Clemons, Mark

Abstract Background: Evidence from randomized trials, including a recent meta-analysis, suggests that adjuvant bisphosphonates can decrease recurrence and death in postmenopausal women with early-stage breast cancer. Bisphosphonates (BP) have been included as adjuvant therapy for postmenopausal breast cancer patients in multiple guidelines. SWOG S0307 compared efficacy of 3 BPs in early stage breast cancer, with no evidence of differences in efficacy on breast cancer outcomes by type of bisphosphonate, either in the overall analysis or subgroups. BPs are generally well tolerated, with a relatively low risk of serious adverse effects. Treatment for hormone sensitive breast cancer frequently includes treatment with an aromatase inhibitor (AI) or ovarian function suppression (OFS), both of which can accelerate bone loss, decrease bone density, and increase fractures. In addition to decreasing breast cancer events, BPs have been shown to decrease fractures in breast cancer patients receiving AIs or OFS. However, concerns have been raised about the risk of atypical femur fractures (AFF), a rare subtype of fragility fractures, which appear to increase with longer BP use (3-100/100,000 person-years) (Shane 2013). This substudy evaluated all fractures occurring in patients enrolled on S0307. Methods: Patients with stage I-III breast cancer who were receiving adjuvant systemic therapy were randomized to receive 3 years of intravenous zoledronic acid (ZA) 4 mg IV given every 4 weeks for the first six months, and then every 3 months for the following 2.5 years, oral clodronate (CLOD) 1,600 mg/day orally, or oral ibandronate (IBAN) 50 mg/day orally. The primary endpoint was disease-free survival (DFS). On-treatment data collection forms specifically queried whether a fracture had occurred during the reporting period, the site of the fracture, and whether or not it was associated with trauma. Results: A total of 6,097 patients were randomized to S0307, with a median age of 53 years. Rates for overall fractures at 7.7 years were higher for CLOD (9.3%) compared to IBAN (7.4%) and ZA (7.1%) (p=0.02), with differences being mostly in the spine. Traumatic fracture differences were not significant (CLOD 2.0%, ZA 1.9%, IBAN 1.7%; p=0.83). Fragility fracture rates were 5.2% with ZA, 7.2% with CLOD, and 5.6% with IBAN. Ankle fractures were the most common fracture site at 2.8% overall. Leg fractures, including femur fractures, were relatively low with a rate of 1.5% overall and not different between agents. AFF were not specifically queried/determined. Conclusion: In S0307, BPs were used in higher doses than is recommended for treatment of postmenopausal osteoporosis. There is limited data comparing the long-term effects across BP drugs used at these higher doses on the skeleton. In S0307, an overall fracture rate of 8% was seen in early stage breast cancer patients despite receiving BPs along with conventional systemic therapy. Fracture rates were slightly higher for CLOD than ZA and IBAN for fragility and overall fractures, but similar for traumatic fractures. This may reflect the potency of CLOD or the dosing schedule. Rates of femur fractures were relatively low in all arms without evidence of excess femur fractures. Funding: NIH/NCI CA180888, CA180819, CA180820, CA180821, CA180868, CA180863, CA196175; BCRF, Komen, Berlex (Bayer), Roche/Genentech, Novartis. Citation Format: Rachel L (MD) Yung, Jieling Miao, Alexander HG Paterson, Mark Clemons, Elizabeth C Dees, James N Ingle, Carla I Falkson, William Barlow, Gabriel N Hortobagyi, Julie R Gralow. Fractures in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG S0307 trial (ClinicalTrials.gov Identifier: NCT00127205) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-18-02.

Abstract Background Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. Methods Patients with stage I–III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. Results A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). Conclusions We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.

552 Background: Bisphosphonates reduce the risk of bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of osteonecrosis of the jaw (ONJ). We used the data collected in the S0307 trial to describe factors associated with provoked and unprovoked ONJ. Methods: In S0307, 6097 patients with Stage I-III breast cancer who had surgery were randomized to receive zoledronic acid (ZA) 4mg IV monthly for 6 months, then every 3 months, clodronate (CL) 1600mg daily, or ibandronate (IB) 50mg daily for three years, with no difference in bone metastases or disease-free survival. Patients completed dental procedures prior to and had a dental exam at enrollment. Pearson’s Chi-squared and Student’s T-test were used to test differences in categorical and continuous variables, respectively; logistic regression was used test independent association. Results: Of 5836 evaluable women, 48 developed ONJ, which was associated with bisphosphonate type (28/2124 (1.26%) for ZA, 8/2185 (0.36%) for CL and 12/1527 (0.77%) for IB (p = 0.002). Median time to onset of ONJ was 24.9 (1.4-66.6) for ZA, 41.2 months (range 33.8-67.4) for CL, 23.9 (2.1-75.3) for IB (p = 0.0447). Infection was present in 21 (43.8%) and absent in 20. ONJ was considered unprovoked in 20 (41.7%) and provoked by dental extraction in 20 (41.7%), periodontal disease in 14 (29.2%), denture trauma in 6 (12.5%), other dental surgery in 3 (6.3%). ONJ was associated with dental calculus (OR 2.03 (95% CI: 1.08-3.81), gingivitis (OR 2.11, 95% CI: 1.12-3.98), and periodontal disease (OR 2.87, 95% CI 1.45-5.53) that were moderate/severe and > 4mm periodontitis (OR 2.20, 95% CI 1.18-4.08). Patients with provoked and unprovoked ONJ had similar amounts of dental disease and lesion location. ONJ was not associated with dentures, plaque, chemotherapy, corticosteroids or renal adverse events. In multivariate analysis (limited by small sample), only bisphosphonate type was associated with ONJ. Conclusions: ONJ prevalence was low, likely due to patients completing dental procedures before enrollment. ZA carried a higher risk of ONJ (though current adjuvant dosing interval recommendations are less frequent), with time to onset similar to IB. Oral CL and IB (not currently available in the United States) are thus likely more appropriate for patients with poor dental health. Clinical trial information: NCT00127205.