Bone metastases: biology, treatment and palliation

Highlights from ASCO-GU 2016

Salvatore Grisanti

Francesca Valcamonico, Alberto Dalla Volta & Alfredo Berruti

Oncologia Medica

Università degli Studi & Spedali Civili di Brescia

AIOM Post ASCO-GU review, Milano 22 novembre 2016

Disclosure of potential conflict of interest

Dr. Grisanti has served as member of a Veridex European Advisory Board, Hamburg, May 2011

Bone metastases in GU neoplasms Neoplasm Frequency (%) Ref

Prostate >75 Coleman RE. Clin Cancer Res. 2006

Kidney 35-40 Woodward et al. Bone 2011

Bladder 12-35 Zaghloul et al. Int J Clin Oncol. 2010

Testis GCT <1 Jamal-Hanjani et al. BJU Int. 2013

Penis <1 Braumann et al. Case Rep Urol. 2015

Outline of highlights ASCO GU 2016 (bone)

• What is the place of Biphosphonates/Zoledronic acid after the STAMPEDE trial and meta-analysis (Lancet Oncol dec 2015)?

• Alpha-emitters particles (Radium-223)

• Imaging of bone metastases (M. Rizzo)

• Biology & Biomarkers for bone targets/activity & selection of patients

Interpretation: No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small.

Vale CL et al. Lancet Oncol. 2015

Biphosphonates + SOC in M1 pts

Biphosphonates + SOC in M0 pts

Zoledronic acid + SOC in M1 pts

Zoledronic acid + SOC in M0 pts

What after the STAMPEDE trial? Study hypothesis: Early use of therapies may give larger absolute benefit in OS

Supplement to dx.doi.org/10.1016/S0140-6736(15)01037-5

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Supplem ental Figure 1 : Overall t r ia l design

Domanda ECM: Celecoxib non è un trattamento riconosciuto per le M+ ossee

Take home: • ZA non aumenta il clinical outcome in HSPC • Osteoclast-therapy non dovrebbe essere usata in HSPC per

prevenire SRE

Take home: • BTT può avere effetto additivo ad Abiraterone • Ma si tratta di un’analisi post-hoc

Mechanism of action of Radium-223

1. R223 mimics calcium and is incorporated in areas of new bone formation (complexes of hydroxyapatite) 2. R223 emits alpha-particles with high efficiency (multiple double-strands DNA breaks) and in a short range

(<10 cell diameter)

Re-treatment with Radium-223: 6 + 6 injections?

What is the difference between a “winner” and a “loser”?

James N et al. Lancet Oncol 2015

Stampede trial Alsympca trial

Parker C et al. NEJM 2013

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Prostate Cancer Survival

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20

40

60

80

100

0 120 240 360 480 600 720 840 960

Days*

Perc

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Median, days P value

ZOMETA® 4 mg 546 .103

Placebo 469

*Time after start of study drug.

Zol 4 mg 214 162 113 56 10

Placebo 208 148 94 40 5

Saad F et al. JNCI 2002

Bone pre-metastatic niche & metastasis formation

Schuettpelz LG et al. J Clin Investig 2011

Osteolytic bone lesions

Osteoblastic bone lesions

Bone pre-metastatic niche & metastasis formation

Schuettpelz LG et al. J Clin Investig 2011

Biphosphonates Denosumab

Osteolytic bone lesions

Mechanism of action of Radium-223

Biphosphonates Denosumab

Radium-223

Are CTCs expression of a dormant vs active niche?

Lam H et al. Drug Discov Today Technoll 2014

NATURE REVIEWS | CLINICAL ONCOLOGY VOLUME 6 | JUNE 2009 | 347

REVIEWS

a new blood supply from pre-existing vasculature, and is

stimulated by an angiogenic ‘switch’ that occurs when the

ratio of inducers to inhibitors tips in favor of inducers.

There is ample preclinical evidence that the angiogenic

switch is important for the escape from cancer dormancy

and the subsequent formation of metastases.75 Using

mouse models of pulmo nary metastasis, Gao et al.76

identified bone-marrow-derived endothelial progeni-

tor cells as critical regulators of this angiogenic switch.

Nonetheless, information on the expression of angio-

genic factors in DTCs/CTCs is sparse, with only one

publication demonstrating frequent VEGF expression

on CTCs (68% of total CTCs) in patients with metastatic

breast cancer.77

Additional microenvironmental processes might influ-

ence the dormant state of DTCs and micrometastases.

For example, during inflammation and wound healing

a plethora of cytokines are released and some of these

factors can induce the migration and growth of epithelial

tumor cells.78 Interestingly, a gene-expression signature

specific for wound healing predicted metastatic relapse

in patients with breast cancer.79 Briefly, on the basis of

gene expression profiles of fibroblasts, the investigators

identified a stereotyped genomic expression program in

response to serum exposure, which reflects the multi-

faceted role of fibroblasts in wound healing. These genes

are expressed in tumors by the tumor cells themselves, by

tumor-associated fibroblasts, or both. The tran scriptional

signature of the response of fibroblasts to serum provides

a possible link between cancer progression and wound

healing, as well as being a powerful predictor of the clinical

course in several common carcinomas.

Cancer stem cells

Cancer stem cells or cancer-initiating cells are a rare,

self-renewing population within the tumor mass, which

also have a differentiation component and are required

for initiation and maintenance of tumor growth.80,81

It is assumed that cancer stem cells can disseminate

from the primary tumor to distant sites (Figure 1). This

assumption is supported by the observation that primary

tumor stem cells show an expression profile associated

with meta static relapse in patients with breast cancer.82

Moreover, expression of a new breast stem cell marker

(ALDH1) was associ ated with poor clinical outcome in

patients with breast cancer. Furthermore, in vivo experi-

ments showed that only ALDH1 positive cells were able

to form meta stases in mice.83

What is the evidence that the founder cells of overt

metastases (that is, ‘metastatic stem cells’) might be

among the DTCs/CTCs detected by current methods

(Figure 1)? Firstly, the presence of DTCs in bone marrow

is significantly correlated with metastatic relapse.33

Secondly, most DTCs/CTCs are nonproliferating (that

is, Ki-67 negative) and resistant to chemotherapy35,84,85

as postulated for cancer stem cells, and they can persist

in the bone marrow of patients with breast cancer many

years after primary surgery.68,86 Thirdly, subsets of

DTCs/CTCs have a breast cancer stem-cell phenotype

(for example, CD44+CD24–/low, cytokeratin 19+MUC1–,

EpCAM+).21,87–89 Fourthly, the two stem cell factors,

EGF and fibroblast growth factor 2, were required for

the in vitro growth of DTCs obtained from the bone

marrow of patients with cancer.90 Nevertheless, strong,

direct evidence that some of the DTCs or CTCs detected

in bone marrow or blood samples have cancer stem cell

properties is still lacking. Future studies, including xeno-

transplantation of DTCs/CTCs into immunodeficient

mice, are needed to demonstrate that these cells are the

actual founder cells of overt metastases.

Numerous studies have shown that bone marrow is a

common homing tissue for DTCs derived from various

epithelial tumors, including breast, prostate, lung and

colon cancer.1,33,91 Although DTCs might be present in

other organs, bone marrow might serve as a reservoir

of DTCs from where they might recirculate into other

distant organs such as liver or lungs, where better growth

conditions might exist. The observed correlation between

DTCs in bone marrow and local relapse suggests that

these cells might circulate back to the primary tumor site

(Figure 1).34 Future research will show whether DTCs use

the same bone marrow niches as normal stem cells92 to

persist over many years in patients with cancer.68

Molecular propert ies of DTCs and CTCsThere are several studies on the molecular properties of

DTCs and CTCs assessed by immunocytological and

molecular analyses.1,91 DTCs in bone marrow frequently

express EpCAM, urokinase-type plasminogen activator

receptor and the protease inducer extracellular matrix

Metastasis

Anti-apoptotic proteins

Proteolytic activity

Self renewal/ stemness

Angiogenic factors

DTC growth factors

Apoptosis inducers

Metastasis supressor genes

Angiogenesis inhibitor s

Immune response

Figure 2 | Balance of factors regulating the onset of metastasis (escape of

dormancy). The escape from cancer dormancy and the onset of overt metastasis

is thought to be regulated by a number of different factors and cellular processes

supporting (arrow pointing upwards) or suppressing (arrow pointing downwards)

metastatic progression, as shown on the left or right tip of the balance,

respectively. Data from experimental studies on tumor dormancy include genes

encoding the MKK4 and Kiss1 metastasis suppressors, as well as Bcl-xL and

α5β1 integrin–fibronectin as apoptosis inhibitors.75,102 and stanniocalcins as

survival factors.103 Analyses of bone marrow and blood from patients with cancer

have reveled that upregulation or re-expression of HER2 and the urokinase-type

plasminogen activator receptor (uPAR) in DTCs could serve as a switch to interrupt

dormancy.55,56,104,105 Abbreviations: DTC, disseminated tumor cell; HER2, human

epidermal growth factor receptor 2.

Active vs Inactive BM niche ?

CTCs by CellSearchTM in the prostate cancer continuum

Grisanti S et al. submitted Clin Genitourin Cancer 2016

Domanda ECM: Le CTC hanno valore prognostico

Le CTC hanno valore predittivo di risposta al trattamento

Circulation, re-circulation and self-seeding of CTCs

Domanda ECM: Le CTC hanno valore prognostico

Le CTC hanno valore predittivo di risposta al trattamento