de cancer mamar: premiză pentru terapia metastazelor limfonodale
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1 Limfangiogeneza în formele moleculare IDEI 345/2011 de cancer mamar: premiză pentru terapia metastazelor limfonodale Marius Raica Victor Babes University of Medicine and Pharmacy Timisoara, Romania
2 Cancerul mamar step 1
3 Carcinomul invaziv Ductal invaziv Lobular invaziv Validează diagnosticul. Suport pentru terapia convenţională... Impact prognostic al formei histologice? Medular Mucinos Tubular Ductal/ lobular Impact terapeutic al formei histologice?
4 Step 2 Farmacodiagnostic (HR, HER2, Ki67) ER Ki67 Tipuri moleculare distincte grupate în subtipuri clinice pe baza caracterelor morfologice
5 ER: variability of expression, 200 labs [Pusztai et al, 2006]
6 HER2
7 Step 3: Triplu negative ER, PR, HER2 negative Triplu negative, dar ce exprimă? Puţin sensibile la taxani Vârf de recurenţă: 1-3 ani Majoritatea deceselor specifice:<5 y
8 Step 4: expresia citokeratinelor CK5
9 Some years ago: breast cancer can be classified into subtypes based on gene expression patterns [Perou, Sorlie, 2000, 2001] 84 specimens, 1753 genes
10 IHC, un surogat acceptabil al analizei genice Bhargava et al, 2010; Raica et al, 2013, Anticancer Res
11 Panel de anticorpi IHC ER PR HER2 CK5 EGFR P53 Bcl2
12 Basal-like carcinoma
13 Luminal A ER PR HER2 Bcl-2
14 Luminal B ER PR HER2 p53
15 HER2 ER PR HER2 Ki67
16 Normal like/unclassified CK8/18
17 Co-expression Class (n=184) CK5 CK18 EGFR Bcl-2 p53 LA (n=102) LB (n=14) Basal-like (n=16) HER2 (n=40) Unclassified (n=12)
18 Noi entităţi: tipurile hibride LA/HER2 sau LB/HER2 ER PR HER2 EGFR
19 Ki67? HER NEGATIVE ER negative ER positive HIGH Ki67 ER positive LOW Ki67 Suciu et al, Oncol Lett, 2014
20 Alţi biomarkeri? E cadherin Mammaglobin A
21 Basal-like and HER2 types are more sensitive to preoperative chemotherapy than luminal and normal-like [Rouzier et al, 2005; Carey et al, 2007]
22 Procedure [Conforti et al, 2007; Carey et al, 2010] ER + ER+ breast cancer (Lumin al type) Should be followed by splitting luminal A/B ER HER2+ HER2+/ERbreast cancer (HER2 type) ER- HER2- HER2- /ER- CK5+/ EGFR+ (basallike) HER2- /ER- CK5- /EGFR- (nonbasal breast cancer)
23 Clasificarea moleculară Bazal like 15-20% ER, PR, HER2 negativ CK5, EGFR, p53 pozitiv Luminal A 40% ER, PR pozitiv intens HER2 negativ HER % HER2 pozitiv ER negativ Luminal B 20% ER pozitiv/slab, HER2-/+ Ki67 crescut Normal like/neclasificabil 6-8% ER, PR, HER2, CK5, EGFR Gene ţesut adipos Claudin low 12-14% ER-, Claudin 3/4/7 -/slab E-cadherin slab, Vim + Tip molecular Predicţia răspunsului la chimioterapie Bazal-like 45% Luminale 6% HER2 45% Neclasificabil 0 După Malhorta et al, 2012, modificat
24 Tumori triplu negative, 7 subtipuri: Bazal-like 1 (BL1) Bazal-like 2 (BL2) Immunomodulator (IM) Mezenchimal (M) Mezenchimal stem-like (MSL) Luminal androgen receptor (LAR) Instabil (UNS) Lehmann et al,
25 Cât de specifici sunt markerii LECs? Există LVs în tumori?
26 LVs intratumorale şi peritumorale Raica şi Ribatti, Curr Med Chem, 2010
27 Implant de ţesut tumoral mamar uman pe CAM
28 CAM model VEGF-A/HGF stimulated VEGF-C VEGFR3 Cimpean et al, Clin Exp Med, 2009
29 Invazia limfovasculară Corelaţia cu LNM Limfangiogeneza în LN precede metastaza(kerjascki et al, 2008; Hirakawa et al, 2010) Creşte rata detecţiei BCa HE: 21% D2-40: 43.8% (Raica et al, 2011)
30 LVs: preexistente sau nouformate? D2-40/Ki67 Prox-1/D2-40 Raica et al, Anticancer Res, 2013
31 Parteneri celulari CD68
32 MCD/LMVD Overall Peritumoral area Intratumoral area Luminal A p=0,389 p=0,025 p=0,366 Luminal B p=0,676 p=0,797 p=0,883 HER2 type p=0,203 p=0,904 p=0,726 Basal-like p=0,003 p=0,029 p=0,100 Unclassified p=0,991 p=0,987 p=0,139 Nr Mast cell density LMVD (n=55) Intratumoral Peritumoral Intratumoral Peritumoral Basal-like (n=8) Luminal A (n=26) Luminal B (n=7) HER2 (n=10) Unclassified (n=4) Raica et al, Anticancer Res, 2013 Avram et al, Braz J Med Biol Res, 2013
33 Statusul VEGF-C şi VEGFR3
34 Limfangiogeneza diferă de la un tip molecular la altul ER HER2 CK5 EGFR VEGF-C VEGFR3 D2-40 HER2/Luminal: corelaţie între VEGF-C/VEGFR3/LMVD şi LNM Fără corelaţie: basal-like, neclasificabil Raica et al, Anticancer Res, 2011
35 Limfangiogeneza poate fi inhibată? Strategie? Blocarea mediatorilor Reducerea LMVD Cum? Anti-VEGF-C Anti-VEGFR3 Inhibitori tirozinkinazici Inhibarea altor factor limfangiogenici Reducerea rate de creştere şi a metastazării Anti-podoplanină Marker LECs Exprimată de unele celule tumorale Corelabilă cu invazia Anti-human pdpn (NZ1)
36 Mulţumiri Anca Maria Cimpean Domenico Ribatti Cristian Suciu Raluca Ceauşu Puşa Gaje Stefana Avram Şerban Comşa Diana Tatucu Lilian Şaptefraţi Valentin Djonov
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