Bone-Modifying Therapy for Stages I, II, and III Breast Cancer

A meta-analysis included data from 18,766 patients from 26 adjuvant trials of bisphosphonates of any type.[95] Overall, reductions associated with bisphosphonate use in recurrence (RR, 0.94; 95% CI, 0.87–1.01; 2-sided P = .08), distant recurrence (RR, 0.92; 95% CI, 0.85–0.99; 2-sided P = .03), and breast cancer mortality (RR, 0.91; 95% CI, 0.83–0.99; 2-sided P = .04) were of only borderline significance, but the reduction in bone recurrence was more definite (RR, 0.83; 95% CI, 0.73–0.94; 2-sided P = .004).

A meta-analysis included data from 18,766 patients from 26 adjuvant trials of bisphosphonates of any type.[95] Overall, reductions associated with bisphosphonate use in recurrence (RR, 0.94; 95% CI, 0.87–1.01; 2-sided P = .08), distant recurrence (RR, 0.92; 95% CI, 0.85–0.99; 2-sided P = .03), and breast cancer mortality (RR, 0.91; 95% CI, 0.83–0.99; 2-sided P = .04) were of only borderline significance, but the reduction in bone recurrence was more definite (RR, 0.83; 95% CI, 0.73–0.94; 2-sided P = .004).

In a prespecified subgroup analysis among premenopausal women, treatment had no apparent effect on any outcome, but among 11,767 postmenopausal women, it produced highly significant reductions in recurrence (RR, 0.86; 95% CI, 0.78–0.94; 2-sided P = .002), distant recurrence (RR, 0.82; 95% CI, 0.74–0.92; 2-sided P = .0003), bone recurrence (RR, 0.72; 95% CI, 0.60–0.86; 2-sided P = .0002), and breast cancer mortality (RR, 0.82; 95% CI, 0.73–0.93; 2-sided P = .002).[95]

The ABCSG-18 trial (NCT00556374) included 3,435 postmenopausal women with receptor-positive breast cancer who were receiving an AI. Patients were randomly assigned to receive denosumab or a placebo every 6 months during AI therapy.[96] The patients were unblinded when results related to bone events were reported, and patients on placebo were allowed to cross over to the active drug.

The ABCSG-18 trial (NCT00556374) included 3,435 postmenopausal women with receptor-positive breast cancer who were receiving an AI. Patients were randomly assigned to receive denosumab or a placebo every 6 months during AI therapy.[96] The patients were unblinded when results related to bone events were reported, and patients on placebo were allowed to cross over to the active drug.

In an intent-to-treat analysis according to the original assignment, DFS, a secondary end point, was improved in patients who received denosumab (5-year DFS rate, 89.2% vs. 87.3%; HR, 0.82; 95% CI, 0.69–0.98; P = .0260).[96][Level of evidence B1]

The ABCSG-18 trial (NCT00556374) included 3,435 postmenopausal women with receptor-positive breast cancer who were receiving an AI. Patients were randomly assigned to receive denosumab or a placebo every 6 months during AI therapy.[96] The patients were unblinded when results related to bone events were reported, and patients on placebo were allowed to cross over to the active drug.

The frequency of adverse events was similar in the two groups.

The D-CARE trial (NCT01077154) randomly assigned 4,509 women with stage II or stage III breast cancer to receive denosumab or placebo.[97]

The D-CARE trial (NCT01077154) randomly assigned 4,509 women with stage II or stage III breast cancer to receive denosumab or placebo.[97]

The primary end point of bone metastasis–free survival was not significantly different between the groups (median, not reached in either group; HR, 0.97; 95% CI, 0.82−1.14; P = .70).[97][Level of evidence B1]

The SUCCESS trial (NCT02181101) included 3,421 patients with node-positive or high-risk (≥pT2, grade 3, hormone receptor–negative, or aged 35 years or younger) node-negative breast cancer who completed adjuvant chemotherapy. Patients were randomly assigned to receive zoledronate 4 mg intravenously (IV) for either 2 years (every 3 months) or 5 years (every 3 months for 2 years and then every 6 months for 3 years). Only those patients who completed 2 years of zoledronate treatment (1,447 on the 2-year arm; 1,729 on the 5-year arm) were included in the final analysis. The main study end points were DFS and OS.[98]

The SUCCESS trial (NCT02181101) included 3,421 patients with node-positive or high-risk (≥pT2, grade 3, hormone receptor–negative, or aged 35 years or younger) node-negative breast cancer who completed adjuvant chemotherapy. Patients were randomly assigned to receive zoledronate 4 mg intravenously (IV) for either 2 years (every 3 months) or 5 years (every 3 months for 2 years and then every 6 months for 3 years). Only those patients who completed 2 years of zoledronate treatment (1,447 on the 2-year arm; 1,729 on the 5-year arm) were included in the final analysis. The main study end points were DFS and OS.[98]

Outcomes were similar between the two arms for DFS (HR, 0.97; 95% CI, 0.76–1.25; P = .83) and OS (HR, 0.93; 95% CI, 0.65–1.34; P = .71).[98][Level of evidence A1]

The SUCCESS trial (NCT02181101) included 3,421 patients with node-positive or high-risk (≥pT2, grade 3, hormone receptor–negative, or aged 35 years or younger) node-negative breast cancer who completed adjuvant chemotherapy. Patients were randomly assigned to receive zoledronate 4 mg intravenously (IV) for either 2 years (every 3 months) or 5 years (every 3 months for 2 years and then every 6 months for 3 years). Only those patients who completed 2 years of zoledronate treatment (1,447 on the 2-year arm; 1,729 on the 5-year arm) were included in the final analysis. The main study end points were DFS and OS.[98]

An accompanying editorial explained why the results of this study do not definitively establish how long bisphosphonates should be administered.[99]