Reports

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PRIORITY PRESS - 33rd Annual San Antonio Breast Cancer Symposium

San Antonio, Texas / December 9-12, 2010

Bisphosphonates (BPs) have a well-established therapeutic role in prevention of skeletal events in cancer patients by impairing malignant osteolysis to interrupt bone destruction and cancer growth. Preclinical studies have suggested that BPs, especially nitrogen-containing agents such as zoledronic acid, have inherent anticancer activity (Oncologist 2004;9(suppl 4):3-13, Cancer Treat Rev 2008;34:453-75). Evidence of anticancer activity includes studies showing it to improve survival in experimental models of cancer following treatment (J Bone Miner Res 2003;18:482-92, Int J Cancer 2010;126:239-46).

In several large studies involving patients with different types of cancer, zoledronic acid has produced evidence of anticancer activity. In one study of adjuvant therapy in breast cancer, patients who received zoledronic acid in addition to an aromatase inhibitor (AI) had a statistically significant 41% reduction in the risk of recurrence or death (P=0.017) (SABCS 2009, Abstract 4082).

AZURE: Rationale Behind Adjuvant Treatment

A strong rationale existed for evaluating zoledronic acid as a component of adjuvant therapy in patients with breast cancer, stated Dr. Robert E. Coleman, University of Sheffield, UK. That rationale led to the multicentre AZURE (Adjuvant Treatment with Zoledronic Acid in Stage II/III Breast Cancer) trial.

Investigators at 174 centres enrolled 3360 women with stage II/III breast cancer and randomized patients to standard adjuvant therapy (endocrine, chemotherapy or both) or to standard therapy plus zoledronic acid. Patients received 4-mg doses once q3 to 4 weeks for 6 months, then once q3 months for approximately 2 years and finally once q6 months for approximately 2.5 years. Altogether, patients randomized to adjuvant BP therapy received 19 doses over 5 years. The primary end point was disease-free survival (DFS) and key secondary end points included invasive DFS, overall survival (OS) and bone metastasis-free survival.

Influence of Menopausal Status

The results stood in contrast to the Austrian Breast Cancer Study Group (ABCSG) XII trial that showed a significant reduction in the DFS hazard events for patients who received zoledronic acid. ABCSG XII limited enrolment to premenopausal patients with stage I-II hormone receptor-positive breast cancer.

Statistical comparison of the 1800 patients in ABCSG XII and the 1200 premenopausal women in the AZURE trial revealed significant heterogeneity (P=0.02) and the beginnings of an explanation for the apparently contradictory results. “The AZURE results are strikingly different to those observed in the ABCSG XII trial,” explained Dr. Coleman. “A highly significant heterogeneity of effect by menopausal status was seen, with improved DFS and OS in those patients more than 5 years’ postmenopause.”

A prespecified, preplanned secondary end point analysis of the AZURE data by menopausal status showed that premenopausal patients and those who were <5 years removed from menopause had an increased hazard for DFS events when treated with zoledronic acid. In contrast, postmenopausal patients derived a benefit from the BP that was comparable to the risk reduction observed in ABCSG XII. Moreover, there was a statistically significant 29% reduction in the risk of death (P=0.017), whereas premenopausal patients in both groups had virtually identical OS (Figure 1).

Figure 1.

“Adjuvant BP efficacy may be dependent on a low estrogen concentration within the bone microenvironment,” Dr. Coleman told delegates.

Overall adverse events were similar in the treatment groups and mostly attributable to other therapy. Dr. Coleman pointed out that the 17 (1.6%) confirmed cases of osteonecrosis of the jaw were consistent with the known experience with the drug.

Benefits Maintained Long-Term: ABCSG XII

An updated analysis of the ABCSG XII study confirmed the original findings and showed that the favourable effect of zoledronic acid on the risk of breast cancer recurrence is maintained beyond 5 years of follow-up. After a median follow-up of 48 months, patients assigned to the BP arm had a 36% reduction in the hazard for DFS events (HR 0.64, P=0.02). “In particular, we observed a strong trend toward a reduced risk of death in patients treated with zoledronic acid [HR 0.60, P=0.11],” reported Dr. Michael Gnant, Medical College of Vienna, Austria.

Continued follow-up to a median of 62 months showed minimal change in the initial results. Patients allocated to the BP still had a highly significant 32% reduction in the hazard for DFS events (HR 0.68, P=0.006). Moreover, the analysis revealed an advantage for each of the components of DFS: overall recurrence (65 vs. 92), distant recurrence (44 vs. 56), bone metastases (21 vs. 32), locoregional recurrence (15 vs. 30), contralateral breast cancer (6 vs. 8) and secondary malignancy (11 vs. 16). It did not increase the incidence of adverse effects compared with endocrine therapy alone.

“Combining zoledronic acid with adjuvant endocrine therapy should be considered for premenopausal women with early-stage endocrine-responsive breast cancer,” stated Dr. Gnant.

Data favouring an antitumour effect of this agent has persuaded several countries in Latin America to approve the BP for use in the setting of adjuvant therapy for breast cancer, he added. Moreover, the European Medicines Agency and the FDA are considering the indication. “Recent guidelines from the European Society for Medical Oncology now recommend that zoledronic acid may be appropriate to prevent bone loss and reduce the risk of breast cancer recurrence in premenopausal women receiving endocrine therapy and in postmenopausal women receiving AI therapy,” Dr. Gnant concluded.

Bone Protection: ZO-FAST

Five-year follow-up from another large clinical trial provided additional confirmation of zoledronic acid efficacy for preventing bone loss among breast cancer patients treated with AIs. In ZO-FAST (Zometa-Femara Adjuvant Synergy Trial), investigators in 28 countries randomized 1065 patients with stage I-IIIa breast cancer to adjuvant endocrine therapy with letrozole plus concomitant or delayed zoledronic acid.

Patients in the delayed-therapy group received zoledronic acid only in the event of a decline in bone mineral density (BMD) to a T-score =2, clinical fracture or asymptomatic fracture at 36 months, explained Dr. Richard de Boer, Royal Melbourne Hospital, Victoria, Australia. The primary end point was change in lumbar-spine BMD after 12 months. Secondary end points included fracture, disease recurrence, death and change in bone-turnover markers.

In the primary analysis at 12 months, patients assigned to immediate BP therapy had a 2% increase in lumbar-spine BMD compared with a 3.8% decline in the delayed-therapy group (P<0.0001). The between-group difference continued to increase over time, and at the 60-month follow-up, patients randomized to upfront zoledronic acid maintained an overall BMD advantage of 9.7% vs. the delayed-therapy group (P<0.0001).

The 5-year analysis also showed a 3.6% absolute difference in the composite of disease recurrence or death (91.9% vs. 88.3%) in favour of immediate BP therapy, translating into a 34% reduction in the relative risk (HR 0.66, P=0.0375). The 5-year OS was 95.2% with immediate therapy and 93.9% with delayed therapy, a nonsignificant difference. Investigators concluded that the 60-month follow-up of the ZO-FAST study confirms and extends BMD improvements with immediate vs. delayed zoledronic acid reported at earlier timepoints. This difference in BMD between treatment arms was maintained despite the initiation of the BP in a substantial proportion of the delayed-therapy group.