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Current Approaches and New Directions in Treating Bone Metastases from Breast Cancer Erica L. Mayer MD MPH Dana-Farber Cancer Institute May 16, 2009 Outline • Biology • Symptoms/Imaging • Treatment • New Directions Bone Metastases in Breast Cancer • Up to 70% of women with advanced breast cancer may develop bone metastases – Early site of spread – 20% of women have “bone only” disease – More common if tumor is hormone receptor positive • Cancer cells target bones with an extensive blood supply: arms, legs, ribs, spine, pelvis. Tend not to travel to hands and feet. • Breast cancer growth in bone is typically slow; therefore optimizing treatment is crucial Normal Bone Biology Bone is always in an active state of remodeling (build up/break down) • Resorption: stimulated osteoclasts erode bone, creating a cavity • Reversal: bone surface is prepared for osteoblasts to begin forming bone • Formation: osteoblasts replace resorbed bone and fill the cavity with new bone • Resting: bone surface rests until a new remodeling cycle begins Adapted from Novert's Pharmaceuticals Bone Metastases: General Mechanism Primary cancer Angiogenesis Invasion Embolism Response to microenvironment Extravasation Tumor cell proliferation Bone metastases Adapted from Guise and Mundy. Endocr Rev. 1998;19:18. Adherence Arrest in distant capillary bed in bone Transport Multicell aggregates (lymphocytes, platelets) Osteolytic metastases • Tumor cells produce growth factors that stimulate bone destruction • i.e. RANK ligand • Osteoclasts are activated and break down bone • Osteoblasts cannot build bone back fast enough • Decreased bone density and strength; high risk for fracture Patel, B. and DeGroot, H. Orthopedics Journal. 2001;24:612-7. Osteoblastic Metastasis • Osteoblasts are stimulated by tumors to lay down new bone • Bone becomes abnormally dense and stiff • Paradoxically bones are also at risk of breaking Radiology: How to Evaluate • Imaging tests – X-ray – Bone scan • Sensitive, not specific. • False positives: trauma, arthritis, infection – CT (“CAT” scan) – PET scan – MRI scan • Bone biopsy – for confirmation • Blood tests – Calcium, alkaline phosphatase Bone Scan MRI imaging T1 T2 Symptoms/Complications Related to Bone Metastases • Pain • “Pathologic” fracture – broken bone after minimal trauma • Bone marrow (“blood factory”) involvement -> low blood counts • High calcium levels: confusion, drowsiness • Nerve compression – Pain – Spinal cord compression Goal is to use multidisciplinary management to reduce/eliminate all symptoms! Treatment Options • Goals: – Attack the cancer – Strengthen the bone – Reduce symptoms • Includes: – Systemic therapy – Local therapy Systemic Therapies Anti-cancer therapy – Endocrine therapy • Tamoxifen, aromatase inhibitors, ovarian suppression – Chemotherapy • Many choices – Biologic therapies • Herceptin, Tykerb, Avastin Systemic Therapies Pain control – Pain medication • Tylenol, NSAIDs (ibuprofen), narcotics, steroids • Success can be limited by side effects – Radiopharmaceuticals • Strontium-89 and samarium-153: radioactive particles travel directly to tumor in bone • Can reduce pain refractory to other measures • Infrequently used Systemic Therapies: Bisphosphonates • Bind to and inhibit osteoclast action – Inhibit bone breakdown – Prevent bone damage – Improve bone density and strength • Recommended for almost everyone with breast cancer bone metastases Evidence Supporting Bisphosphonates in Breast Cancer • Multiple clinical trials have demonstrated treatment with bisphosphonates can reduce: – – – – – Bone pain Fractures High calcium levels Radiation therapy to bone Surgery to bone • May also significantly improve quality of life in women with breast cancer Lipton. Clin Breast Cancer 2007 Oral Bisphosphonates: Clodronate • Generally well tolerated • Demonstrated benefits in clinical trials • Issues for consideration – Not absorbed well from GI tract – may be less effective than IV – Adherence to oral therapy a concern • Not commercially available in US Solomon et al. Arch Intern Med. 2005;165:2414. IV Bisphosphonates • More potent than oral bisphosphonates • Improved adherence in clinic setting; given once every 4 weeks • Side events – – – – Flu-like symptoms Injection-site reactions Renal toxicity – need to check kidney function before giving Long-term use • Osteonecrosis of the jaw • Electrolyte abnormalities (low calcium) Conte et al. Oncologist. 2004;9(suppl 4):28. Available IV bisphosphonates Pamidronate (Aredia™) • In placebo-controlled trials significantly reduced fracture, radiation, pain Zoledronic Acid (Zometa™) • More potent agent; equally effective in trials • Shorter infusion time (15 min vs 3 hours) Theriault, R. L. et al. J Clin Oncol; 17:846 1999 Newest Bisphosphonate: Ibandronate • Both oral and IV forms • Prevents bone events (fractures, radiation, surgery ) compared with placebo • Can relieve bone pain when given with a loading dose (but takes up to 12 weeks) • May have less kidney toxicity • Ongoing comparisons to zoledronic acid are underway Cameron et al, The Oncologist, 2006 Osteonecrosis of the jaw (ONJ) • What is ONJ? – Exposed jawbone that does not heal – Treated with surgery, antibiotics – Rare side effect: about 5% in breast cancer population • Who could get ONJ? – Risk related to cumulative exposure – Recent invasive dental procedure or poor oral health are risk factors • Tooth extraction • Dental implant ONJ Prevention • Potential benefits of bisphosphonates typically outweigh small risks of ONJ • How to prevent: – See dentist before beginning bisphosphonate – Pursue optimal preventative dental care – Practice good oral hygiene • In those with stable disease after prolonged therapy, can consider reducing frequency of treatment New Systemic Therapy: Denosumab • Denosumab: antibody against RANK ligand, the stimulator for osteoclasts • Once-a-month subcutaneous injection • Promising results as osteoporosis treatment in clinical trials • Emerging role in the treatment of bone metastases Ellis SABCS 2007; Lipton ASCO breast 2008; McClung et al, NEJM 2006 Blocking RANK ligand in a mouse can fill in a mouse bone metastases OPG Control Morony et al. Cancer Res. 2001;61:4432. Treated Denosumab prevents osteoporosis in women receiving aromatase inhibitors • 250 patients receiving placebo or denosumab • Results: increased bone density with denosumab • Side effects: joint pain, body ache, fatigue Ellis, G. K. et al. J Clin Oncol; 26:4875-4882 2008 Denosumab vs Zoledronic Acid • Phase 2 trial of first-line denosumab vs zoledronic acid – 255 women enrolled – Equivalent reduction in bone breakdown – Equivalent prevention of bone events (fracture, radiation, surgery) • Phase 3 trials underway comparing denosumab and zoledronic acid head to head Lipton et al, CCR 2008 Denosumab after Zoledronic Acid • Phase 2 trial of denosumab vs zoledronic acid after prior bisphosphonate therapy • 111 patients enrolled with bone breakdown despite zoledronic acid – Denosumab reduced markers of bone breakdown – Less fracture, radiation, surgery in those receiving denosumab A future role may exist for denosumab for bisphosphonate-refractory disease Fizazi, JCO 2009 Systemic Agents in Development • Cathepsin K inhibitors – Cathepsin K degrades the bone – An oral inhibitor reduced bone turnover from breast cancer bone metastases (ASCO 2009 poster) • SRC kinase inhibitors (dasatinib) – SRC necessary for osteoclast bone breakdown – Dasatinib is oral, approved for chronic leukemia, may have activity against breast cancer as well • Ongoing trials are using these drugs after, with, or instead of zoledronic acid Local Therapies • Local therapies treat a limited number of locations; do not treat the whole body • Types: – Radiotherapy – Interventional Radiology – Surgery • Goals: – – – – Relieve pain Prevent fracture Enhance mobility and function Preserve quality of life Radiation Therapy • Radiation therapy can be used to treat painful bone metastases refractory to systemic therapies – 80-90% of breast cancer patients experience relief of symptoms – 40-46% experience full relief – 70% never have pain in that region again – May take months before full pain relief is realized Tong et al, Cancer 1982 Radiation Therapy: Specifics • Can take 1-4 weeks; 2 weeks is most common • Chemotherapy is usually on hold during RT • Side effects: nausea, diarrhea, low blood counts, fatigue • Typically radiation is not used again in the same place Interventional Radiology • What is it? – Minimally invasive procedures performed by specialized radiologists to treat symptoms from bone metastases • Indications: – To treat bone pain refractory to other conservative pain control measures – Specialized technique for metastatic cancer to spine bones • Stabilize broken bone Interventional Radiology: Techniques • Vertebroplasty: – Injection of bone cement to support weakened bones – Provides immediate and substantial pain relief • Kyphoplasty: – Balloon inflation of compressed spine bone is performed before cement injection – Used for compression fractures Positioning in Interventional Radiology Example: Vertebroplasty Example: Vertebroplasty Concept of kyphoplasty Concept of kyphoplasty Other Local Techniques • Radiofrequency Ablation (RFA) and cryoablation – Minimally invasive procedures to “burn” or “freeze” a tumor – Desensitizes by killing nerve endings near the metastasis • Most commonly used for cancer in the spine • Techniques can achieve excellent pain control • Use may expand with further data Surgical Joint Stabilization • Indications for surgery for bone metastases: – Prevention of bone fracture (“prophylactic”) • Risk depends on location of metastasis, type, size, and presence of symptoms – Alleviation of pain – Maintain ability to walk (for hip metastases) – Stabilize broken bone after pathologic fracture Beals et al, Cancer 1971 Surgical Joint Stabilization • Benefits of surgery – Procedures designed for rapid recovery • Simple pin placement to full hip replacement – Most are walking again soon after hip surgery – Most have good to excellent pain relief – Can dramatically improve healing after fracture • Typically performed in combination with radiotherapy Ryan et al. J Bone Joint Surg Am, 1976 Future Directions • Can we prevent bone or other metastases by using bone medicines earlier on? • Increasing evidence suggests bisphosphonates may have anti-cancer activity ABCSG 12 Ovarian suppression + tamoxifen Zoledronic Acid (Zometa) 4 mg IV, Every 6 Months for 3 years Ovarian suppression + No Rx N= 1803 anastrozole All patients premenopausal, HR+ No adjuvant chemo Stage I-II breast cancer - 30% with T2 tumors - 25% with positive nodes At 5 years, 36% reduction in risk of recurrence in those taking Zometa Conclusions • Bone metastases are common in advanced breast cancer, and can cause significant symptoms • Multiple systemic and local therapies are available; standard therapy includes monthly zoledronic acid • Better understanding of toxicities can improve the safety of treatment • New agents take advantage of increased understanding of the biology of bone turnover • Women with advanced breast cancer may live with bone metastases for many years, therefore optimizing therapy is crucial