevention of breast cancer, Gralow said, the data from the WHI should add “fuel to the fire.”