Bisphosphonates and RANKL-Antibody Denosumab

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1 Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer Bisphosphonates and RANKL-Antibody Denosumab

2 Bisphosphonates and RANKL-Antibody Denosumab Versions until 2011: Diel / Fehm / Friedrich/ Jackisch / Schaller/ Scharl / Schütz / Solomayer Version 2012: Lux / Solomayer

3 Bisphosphonates in Breast Cancer Hypercalcemia 1a A ++ Reduction of skeletal events (complications) 1a A ++ Reduction of bone pain 1a A ++ Treatment beyond progression of bone met s 5 D ++ In combination with neoadjuvant chemotherapy 2b C +/- Prevention of metastases Primary breast cancer in subgroups 1b B + Advanced breast cancer 2b C +/- Tumor therapy-induced bone loss Prevention 1b B + Therapy 1b B ++ Prevention of breast cancer with oral BPs 3b C +/- (in women receiving BP for low BMD) Oxford / AGO LoE / GR

4 Bisphosphonate Use And Breast Cancer Incidence Chlebowski RT et al. Oral Bisphosphonate Use and Breast Cancer Incidence in Postmenopausal Women. J Clin Oncol 28:

5 RANKL-Antibody Denosumab in Breast Cancer Oxford / AGO LoE / GR Reduction of hypercalcemia 2a A ++ Reduction of skeletal complications 1a A ++ Reduction of bone pain 1b B ++ Treatment beyond progression 5 D + Progression while therapy with bisphosphonates 4 C +/- Prevention of tumor therapy-induced osteoporosis 1b B + Therapy of tumor therapy induced osteoporosis 1b A ++

6 Therapy and Prevention of Tumor Therapy- Induced Bone Loss / Osteoporosis Oxford / AGO LoE / GR Regular BMD-measurement recommended 2b B + Bisphosphonates 1b B ++ RANK-ligand antibody Therapy 1b A ++ Prevention 1b B + HRT (independent from ER-status of BC) 5 D - Further recommendations (based on the guidelines for osteoporosis)* Physical activity 4 C ++ Calcium ( 500 1,200 mg/d) 4 C ++ Vitamine D suppl. (800 2,000 U/d) 4 C ++ Reduction of smoking 4 C ++ Avoiding BMI < 20 mg/m 2 3b C ++ *

7 Bisphosphonates and Denosumab for the Therapy of Bone Metastases Oxford / AGO LoE / GR Clodronate PO 1600 mg daily 1a A ++ Clodronate IV 1500 mg q3w / q4w 1a A ++ Pamidronate IV 90 mg q3w / q4w 1a A ++ Ibandronate IV 6 mg q3w / q4w 1a A ++ Ibandronate PO 50 mg daily 1a A ++ Zoledronate IV 4 mg q4w 1a A ++ Denosumab 120 mg s.c. q4w 1a A ++ Other doses or schedules, e.g. derived from studies of adjuvant therapy or therapy of osteoporosis 5 D - -

8 Denosumab vs. Zoledronat to Reduce Skeletal Events Stopeck AT et al. Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study, J Clin Oncol 28:

9 Adjuvant Bisphosphonate Treatment in Primary Breast Cancer Oxford / AGO LoE / GR Clodronate PO 1600 mg daily for 2 y 1b B + Zoledronate IV 4 mg every 6 months for 3 5 y Postmenopausal patients 2b B + HR+ premenopausal patients Adjuvant endocrine therapy only 1b B + Adjuvant chemotherapy 5 D +/- HR- premenopausal patients 1b C +/-

10 AZURE-trial Postmenopausal Women Coleman RE et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011;365(15):

11 Zoledronic Acid in Premenopausal Women - the ABCSG12-trial Gnant M, Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360(7): Reduction of risk for event (DFS) by 36% No. of Hazard ratio (95% CI) events/ # at risk vs. No ZOL P -value ZOL 54/ (0.46; 0.91) No ZOL 83/ 904

12 Zoledronic Acid in Premenopausal Women - Update of the ABCSG12-trial Gnant M, Mlineritsch B, Luschin-Ebengreuth G et al. Long-term follow-up in ABCSG-12: Significantly improvedoverall survival with adjuvant zoledronic acid in premenopausal patients with endocrine-receptor positive early breast cancer. Cancer Res. 2011; 71(24 Suppl.):95s-96s

13 Side-Effects and Toxicity Bisphosphonates (BP) and Denosumab (Db) Renal function deterioration due to IV-aminobisphosphonates Oxford LoE Osteonecrosis of the jaw (ONJ) mostly under IV-BP and denosumab therapy (1.8%/ 1.8%) 1b Association with anti-angiogenetic therapies 3b Acute phase reaction (IV Amino-BPs, Db) 10-30% Gastrointestinal side effects (oral BPs) 2-10% 1b 1b 1b In adjuvant bisphosphonate therapy, major side effects were rarely observed (except APR).

14 Recommendations for Precautions to Prevent ONJ* Oxford LoE: 4 GR: C AGO: + During bisphosphonate or denosumab treatment, avoid any elective dental procedures, which involve jaw bone manipulations if interventions are inevitable, prophylactic antibiotics are recommended (LoE 2b) Optimize dental status before start of bisphosphonate or denosumab treatment, if feasible (LoE 2b) Inform patients about ONJ risk and educate about early symptom reporting In case of high risk for ONJ, use oral bisphosphonate In adjuvant bisphosphonate therapy, ONJ was extremely rare *Osteonecrosis of the jaw

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