SAN FRANCISCO -- Women whose primary breast tumors express higher levels of RANK (receptor activator of nuclear factor kappa-B) may be at higher risk of relapse and bone metastases, compared with women whose tumors express less of the protein, researchers reported here at the Breast Cancer Symposium. Two other studies suggest that everolimus-exemestane therapy may reduce the risk of bone metastases compared with exemestane alone, and that statin use may be associated with a reduction in risk of bone metastases in breast cancer patients.
RANK Ligand as Predictor of Risk
In a study of 149 women who took part in the ISPY-1 trial (Abstract 2), Jiali Li, MD, PhD, Clinical Instructor at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, and colleagues found that RANK expression correlated with an increased risk of relapse. Specifically, if the patients were divided between those whose primary tumors had high RANK expression (cutoff of 63 percent or greater positive cells) and those whose tumors had low expression, there was a statistically significant difference in relapse-free survival.
The observation was validated in a second, independent cohort of 425 women from an MD Anderson Cancer Center database of women with early breast cancer who had undergone neoadjuvant chemotherapy. In that database, the difference between high- and low-expressors was even more significant, with a cutoff of 61 percent cell positivity.
The investigators also found that, on average, RANK expression was significantly higher in estrogen receptor-negative tumors compared with estrogen receptor-positive lesions, and in basal subtype cancers compared with luminal A/B or HER2-positive tumors. However, RANK expression did not correlate with tumor grade or response to neoadjuvant chemotherapy.
“The most interesting finding in this study is that RANK expression in the primary tumor is associated with bone-dominant metastases,” Li said, during a presentation of the data in the general session. RANK was expressed at a significantly higher median level in the bone-dominant tumors than in the tumors that predominantly metastasize elsewhere, even after adjustment for estrogen-receptor positivity and intrinsic subtype.
“We hypothesize that RANK ligand may serve as a chemokine to attract RANK-expressing cancer cells to the bone,” she said. “Our study suggests that the RANK/OPG/RANKL pathway could be a potential target for preventing bone-dominant metastases in patients with early breast cancer.”
The team is currently testing the hypothesis in a Phase II clinical trial in which women with early breast cancer who have circulating tumor cells are treated for one year with denosumab, an antibody that binds the RANK ligand.
BOLERO Data Suggest Reduction on Bone Metastases
Meanwhile, exploratory analyses from the BOLERO-2 trial suggest that inhibiting mTOR with everolimus might also reduce the risk of bone metastases (Abstract 102). The phase III trial compared exemestane plus everolimus with exemestane plus placebo in women with metastatic or locally advanced estrogen-receptor positive, HER2-negative breast cancer refractory to non-steroidal aromatase inhibitors. The primary results showed a significant improvement in progression-free survival with the combination at a median follow-up of 18 months.
To assess the drug’s impact on bone metabolism, the researchers compared the levels of several bone markers at baseline and at six and 12 weeks. They found a decrease in all three serum markers tested in the combination-treated patients, while those in the control arm showed an increase of the markers over time.
The investigators also saw a significant reduction in disease progression in the bone with the exemestane-everolimus combination compared with the control arm. When the disease-progression analysis was restricted to just those patients with bone metastases at baseline, there was a statistically significant reduction in the risk of progression with the addition of everolimus, compared with exemestane alone.
“Everolimus does appear to reduce progression to bone, which is an important finding as bone metastasis is a considerable cause of morbidity and mortality in our patients with estrogen receptor-positive metastatic breast cancer,” said Matthew Ellis, MD, PhD, the Anheuser-Busch Professor of Medical Oncology from the Siteman Cancer Center and Washington University, St Louis, during a poster discussion session.
“How it does this is a little bit speculative, but it is thought that it may have an effect on RANK ligand production, such that when patients are on everolimus it reduces the adverse effects of exemestane on bone. This doesn’t seem to be associated with any adverse side effects we associate with that, such as osteonecrosis of the jaw,” he continued.
“This could be potentially something of tangential value when everolimus is tested in the adjuvant setting, which I believe it will be in an upcoming SWOG-NSABP study”
Fewer Bone Metastases with Statin Use
Finally, in a retrospective chart review, investigators from the Albert Einstein Medical Center in Philadelphia found that statin use was associated with a reduced likelihood of bone metastases (Abstract 40). The team examined the records of 841 patients with Stage II or III cancer treated between 1999 and 2010. Of those, 223 were identified who had taken statins for three or more months.
Eleven women (5%) taking statins developed bone metastases compared with 77 (12.5%) not taking statins, which was a statistically significant difference. The rate of metastases to other sites was not significantly different between the two groups (10.8% in the statin group vs. 18.6% in the no-statin group).
The investigators note that in-vitro studies have previously linked the mevalonic acid pathway, which statins inhibit, with promotion of a microenvironment that favors bone metastases in breast cancer. Also, prior work suggested that statins reduce neoplastic growth and osteoclast activity in vitro.
Based on these observations, the researchers suggest that statins should be examined further for the chemoprevention of bone metastases in breast cancer patients.