02 Pierfranco Conte Treating BC and skeletal mets.ppt

implant

1. Treating breast cancer and skeletal
metastases
Pierfranco Conte
University of Modena and Reggio Emilia
Modena, Italy

2. Breast cancer:
the global burden (2000)
0 200 400 600 800 1,0001,200
Breast
Cervix uteri
Colon/rectum
Lung
Stomach
Women (thousands)
Deaths
Cases
Ferlay J et al, 2000

3. Why is breast-cancer mortality declining?
Jatoi I. Lancet Oncol 2003;4:251─4
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Trends in mortality from breast cancer in countries that have
introduced breast screening (WHO Cancer Mortality Data Bank)
UK
Netherlands
Canada
USA
Sweden
Finland

4. Early breast cancer:
effect of adjuvant treatments (10 years)

RR (%)
Absolute
improvement (%)
Treatment Relapse Death Relapse Death
CMF 24 15 7.3 3.7
Anthra 12 15 3.5 4.6
TAM* 40 30 13.4 7.9
OA* 31 31 10.4 10.3
CT+HT vs HT* 20 25/11** NA NA


*ER positive patients; **≤50 years/50–69 years

5. Summary of adjuvant trials with taxanes
HR
NSABP
B28
CALGB
9344 MDACC
BCRIG
001
Relapse 0.83* 0.83* NS 0.72*
Death 0.94 0.82* NA 0.70*
*Significant interaction with tamoxifen

6. ATAC trial: disease-free survival in
intent-to-treat (ITT) population
Curves truncated at 42 months
Time to event (months)
P
r
o
p
o
r
t
i
o
n

e
v
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n
t

f
r
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(
%
)
100
95
90
85
80
0
Anastrozole
Tamoxifen
Combination
0 6 12 18 24 30 36 42
HR 95.2% CIp-value
AN vs TAM 0.830.71–0.960.0129
Comb vs TAM1.020.88–1.180.7718

7. MA.17 results: disease-free survival
Femara
(n=2,575)
Placebo
(n=2,582)
Hazard ratio
(95% CI)

p-value
4-year DFS rate 93% 87% 0.57
(0.43–0.75)
0.00008
Events 75 132


Femara decreased the risk of recurrence by 43%
versus placebo
Median duration of follow-up was 2.4 years
Goss et al. N Engl J Med 2003;349:1793─802

8. Summary of metastatic breast cancer
patients’ characteristics
25–30% of breast cancer patients develop
distant metastases
Mean age at diagnosis of metastases: 66 years
70–80% prior adjuvant chemotherapy
Median RFS: 3 years
Hormonal receptor status: 55–65% positive
HER2 overexpression: 25–30%

9. Treatment options for ABC patients
Criteria HT CT
ER/PGR status Positive* Negative
HER2 status Negative Positive**
DFI >2 years <2 years
Visceral metastases No Yes
PS All 0–1


*At last all patients will require chemotherapy
**Plus trastuzumab

10. Number ofOdds ratio HR
Comparison patients response death
Poly/single 2,442 1.79* 0.82*
Anthra/no anthra 5,241 1.30* 0.96
Taxanes/no taxanes 3,643 1.29* 0.90*
Chemotherapy +
Herceptin/chemotherapy** 469 2.83* 0.80*
Fossati R et al. J Clin Oncol 1998;16:3439─60
Ghersi D et al. The Cochrane Library, 2003
*Significant difference
**HER2+
Overview of metastatic breast cancer
chemotherapy

11. Bone and breast cancer
Cancer treatment induced bone loss
Prevention of bone metastases
Treatment of bone metastases

12. Treatment-induced decrease in
bone mineral density
Chemotherapy
Hormone therapy
Aromatase inhibitors
GnRH agonists
Oestrogen depletion
Bisphosphonates can prevent bone loss in
breast cancer patients

13. Changes in bone mineral density after
chemotherapy-induced ovarian failure
Change in bone mineral
density (%)
Study n Hip Spine
Powles et al 12 NR –2.7
Saarto et al 27 –1.9 –6.8
Delmas et al 12 NR –4.0
Shapiro et al 17 –4.6 –7.7

14. Adjuvant tamoxifen versus
aromatase inhibitors: bone safety
*p=0.0001; **p=0.001; ***p=0.07
ATAC MA-17
Anastrozole
(n=3,092)
Tamoxifen
(n=3,093)
Placebo
(n=2,582)
Letrozole
(n=2,575)
Muscoloskeletal
disorders (%) 30.3* 23.7* 26.1** 33.1**
Fractures (%) 7.1* 4.4* 2.9 3.6
Osteoporosis (%) NA NA 4.5*** 5.8***
Median follow-up
(months) 48 28

15. Bone and breast cancer
Cancer treatment induced bone loss
Prevention of bone metastases
Treatment of bone metastases

16. Randomised adjuvant trials of clodronate
Number of
patients
Bone
metastases
at 5 years 5 years
RR
(5-year)
Diel
ASCO 2000
302 14% vs 24%
p=0.04
91% vs 77%
p=0.002
0.41
Powles
J Clin Oncol 2002
1,06911.1% vs 10.2%
p=0.127
82.9% vs 79.3%
p=0.047
0.77
p=0.127
Saarto
J Clin Oncol 2001
299 21% vs 17% 70% vs 83%
p=0.009
NA,
increased
risk

17. Bone and breast cancer
Cancer treatment induced bone loss
Prevention of bone metastases
Treatment of bone metastases

18. Incidence of metastatic bone disease
Coleman RE. Cancer Treat Rev 2001;27:165–76
Primary tumour type Incidence (%)
Myeloma 70–95
Breast 65–75
Prostate 65–75
Thyroid 60
Bladder 40
Lung 30–40
Renal 20–25
Melanoma 14–45

19. Introducing metastatic bone disease
Many patients with advanced cancer will develop
metastatic bone disease
Arises when primary tumour cells metastasize
to active haematopoietic bone-marrow tissue
Affected areas include the skull, spine, pelvis, femur
and humerus
Onset is devastating for the patient as it signals that
the disease is incurable
Disease burden is enormous
Body JJ, editor. Tumor bone diseases and osteoporosis in
cancer patients. New York: Marcel Dekker, 2000

20. Metastatic bone disease:
clinical consequences
Bone pain
Spinal cord
compression
Radiation
therapy
Orthopaedic
surgery
Hypercalcaemia
Fractures
Skeletal event typically occurs every 3– 4 months in
patients with bone metastases from breast cancer

21. Burden of metastatic bone disease
Poor quality
of life
Treatment
side effects
Poor functional
capacity
Impaired
mobility
Long and painful
recovery from
fractures
Severe
bone pain
Dependence
on family/carers
Inconvenient
hospital/clinic
visits
Pain and paralysis
from spinal cord
compression

22. Treatment goals in
metastatic bone disease
Primary goals
Prevent skeletal events
–minimise disability
Provide pain relief
–improve functioning
–quality-of-life benefits
Other considerations
Limit adverse events
Improve patient
acceptability
–consider patient
lifestyle
Reduce healthcare costs

23. Strategy Usage
Chemotherapy and
hormone therapy,
monoclonal antibodies
Treat primary tumour and metastases
Radiotherapy Treat primary tumour, treat painful
metastatic lesions and prevent/treat
fractures in at-risk patients
Surgery Prevent/treat pathologic fractures
Analgesics (opioids) Bone-pain management
Antiresorptive therapy
(bisphosphonates)
Prevent skeletal events,
help treat bone pain
Treatment strategies for
metastatic bone disease

24. Role of bisphosphonates in
breast cancer: ASCO Guidelines
Patients with radiographic evidence of bone destruction:
intravenous pamidronate (90mg over 2-hour infusion) or
zoledronic acid (4mg over 15-minute infusion) every
3 to 4 weeks
Reduction of skeletal event rate by 20–48%
Reasonable in case of normal radiograph but abnormal bone
scan, and documented bone destruction at CT-scan or MRI
Once therapy with bisphosphonates has begun, it is not
advised to discontinue treatment even in the event of a
skeletal complication
Patients should continue bisphosphonate therapy until
performance status declines significantly
Hillner BE et al. J Clin Oncol 2003;21:4042–57

25. Conclusions: treating breast cancer
Nowadays survival from metastatic breast cancer
is significantly prolonged with newer drugs
Prolonged survival is associated with a higher
likelihood of developing bone metastases
Metastatic bone disease is an enormous burden
for the patient and the society
Primary goal of therapy is to minimise pain and
morbidity while improving mobility and quality of life