Clinical Spotlights from SABCS: December 11, 2009

	Bone-targeted Therapies and Breast Cancer December 13, 2009–During the 2009 San Antonio Breast Cancer Symposium in San Antonio, data were presented from several interesting studies examining the topic of bone health and breast cancer. Bisphosphonate use and breast cancer Emerging evidence suggests that treatment with bisphosphonates may prevent breast cancer recurrence. Rowan Chlebowski, MD, PhD (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torance, United States) presented results from the Women's Health Initiative (WHI) regarding the association between oral bisphosphonate use and incidence of breast cancer in 154,768 postmenopausal women. Data from this analysis of 2,216 women showed a lower invasive breast cancer incidence (~32%, P<0.01) in women who took oral bisphosphonates (90% alendronate, 10% etidronate). This result suggests that oral bisphosphonates may have direct inhibitory effects on development of breast cancer. In terms of clinical implications, these findings in healthy postmenopausal women are hypothesis generating but suggest that the additional anticancer benefits of bisphosphonates seen in this exploratory analysis need to be considered in relation to the usage of bisphosphonates to prevent bone mineral density loss. Cancer Res. 2009;69(Suppl): Abstract 21. Gad Rennert, MD, PhD (Carmel Medical Center, Haifa, Israel) presented data from the Breast Cancer in Northern Israel Study (BCINIS), a population-based case-control study in northern Israel of breast cancer cases and age/clinic/ethnic-group matched controls, evaluating the association between the use of bisphosphonates and the risk of developing breast cancer. A total of 4,575 healthy postmenopausal women self-reported use of bisphosphonates over a 5-year period, and it was found that the use of bisphosphonates for more than 1 year was associated with a significant 34% reduction in the incidence of breast cancer. In addition, breast cancers detected in bisphosphonate users exhibited better prognostic factors. Cancer Res. 2009;69(Suppl): Abstract 27. Denosumab versus zoledronic acid in metastatic bone disease Alison Stopeck, MD (Arizona Cancer Center, Tucson, United States) presented data from a pivotal non-inferiority head-to-head trial of denosumab versus zoledronic acid in patients with breast cancer metastatic to bone. This international phase III, randomized, double-blind double-dummy study was conducted to compare the difference in terms of time to first on-study skeletal related events (SRE), which was predefined as pathologic fracture, radiation or surgery to bone, or spinal cord compression. Denosumab was numerically superior to zoledronic acid and led to a 23% reduction for the primary endpoint (P = .01). Time to cancer progression was similar in both treatment arms, and denosumab did not show any advantage over zoledronic acid for disease progression (P = .5) and overall survival (P = .9). The incidence of adverse events was consistent with previous studies involving these agents, and was comparable between the two treatment arms. It should be noted that osteonecrosis of the jaw (ONJ) was an infrequent occurrence in patients treated with either denosumab (20 cases) or zoledronic acid (14 cases), and there was no statistically significant difference in the rate of ONJ between the two groups. Overall, denosumab was non-inferior to zoledronic acid in regard to delaying or preventing SREs in patients with breast cancer metastatic to bone. Cancer Res. 2009;69(Suppl): Abstract 22. Letrozole and zoledronic acid Zoledronic acid administered sequentially after doxorubicin has been found to decrease cancer growth compared to the reverse sequence or either agent alone in preclinical studies. Nigel Bundred, MD, FRCS (University Hospital of South Manchester, Manchester, United Kingdom) presented data from a study analyzing the proliferation and apoptosis in 110 patients with early invasive breast cancer. Results from this controlled randomized trial, which compared 3 therapeutic options of 14 days treatment with placebo, letrozole, or letrozole and zoledronic acid administered pre-operatively in women with estrogen receptor-positive breast cancer, demonstrated that letrozole reduced proliferation by 52% (P<0.01) when used for 14 days prior to surgery. The authors conclude that zoledronic acid administration prior to surgery is safe; however, when administered as a single dose at a median of 3 days before surgery, there was no significant increase in apoptosis or decreased proliferation compared to letrozole alone. This lack of difference may be attributed to the small sample size in this study. Cancer Res. 2009;69(Suppl): Abstract 2009. Adam Brufsky, MD, PhD (Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, United States) presented data on the effect of zoledronic acid on aromatase inhibitor–associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. These results, obtained from the 5-year final follow-up of the Z-FAST study, demonstrated that upfront treatment with zoledronic acid (4 mg IV every 6 months) effectively prevents/treats bone loss when compared with delayed-start treatment in postmenopausal women receiving at least 5 years of AI therapy, regardless of baseline T score, chemotherapy status, or osteoporotic risk factor frequency. The absolute difference in bone mineral density at 5 years between the upfront and delayed arms was +8.61% (P<0.001). In addition, fewer patients randomized to upfront zoledronic acid had disease recurrence compared with patients in the delayed-start zoledronic acid arm, though this difference was not statistically significant. It must be noted that at this stage of follow-up (61 months), approximately 25% of patients in the delayed treatment arm had received zoledronic acid for at least 2 years, thus benefiting from the anticancer activity of zoledronic acid. Cancer Res. 2009;69(Suppl): Abstract 4083. Medical ozone oil or gas applications in patients treated with bisphosphonates There are limited options to treat osteonecrosis of the jaw (ONJ) lesions, and current recommendations for the treatment of ONJ include prophylactic antibiotics, the use of oral antimicrobial rinses, and preventative measures (dental exam, invasive procedure done before treatment initiation). Ozone therapy (O₃) has previously been shown to enhance the benefits of surgical and pharmacologic treatments of ONJ when administered before and after treatment procedures. Carla Ripamonti, MD (National Cancer Institute of Milan, Milan, Italy) presented data from a small pilot study assessing the therapeutic efficacy of the localized application of medical O₃ as an oil suspension or gas form in healing ONJ lesions in conjunction with prior antibiotic treatment. The 22 cancer patients in this study had been previously treated with bisphosphonates in the absence of odontoiatric preventive measures. The primary end-point of this study was to evaluate the level of healing response, and radiological lesion disappearance with complete reconstitution of oral tissue. Results of this study demonstrated that application of medical O3 either as an oil suspension or gaseous form in patients following antibiotic therapy enables a complete resolution of ONJ in more than 73% of patients without any adverse effects. While medical O₃ oil is more effective in treating minor ONJ lesions (≤2.5 cm), the application of O3 gas appears to be very useful in patients with more severe lesions (>2.5 cm). Cancer Res. 2009;69(Suppl): Abstract 5046.