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 BiologyBone 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

Adapted from Guise and Mundy. Endocr Rev. 1998;19:18.

Primary cancerAngiogenesis Invasion Embolism

Multicell aggregates(lymphocytes, platelets)

Response tomicroenvironment

Tumor cellproliferation Bone

metastases

Extravasation Adherence Arrest in distantcapillary bed in bone

Tra

ns

po

rt

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.

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)

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 Treated

Morony et al. Cancer Res. 2001;61:4432.

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

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

Fizazi, JCO 2009

A future role may exist for denosumab for bisphosphonate-refractory disease

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 realizedTong 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 12ABCSG 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

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