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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
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