Conference Coverage

Treating bone loss ups survival for breast cancer patients


 

FROM ASCO 2022

A final long-term analysis of a study designed to evaluate the safety of a common osteoporosis drug used to treat bone loss in women who were treated for breast cancer, finds the treatment not only reduces fractures long-term, but it may also improve overall survival and increase bone density.

The final analysis of “Adjuvant Denosumab in Breast Cancer (ABCSG-18)” was presented at the annual meeting of the American Society of Clinical Oncology.

“Adjuvant denosumab should be considered for routine clinical use in postmenopausal patients with HR+ breast cancer on aromatase inhibitors treatment,” said the study’s author Michael Gnant, MD, FACS, director of surgery for the Medical University of Vienna.

Denosumab is currently recommended by ASCO as a treatment option for osteoporosis in patients who were successfully treated for nonmetastatic disease.

ABCSG-18 was a prospective, double-blind, placebo-controlled, phase 3 trial that comprised 3,420 patients (mean age 64.5 years) from 58 treatment centers. It included postmenopausal patients with early HR+ breast cancer who were treated with aromatase inhibitors between 2006 and 2013. Among the patients, 1,711 received denosumab 60 mg and 1,709 received a placebo every 6 months.

The primary endpoint was time to first clinical fracture, and the secondary disease outcome-related endpoints were disease-free survival, bone metastasis–free survival, and overall survival.

The hazard ratio for disease-free survival in the denosumab group was 0.83 (95% confidence interval [CI], 0.71-0.97, P = .02) after a median follow-up of 8 years. Disease-free survival (DFS) was 69.0% in the placebo arm and 74.4% in the denosumab arm, with events occurring in 19.8% of patients overall, including deaths in 8.3%.

Bone metastasis–free survival (BMFS) rates were 81.3% and 85.7% in the placebo and denosumab arms, respectively (HR = 0.81, 95% CI, 0.65-1.00, P = .05). Overall survival was 83.6% and 88.8% in the placebo and denosumab arms, respectively (HR = 0.80; 95% CI, 0.63-1.01, P = .06).

There were no new toxicities, nor was there a single positive case of osteonecrosis of the jaw (ONJ) during the study period, which may be due to the low dosage of denosumab. The bone protection dose of denosumab is much lower than that used for treatment of metastases which can be 12 times higher. In those cases, 4%-6% of patients may develop ONJ. “At these very low doses, even after 30,000 treatment years, we did not observe a single confirmed ONJ case,” he said.

Exploratory observations showed the majority of events to include distant recurrences in bone, liver, and lungs. Analysis revealed a trend toward reduction in contralateral breast cancer in the denosumab arm (24 versus 29 events), with a reduction in second non-breast primary malignancies (101 versus 127 events).

In a much earlier ABCSG-18 study from 2015, the primary endpoint of fracture risk was reduced significantly with denosumab (HR = 0.50, P < .0001), with highly significantly longer time to first clinical fracture, higher percent increase in bone mineral density (P < .0001 for both) and fewer vertebral fractures (P = .009). There is evidence that older generation bisphosphonates have potential beyond bone health, such as reducing metabolism (which benefits bone turnover), and improving breast cancer outcomes. These benefits sparked interest in potential long-term cancer reduction with denosumab, Dr. Gnant said.

“Bone marrow is a putative source of late relapse. Tumor cells can harbor there in a quiescent state for 10-15-20 years, and then for some reason wake up and cause metastases. So, all bone-targeted agents are also evaluated for reductions in cancer which is what we were looking to investigate here in this 15-year data,” he said. Denosumab is more targeted than the bisphosphonates, and directly inhibits the RANK ligand which is an important mediator of osteoclast activation. “This ligand is believed to support metastases in the process of waking up,” Dr. Gnant said.

A limitation of the study is that the outcome endpoints of ABCSG-18 are secondary ones, making the results technically descriptive. The study was sponsored by Amgen.

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