Transcript Brain metastases are genetically different from primary cancer and

Highlights RedLANO 2016
Andrés Felipe Cardona, MD MSc PhD.
Clinical and Translational Oncology Group
Institute of Oncology, Fundación Santa Fe de Bogotá
Clinical Epidemiology
Universidad El Bosque
Foundation for Clinical and Applied Cancer Research
Cochrane Colombian Branch / LATINREC / ONCOLGroup
104 cases: Primary + brain metastases
86 cases: Primary + 2 brain metastases
15 cases: Primary+ brain + extra-neural metastases
Shared Somatic
Mutations
Brain
metastases
Primary
cancer
53% of brain metastases had actionable
mutations not present in primary
P53 and KRAS were more frequently
shared mutations
Brain metastases are genetically different from primary cancer
and other distant metastases
Astrocytes
secrete
exosome
microRNA that
induce PTEN
loss
ASTROCYTES
Exosomes
microRNA
CANCER
Cell
PTEN
CANCER
Cell
PTEN
CANCER
Cell
PTEN(-)
CANCER
Cell
PTEN
CCL2
CANCER
Cell
PTEN(-)
Recruit myeloid
cells and
microglia
to form niche
Plasticity of the cancer cell demonstrating the cross-talk between the
Blocking exosomes and/or CCL2 may prevent the
tumor cells and metastatic niche and provide opportunities for design
formation of
ofmore
the effective
brain metastases
niche
therapies
The Brain Metastatic Niche- Angiogenesis
J Mol Med (2015) 93:1213–1220
Perivascular pathways and induction of sprouting
angiogenesis can be employed to successfully grow in the
brain.
Mol Cancer Ther; 15(4); 702–10. 2016
Bev may prevent brain mets in nsclc but not breast
cancer
Generalidades
Smoll N. Cancer
(2001)
WNT pathway
15% (1:1)
5y SG 95% - 100%
Mejor pronóstico
CTNNB1 (Catenin beta 1 gene
mutation)
• 6q, 17p
•
•
•
•
Sonic hedgehog (SHH) pathway
• Más frecuente 60% (2,5:1)
• 5y SG 75%
• (100%) Nodulares /
Desmoplásicos
• TP53
• PTCH1, SUFU
• Recaída local
SHH signaling has been shown to induce expres- sion and/or stabilization of MYCN, miR-17/92, Snail1, CXCR4,
Math1/Atoh1, cyclin D1, Sox2, Sox9, abnormal spindle-like microcephaly-associated, Bmi1, and Bcl2 in CGNPs
and brain tumor initiating cells (BTICs), leading to increased proliferation and tumor growth
Tabori U, et al. J Clin Oncol 2013, 31:2927
• Frecuencia 10% (SHH y WNT)
• Inexistente grupo 3 y 4
• Valor pronóstico en SHH (SG
5y 41% vs 90% WNT)
• 50% asociado a cambios
anaplásicos
Tabori U, et al. J Clin Oncol 2013, 31:2927
Grupo 4
• 25% (3:1)
• 5y SG 45% a 75%
• Recaída metastásico (30%-40%)
• Otras alteraciones genéticas y epigenéticas
• Todos los subtipos se han identificados cambios epigenéticos :
– Modificadores de histonas, + metil (MLL2/3) - metil (KDM6A) - Acetil
(CREBBP, HDAC2)
– Remodelación de cromatina
– RNA helicasas
Angiogenesis and VEGF in meningioma
Slide 5
Acta Neuropathol. 2013 Nov;126(5):757-62.
Clin Neuropathol. 2012 Sep-Oct;31(5):352-60.
Positive correlation of VEGF-R2 with PFS
Positive correlation of VEGF-R2 with PFS
Kaley S, et al. Society of Neuro-Oncol. 2015.
Phase II trial of bevacizumab and everolimus as treatment for
patients with refractory, progressive intracranial meningioma
PFS 22 months C4.5-26.8)
Shih K, et al. J Neurooncol. 2016 Jun 16. [Epub ahead of print]
DCR 88%
Phase II trial of bevacizumab and everolimus as treatment for
patients with refractory, progressive intracranial meningioma
Shih K, et al. J Neurooncol. 2016 Jun 16. [Epub ahead of print]
Phase II trial of sunitinib for recurrent and progressive
atypical and anaplastic meningioma
PFS6 = 44% (95% CI: 27.0–59.7); median PFS = 5.2 mo (95% CI: 2.8–8.3 mo); median OS = 24.6 mo
(95% CI: 16.5–38.4 mo); 1-year OS = 79.2% (95% CI: 61.1–89.7); 2-year OS = 51.7% (95% CI: 29.4–70.4).
Neuro Oncol. 2015 Jan;17(1):116-21. doi: 10.1093/neuonc/nou148.
WHO classification of tumors of the CNS 2016. IARC
Yuchen Jiao et al, Oncotarget 2012 (3) : 709
Frequent ATRX, CIC, FUBP1 and IDH1 mutations
refine the classification of malignant gliomas
Yuchen Jiao et al, Oncotarget 2012 (3) : 709
Clinical outcomes
(IDHwT have clinical outcomes similar to GB - TCGA)
Poisson L, et al. TCGA. 2014.