the latest is the greatest… future directions in the ...background • metastatic breast cancer...
TRANSCRIPT
City Wide Medical Oncology Rounds Friday Sept. 21st, 2007
Mark ClemonsHead, Breast Medical Oncology Group
Princess Margaret HospitalCampbell Family Institute for Breast Cancer Research
The Latest is the Greatest…
Future Directions in the Management of Patients with Bone Metastases from Breast Cancer
Conflict of interest• Clinical Research Protocols
– Roche (ibandronate)
• Lab studies– Amgen (denosumab), Novartis (zoledronic acid)
• Talks– AstraZeneca (zactima), Novartis (zoledronic acid),
Roche (ibandronate)
• Bone Metastases Program at PMH– Novartis (zoledronic acid)
Preventing metastasesPreserving bonemineral density
Treating bone metastases
How does bone, “health” affect my patients?
Background
• Metastatic breast cancer• Bone metastases
– incidence– consequences
• Why does breast cancer go to bone?• Are current management strategies the, “best”?• Clinical Trials• The Future
1. Ferlay J, et al. IARC Globocon 2000. Cancer Incidence, Mortality, and Prevalence.2. Coleman RE. Cancer Treat Rev. 2001;27:165-176.3. Coleman RE. Cancer. 1997;80:1588-1594.4. Zekri J et al. Int J Oncol. 2001;19:379-382.
5-year world prevalence,thousands1
Incidence of BM
in cancers2Median survival,
Months2-4
Myeloma 144 70 - 95 6 - 54Renal 480 20 - 25 12Melanoma 533 14 - 45 6Bladder 1,000 40 6 - 9Thyroid 475 60 48Lung 1,394 30 - 40 6 - 7Breast 3,860 65 - 75 19 - 25Prostate 1,555 65 - 75 12 - 53
Mor
e ly
tic
Mor
e bl
astic
Metastatic Bone Disease is Common
Bone metastases are common and important!
• Over 5,000 Canadian women will die of breast cancer this year
• Majority either presented with or subsequently developed bone metastases (BM)
• Two-thirds of patients with BM will subsequently develop skeletal related events (SRE)
What do I do for Mrs J?
• Confirm that she has metastatic breast cancer• Tell her it is incurable• Consider radiotherapy for pain in back (or US trial)• Change tamoxifen (or trial)• Start a bisphosphonate (or trial)
What do I do for Mrs J?
• She then says,
“What does the future hold for me with all these bone metastases?”
Consequences of bone metastases in breast cancer: Mortality
• Median overall survival of patients with– bone only or dominant disease: 2–3 years– pathologic fracture: 12 months– spinal cord compression: 4 months– hypercalcemia: 3 months
The Bisphosphonates
• Inhibitors of osteoclast-mediated bone resorption
• BPs plus to chemo or hormonal therapy significantly– Reduce and delay SREs
• An integral part of clinical practice of patients newly diagnosed with BM
The bisphosphonates are not a panacea!
• Still need analgesia, surgery, radiotherapy, chemo / endocrine therapy
• Even with IV BP around 50% will not have a symptomatic response
• Absolute reduction in number and rate of SREs 13%
• Even with the most “potent” BP zoledronic acid therapy 30% of patients will have SREs in the following 2 years
• Maximisation of BP benefit is needed either:– Some patients do not need a BP– BPs are ineffective in some patients– Route and schedule of administration are not optimal
Can we use bisphosphonates more effectively i.e. why is the absolute benefit so small?
• When should we START bisphosphonates?– practice guidelines: initiate BPs at diagnosis of bone
metastases
• Breast cancer trials contain highly selected patients i.e. the one size fits all model does not work!– majority bone-only disease (61–70%)
– overall 13% reduction in SREs: population with a relatively favorable prognosis
– eligibility criteria include a prognosis of >6 months survival
Percentage of patients with bone only disease
Study N Bone only disease
S&W 190 29%
Hortobagyi 1996 380 60-62%
Theriault 1999 372 66-72%
Body 2003 466 65-68%
Tripathy 2004 435 NA
Kohno 2005 228 49%
Percentage of patients with bone only diseaseStudy N Bone only disease
James 267 32%
Plunkett 859 25-35%
The incidence of fractures
- highest in pts with bone only metastases- lowest in those with co-existing liver disease.
James et al. Bone metastases from breast carcinoma: histopathological - radiological correlations and prognostic features. British Journal of Cancer (2003) 89, 660-665.
Plunkett TA, Smith P, Rubens RD. Risk of complications from bone metastases in breast cancer: implications for management. EurJ Cancer. 2000;36:476-482.
There are essentially 3 groups of patients:
Worst risk group– what ever you do they will
continue to have SREs, need new treatment strategies
Probably over treated
High risk group – who with appropriate
therapy can move to the (and hopefully stay there)
Lower risk group– where SREs are not a great issue
Correctly treated
Need to be better treated
Increased Bone Resorption is the Hallmark of Metastatic Bone Disease
0 10 20 30 40 50
0-50
50-100
>100
Prostate (n=611) Breast (n=744) Myeloma (n=318)
NTX excretion (nmol/mmol creatinine)
%
Coleman et al - J Clin Oncol 2005
Normal young women/men
Pathological
Postmenopausal women /older men
Can N-telopeptide be used to guide more effective treatment strategies for patients
with bone metastases?
• NTX is correlated with:
– Presence of bone mets– Symptoms– Response to treatment – Progression– Survival
Use of Bone Resorption Markers to Direct Zoledronic Acid Therapy - BISMARK
• 1400 patients with bone metastases from breast cancer• Bone resorption assessed every 16 weeks- Urinary NTX• Primary endpoint: Risk of skeletal events (SRE) with time • Non-inferiority design
RANDOMI SE
Bone marker (NTX) directed therapy
Q 4, 8 or 16 weeks
Zoledronic acid 4mg iv 3-4 weekly
Worst Pain Score
±1.96*Std. Err.±1.00*Std. Err.Mean
Box & Whisker Plot: Worst Pain Score
1.5
2.5
3.5
4.5
5.5
6.5
Baseline Week 1 Week 2 Week 3 Week 4 Week 8
±95%CI±1.00*Std. Err.Mean
Worst Pain Score
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 8 Wk 12
Zoledronic Acid Oral Ibandronate
*p = 0.081 and 0.028P < 0.001
±1.96*Std. Err.±1.00*Std. Err.Mean
Box & Whisker Plot: Number of Pain Sites Reported
0.6
1.0
1.4
1.8
2.2
2.6
3.0
3.4
Baseline Week 4 Week 8 Week 12
±95%CI±1.00*Std. Err.Mean
Number of Pain Sites Reported
0.8
1.4
2.0
2.6
3.2
3.8
Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 8 Wk 12
*p = 0.037 and 0.004
Number of Pain Sites
P < 0.001
p= 0.008 *p < 0.01
Urinary NTX Levels
±1.96*Std. Err.±1.00*Std. Err.Mean
Box & Whisker Plot: Log NTX (corrected for Cr) Over Time
2.8
3.0
3.2
3.4
3.6
3.8
4.0
4.2
Baseline Week 1 Week 2 Week 3 Week 4 Week 8 Week 12
±95%CI±1.00*Std. Err.Mean
Log Urinary NTX (corrected for Cr) Over Time
2.6
2.8
3.0
3.2
3.4
3.6
3.8
4.0
4.2
Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 8 Wk 12
Bone Biopsy Program
Activated Osteoclast
CFU-M
Pre-Fusion Osteoclast
MultinucleatedOsteoclast
RANK/RANKL PathwayMechanism of action of AMG 162 – RANKL is a critical mediator of OC differentiation, function and survival
BONEBONEOB
Growth Factors Hormones Cytokines
RANKRANKL
AMG 162
So what’s new?
AMG 162 (Denusomab)
• Fully human monoclonal
antibody to RANKL
• Opposes osteoclast
differentiation and
activation by binding to
RANK-Ligand
Breast Cancer Phase 1: Inhibition of Bone Turnover in AMG 162 vs. Pamidronate
Time (day)
0 14 28 42 56 70 840
20
40
60
80
100
120
140
160
180
200
0.1 mg/kg (n=5-7)0.3 mg/kg (n=5-7)1.0 mg/kg (n=6-7)3.0 mg/kg (n=3)pamidronate 90 mg
Urin
ary
NT x
/Cre
atin
ine
% o
f B
asel
i ne
(Mea
n ±
SD)
Peterson MC, et al. Proc. ASCO 2004
A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid
(Zometa®) in the Treatment of Bone Metastases in Subjects with
Advanced Breast Cancer (20050136)
Status:Recruiting
Purpose:The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid in the treatment of bone metastases in subjects with advanced breast cancer
Phase 3
Summary
• Bone is the most common site of recurrence of breast cancer
• Presence of bone metastases and the occurrence of skeletal related events affects both morbidity and mortality
• Despite the widespread use of BPs it remains unclear– Magnitude of individual benefit?
– Which BP to use?
– Who to treat?
– When to treat?
– For how long?
• Biomarkers of bone destruction now exist and will hopefully enable improved targeting of patients in the future
So…
Is The Latest the Greatest?
Future Directions in the Management of Patients with Bone Metastases from Breast Cancer
010203040
5060708090
0 16 32 48 64 80 96 112
NTX
Weeks
26 treatmentsOver 112 weeks
1 SRE
Fixed Schedule Treatment
NTX level Bisphosphonate treatments
Durable endocrine response? Over-treated
SRE
Aromatase Inhibitor
Rob Coleman
0
20
40
60
80
100
120
140
160
0 16 32 48 64 80 96 112
NTX level
Weeks
NTX level Bisphosphonate treatments
15 treatmentsOver 112 weeks
3 SRE
Sequential response and progression
Marker Directed Treatment
SRE
Non-steroidal AI
Exemestane
Docetaxel
Rob Coleman
SREs
So…
These agents are not without side effects – that may become increasingly important if
bisphosphonates move into the adjuvant setting
Is The Latest the Greatest?
Future Directions in the Management of Patients with Bone Metastases from Breast Cancer