1. Current Approaches and New Directions in Treating Bone Metastases from Breast Cancer Erica L. Mayer MD MPH Dana-Farber Cancer Institute May 16, 2009

2. Outline Biology Symptoms/Imaging Treatment New Directions

3. 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

4. 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

5. Bone Metastases: General Mechanism Adapted from Guise and Mundy. Endocr Rev. 1998;19:18. Primary cancer AngiogenesisInvasionEmbolism Multicell aggregates (lymphocytes, platelets) Response to microenvironment Tumor cell proliferation Bone metastases ExtravasationAdherenceArrest in distant capillary bed in bone Transport

6. 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.

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

8. 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

9. MRI imaging T1 T2

10. 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!

11. Treatment Options Goals: –Attack the cancer –Strengthen the bone –Reduce symptoms Includes: –Systemic therapy –Local therapy

12. Systemic Therapies Anti-cancer therapy –Endocrine therapy Tamoxifen, aromatase inhibitors, ovarian suppression –Chemotherapy Many choices –Biologic therapies Herceptin, Tykerb, Avastin

13. 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

14. 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

15. 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

16. 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.

17. 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.

18. Theriault, R. L. et al. J Clin Oncol; 17:846 1999 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)

19. 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

20. 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

21. 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

22. 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

23. Blocking RANK ligand in a mouse can fill in a mouse bone metastases OPG ControlTreated Morony et al. Cancer Res. 2001;61:4432.

24. Ellis, G. K. et al. J Clin Oncol; 26:4875-4882 2008 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

25. 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

26. 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 Fizazi, JCO 2009 A future role may exist for denosumab for bisphosphonate-refractory disease

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. Positioning in Interventional Radiology

34. Example: Vertebroplasty

36. Concept of kyphoplasty

38. 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

39. 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

40. 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

41. Future Directions Can we prevent bone or other metastases by using bone medicines earlier on? Increasing evidence suggests bisphosphonates may have anti-cancer activity

42. ABCSG 12 Ovarian suppression + tamoxifen Ovarian suppression + anastrozole Zoledronic Acid (Zometa) 4 mg IV, Every 6 Months for 3 years No Rx All patients premenopausal, HR+ No adjuvant chemo Stage I-II breast cancer - 30% with T2 tumors - 25% with positive nodes N = 1803

43. At 5 years, 36% reduction in risk of recurrence in those taking Zometa

46. 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