Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer.

Long-term bisphosphonate therapy is associated with increased risk ofosteonecrosis of the jaw (ONJ). In a retrospective analysis, a 16% ONJ incidence was reported in patients receiving bisphosphonates with anti-angiogenic therapy(bevacizumab or sunitinib) for bone metastases from breast, colon, or renal cell cancers. To assess ONJ incidence with bevacizumab, we analysed data from 3,560patients receiving bevacizumab-containing therapy for locally recurrent ormetastatic breast cancer (LR/MBC) in two double-blind, randomised trials (AVADOand RIBBON-1) and a large, non-randomised safety study (ATHENA). The overallincidence of ONJ with bevacizumab was 0.3% in the blinded phase of the tworandomised trials and 0.4% in the single-arm study. There was a trend towardsincreased ONJ incidence in patients who received bisphosphonate therapy versusthose with no bisphosphonate exposure (0.9 vs. 0.2%, respectively, in the pooled analysis of the randomised trials; 2.4 vs. 0%, respectively, in ATHENA). Inconclusion, this is the largest analysis of ONJ in patients receiving bevacizumabfor LR/MBC. The 0.3-0.4% incidence is considerably lower than previouslysuggested with anti-angiogenic therapy in a small retrospective analysis. Therisk of ONJ appeared to be increased in patients exposed to bisphosphonates, apattern consistent with observations before the introduction of anti-angiogenictherapy to breast cancer management. The 0.9-2.4% incidence seen inbisphosphonate-exposed patients receiving bevacizumab is within the 1-6% rangereported for bisphosphonates alone. Good oral hygiene, dental examination, andavoidance of invasive dental procedures remain important in patients receivingbisphosphonates, irrespective of bevacizumab administration.