Diapositiva 1

TUMORI SOLIDI E METASTASI OSSEE: QUALI NOVITA’ PER il 2015
PATHOPHYSIOLOGY
OF BONE METASTASIS
Le Metastasi ossee da tumori solidi : patogenesi,
incidenza e manifestazioni clinicheE
Francesco Bertoldo
Malattie del Metabolismo
Dipartimento
di Medicina
FRANCESCO
BERTOLDO
AziendaU.S.O
Ospedaliera
Universitaria
Integrata Verona
di Malattie
del Metabolismo
Minerale e Osteoncologia
DIPARTIMENTO DI MEDICINA
UNIVERSITA’ DI VERONA
Elevato turnover osseo nei pazienti con PC
ELEVATO TURNOVER OSSEO
(eta’ –livelli vit D – Terapia ormonale adiuvante- metastasi)
PROGRESSIONE
OSSEA
CTIBL
FRAGILITÀ
SRE
Nuova metastasi
Perdita ossea
CTX
NTX
P1NP
SDF-1
TGF b
PDGF
IGF-1
OP
Scheletro non metastatico
Crescita della
metastasi ossea
Homing delle cellule
tumorali
CTX
NTX
P1NP
SDF-1
TGF b
PDGF
OP
Nicchia premetastatica
CTX
NTX
P1NP
SDF-1
TGF b
PDGF
OP
Metastasi ossea
Bertoldo F
The “Bone Health” concept in Prostate Cancer
Patients
 Adj.Horm.Ther.
 Chemotherapy
Age
 Low vitamin D /high PTH levels
High Bone Turnover
Homing Cancer cell
Pre-metastic niche
SRE
Bone Loss
Fragility Fracture
SURVIVAL
Fracture
Radiotherapy
Spinal Compression
Orth. Surg.
Pain
Bone Metastasis
Bertoldo F
CANCER TREATMENT INDUCED BONE LOSS
Rate of BMD Loss
0.5%
Normal men
1%
Late menop. women
HIGH RATE
BONE LOSS
Early menop women
= HIGH
BONE TURNOVER
2%
Aromatase Inhibitor
2.6%
Bone Marrow transpl
3.3%
Androgen deprivation
4.6%
AI + GNrh agonist
7.0%
Ovarian failure due
chemiother
7.6%
0
2
4
6
8
Lumbar spine BMD (% /year Bone Loss)
Brown SA, Guise TA Crit Rev Eukaryot Gene Expr 2009;19:47-60
Contribution of Androgen Deprivation Therapy to
Elevated Bone
Turnover in Men with Metastatic Prostate Cancer
40-
NTX nM BCE
3530 –
ns
25 –
20 –
*
15 –
10 –
0ADT Meta -
ADT +
Meta -
ADT +
Meta +
n
Michaelson MD et al Clin Canc Res 2004
Schnieder A Endocrinology 2005
Schnieder A Endocrinology 2005
Pretreatment serum CTX (>0.710,) preditcs bone only relaps
Lipton A J Clin Oncol 2011
Santini D et al PlosOne 2011
21.6664 BC pt 10 yr follow up
TIME TO BONE METASTASIS
TIME TO CANCER SPECIFIC MORTALITY
Kremer R et al JNCI 2014
CORRELATIONS BETWEEN BONE TURNOVER AND CLINICAL OUTCOME
IN PATIENTS WITH BONE METASTASES FROM SOLID TUMORS (NO BPs)
Protease
Esposito M.
Osteocyte regulation of bone remodeling
Kowgawa M J Bone Miner Res 2013
Dallas SL et al. Endocr Rev, 2013
PTH
TNFa
IL-6
IL-1 SDF-1
IL-6
RANKL
IL-11
PGE
TGFb
VEGF
BMPs
OPN
BSP
Osteoclast
Bone
Bertoldo F, Textbook of Osteoncology 2009
Activated osteoblast
Lining cell
BRC= Bone Remodeling Compartment
Chim SM
Andersen TL et al Am J Pathol 2009
OSTEOCLAST PRECURSOR
Endothelial cell
Sinusoid in bone
metaphysis
OCL
Receptors
VCAM-1
E-selectin
N-cadherin
CXCR4
RANK
BMP-R Ia,Ib,II
ICAM-1
PTH
TNFa
IL-6
IL-1 SDF-1
IL-6
RANKL
IL-11
PGE
TGFb
BMPs
OPN
BSP
Osteoclast
Bone
Bertoldo F, Santini D .Textbook of Osteoncology 2009
avb3,
avb2
TGFb-RI-II
Activated osteoblast
Lining cell
Endothelial cell
Sinusoid in bone
metaphysis
Cancer Cell
VCAM-1
E-selectin
N-cadherin
Cancer Cell
Receptors
CXCR4
RANK
PLT
BMP-R Ia,Ib,II
ICAM-1
PTH
TNFa
IL-6
IL-1 SDF-1
CSR
IL-6
RANKL
IL-11
PGE
TGFb
VEGF
BMPs
OPN
BSP
PTHrP
TNFa
PDGF
Osteoclast
Bone
Bertoldo F, Textbook of Osteoncology 2009
avb3,
avb2
TGFb-RI-II
Activated osteoblast
Lining cell
CXCR4 pharmacological Inhibition Reduces
Bone Metastatic Burden
Intraventricular injection
Intratibial injection of PC3 cells
RANK IS EXPRESSED IN ANDROGEN-DEPENDENT
PROSTATE CANCER CELL LINE LNCaP
Immunofluorescence assays
Courtesy of Dott. M.Fioramonti
Receptor Activator of NF-kB (RANK) Expression in
Primary Tumors Associates with Bone Metastasis
Occurrence in Breast Cancer Patients
Santini D et al PlosOne 2011
Endothelial Mesenchimal Transition and
MET
Plafox M et al.
cancer
VE
GF
MMP2
FG
F
MMP9
THE “PRE-METASTATIC NICHE”
IL6
IGF
-1
Bone niche
Bone Marrow niche
Periferal circulation
Sinusoidal
endothelial
cells
HPC vegf+
Hemat Stem Cell
SDF1
Opn
RANKL
OB
DTC
Cancer Stem Cell
MMP-2
MMP-9
VEGF
FGF
IL6
IGF-1
SDF1
Opn
Integrin
VEGF
FGF
IL6
IGF-1
MMP-2
MMP-9
Mes Stem Cell
bone
Bertoldo F Textbook of Otseoncology 2009
Wang N J Bone Miner Res 2015
PC cell line
(red)
Osteoblast
( green)
Wang N J Bone Miner Res 2015
Bone Marrow Niche
N cadherin
b1 integrin
CXCR4
NOTCH
OPN
Jagged 1
SDF-1
PTH/PTHrp R1
Wnt/bcatenin
BONE
Ratajczak MZ Leukemia 2010; Kollet Ot Nature 2006; Calvi LM Ann NY Acad Sci 2006
Endosteal niche
OSTEAL Macrophages
Wook Cho S. et al.
Soki FN et al Oncotarget 2015
Soki FN et al Oncotarget 2015
Bone Marrow Niche
N cadherin
b1 integrin
PTH/PTHrp
PTH/PTHrp
CXCR4
NOTCH
OPN
Jagged 1
SDF-1
PTH/PTHrp R1
RANNKL
Wnt/bcatenin
RANK
OSTEAL Macrophages
BONE
Ratajczak MZ Leukemia 2010; Kollet Ot Nature 2006; Calvi LM Ann NY Acad Sci 2006
Endosteal niche
MMP9
CATHEPSIN K
METASTATIC CELL AND RANK/RANKL PATHWAY
OPG
Wnt
Wnt Wnt
Osteoblast
b catenin
b catenin
LEF/TCF
RANKL
RANK
DKK-1
Cathepsin G G
Metastatic
Cancer Cells
Frizzled/LRP5/6 receptor complex
sRANKL
Osteoclast
precursor
Lytic
metastasis
Acitvated
Osteoclast
Bertoldo F, Textbook of Osteoncology 2009
FISIOPATOLOGIA DELLA METASTASI Ossea
IGF1
TGFb-1
Osteocalcina
ALP
TGF-b1
VEGF
IGF1
TGFb-1
ET1
uPA
PTHrP
RANKL
IL-6
Wnt/DDK-1
Chirgwin J J Cell Biochem 2007
by Bertoldo F.
BONE METASTASIS IN PROSTATE CANCER
DIFFERENT PATTERNS IN THE SAME SUBJECT
Blastic Pattern
Lytic Patter
Green = Bone
Red = Osteoid
Pink= Tumor Stroma
% Bone
Volume
Mixed Pattern
The “Bone Health” concept in Cancer Patients
 ADT
 Chemotherapy
High IL, TNFa serum levels
Age
 Low vitamin D /high PTH levels
High Bone Turnover
Homing Cancer cell
Pre-metastic niche
Bone Loss
SRE
Fragility Fracture
Fracture
Radiotherapy
Spinal Compression
Orth. Surg.
Pain
SURVIVAL
Bone Metastasis
Bertoldo F
Eventi correlati all’apparato
scheletrico (SRE)
Eventi correlati all’apparato scheletrico – skeletalrelated events (SRE):1,2
radioterapia
all’osso
PAIN ?
fratture
patologiche
compressione
del midollo
spinale
interventi
chirurgici
all’osso
HYPERCALCEMIA?
1. Saad F, et al. J Natl Cancer Inst 2004;96:879–82;
2. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf (Accessed 2 March 2011).
Skeletal-Related Events Are Prevalent in the
Absence of Bisphosphonate Therapy
Placebo arm*
90
79%
Patients with SRE, %
80
70
60
50
50%
49%
51%
46%
40
30
20
10
0
Breast
cancer1
NSCLC
Prostate Multiple
cancer2 myeloma3 and OST4
RCC5
NSCLC = Non-small cell lung cancer; OST = Other solid tumors; RCC = Renal cell carcinoma.
*Placebo arm from zoledronic acid and pamidronate clinical trials.
1. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321; 2. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882; 3. Berenson JR, et
al. J Clin Oncol. 1998;16:593-602; 4. Rosen LS, et al. Cancer. 2004;100:2613-2621; 5. Mulders PF. Presented at: EAU 2007.
Clinical Trials Indicate Skeletal-Related Events Are
a Serious Threat To Breast Cancer Patients*
Patients with SRE, %
70%
60%
Total SREs
Pathologic fracture
64%
Radiation therapy
Surgical intervention
52%
50%
Spinal cord compression
43%
40%
30%
20%
11%
10%
3%
0%
n = 384
SRE = Skeletal-related event.
*24-month data from placebo arm of randomized study.
Data from Lipton A, et al. Cancer. 2000;88:1082-1090.
Clinical Trials Indicate Skeletal-Related Events (SREs)
Are Serious Threats to Prostate Cancer Patients*
Total SREs
Pathologic fracture
Patients with SRE, %
60%
50%
49%
Radiation therapy
Surgical intervention
Spinal cord compression
40%
30%
33%
25%
20%
8%
10%
4%
0%
n = 208
*24-month data from placebo arm of randomized study.
Saad F, et al. Presented at: AUA 2003. Abstract 1472.
Tempo mediano alla comparsa del primo SRE:
generalmente inferiore a 12 mesi
CORRELATIONS BETWEEN BONE TURNOVER AND CLINICAL OUTCOME
IN PATIENTS WITH BONE METASTASES FROM SOLID TUMORS (NO BPs)
Biochemical Response Correlates With Improved Outcome
Skeletal Complications
E-E group (n = 36)
E-N group (n = 160)
N group (n = 132)
Persistently elevated NTx
0.8
1.0
0.8
Normalized NTx
0.6
Normalized
baseline NTx
0.4
0.2
Persistently elevated NTx
Proportion Died
Proportion With SRE or Death
1.0
Survival
E-E group (n = 36)
E-N group (n = 160)
N group (n = 132)
0.6
Normalized NTx
0.4
Normalized
baseline NTx
0.2
E-N vs E-E
risk reduction: 49%
0.0
3
6
P=
.0020
9 12 15 18 21
Time on Study (Mos)
24
Lipton A, et al. Oncologist. 2007;12:1035-1043..
E-N vs E-E
risk reduction: 48%
0.0
3
6
9 12 15 18 21
Time on Study (Mos)
P=
.0017
24
Probability
SREs Are Associated With Lower Survival in
Prostate Cancer
360 Days’ Survival
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
 No SRE: 49.7%
 ≥1 SRE: 28.2%
 P = .02
Median Survival Times
 No SRE: 338 days
(95% CI = 189, 460)
0
90
180
270
Survival, days
360
 ≥ 1 SRE: 248 days
(95% CI = 181, 296)
No SRE (n = 355)
≥ 1 SRE (n = 116)
Abbreviation: CI, confidence interval; SRE, skeletal-related event.
Reprinted from DePuy V, et al. Support Care Cancer. 2007;15(7):869-876.
48
Patients With Bone Metastases May Suffer
Potentially Lethal Skeletal-Related Events
SRE
Potential complication
Pathologic fracture
• Extended healing time1
• Surgical fixation or prosthetic replacement2
• 58.6% higher mortality rate associated with fracture3
Pain requiring
radiation to bone
• Negative impact on quality of life4
• Narcotics
Surgery to bone
• Hospital stay
• Increased mortality2
Spinal cord
compression
• Excruciating pain5
• Irreversible paraparesis or paraplegia6
• Chronic narcotics for analgesia6
Hypercalcemia of
malignancy
• Heart failure
• Coma
• Death
1. Gainor BJ, et al. Clin Orthop Relat Res. 1983;178:297-302. 2. Jacofsky DJ, et al. J Orthop Trauma. 2004;18:459-469.
3. Hei YJ, et al. Presented at: SABCS 2005. Abstract 6036; 4. Smith JA Jr, et al. Urology. 1999;54(suppl):8-14.
5. Coleman RE. Cancer. 1997;80:1588-1594; 6. Abrahm JL. J Support Oncol. 2004;2:377-388.
SKELETAL RELATED EVENT CRITICISMS
1. SRE is used in RCT but not in clinical practice
2. Preplanned control (radiographs)
3. Symptomatic vs asymptomatic events, i.e fractures
4. SRE are composite end points .Different clinical weight
of component
5. Include complications of BMT and therapeutic or
preventive measure (orthopedic surgery or radiation )
6. No direct measure of factors that are important to
patients (pain or mobility)
SRE >>>>> SSE (Symptomatic Skeletal Events)
51
Fizizi et al Eur Urol 2015
(SSE CUMULATIVE INCIDENCE)
Oster G et al
TIME TO EVENT BY TYPE OF SRE (SSE ) IN PC PATIENTs STAGE IV
(2000-2007)
L’estensione delle lesioni ossee è associata ad aumento della mortalità
No bone lesions
<6 bone lesions
12
18
Median OS,
months
18.2
8.1
≥6 bone lesions
84
6.1
60
80
1.0
n
Cumulative survival
0.8
0.6
0.4
0.2
0
0
20
40
Time (months)
Pezaro C, et al. Eur Urol 2014;65:270−3
SREs sono associati ad incremento della mortalità
5-year
survival rate, %
Patients (%)
100
Without bone metastasis
With bone metastasis
With bone metastasis + SRE
90
80
70
60
50
40
30
20
10
0
0
1
6
8
4
7
5
2
9
3
Years after initial prostate cancer diagnosis
N=23 087 with median follow-up of 2.2 years (Danish National Patient Registry)
SRE, skeletal-related event
Nørgaard M et al. J Urol 2010;184:162-7
10
56
3
<1
Mortality following bone metastasis and skeletal-related
events among women with breast cancer: a population-based
analysis of U.S. Medicare beneficiaries, 1999–2006
Sathiakumar N et al Breast Cancer Res Treat (2012) 131:231–238
Post-operative breast cancer patients diagnosed with skeletal
metastasis without bone pain had fewer skeletal-related
events than those with bone pain
Koizumi et al. BMC Cancer 2010, 10:423
58
Fizizi et al Eur Urol 2015
Treatment goals in cancer patients
bone metastasis
PALLIATION
SRE
prevention/delay
THERAPY
Overall survival
(OS)
Prevent/delay
SREs
as part of OS
Jernberg E et al PLOS/one 2014
Jernberg E et al PLOS/one 2014
Jernberg E et al PLOS/one 2014
ABI
ENZA
ABI
ENZA
Jernberg E et al PLOS/one 2014