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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