Current Approaches and New Directions in Treating Bone Metastases from Breast Cancer

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.
19981918.
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.
200124612-7.
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
T2
T1
10
Symptoms/Complications Related to Bone Metastases

• Pain
• Pathologic fracture broken bone after minimal
  trauma
• Bone marrow (blood factory) involvement -gt 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. 20051652414.
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. 20049(suppl 4)28.
18
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 17846 1999
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
Control
Treated
Morony et al. Cancer Res. 2001614432.
24
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 264875-4882
2008
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

A future role may exist for denosumab for
bisphosphonate-refractory disease
Fizazi, JCO 2009
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
35
Example Vertebroplasty
36
Concept of kyphoplasty
37
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
Zoledronic Acid (Zometa) 4 mg IV, Every 6 Months
for 3 years
N 1803
Ovarian suppression anastrozole
No Rx
All patients premenopausal, HR No adjuvant
chemo Stage I-II breast cancer - 30 with T2
tumors - 25 with positive nodes
43
At 5 years, 36 reduction in risk of recurrence
in those taking Zometa
44
(No Transcript)
45
(No Transcript)
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