Triple negative breast cancer Biology and targeted therapy

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1 Triple negative breast cancer Biology and targeted therapy MR SCI MED DR I BOŽOVIĆ -SPASOJEVIĆ INSTITUT ZA ONKOLOGIJU I RADIOLOGIJU SRBIJE I VA N A B O Z O V I O U T L O O K. C O M

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4 Current challanges in defining optimal regiments for TNBC Biological Intrinsic heterogeneity within TNBC Lack of targeted therapies Clinical Higher risk and lower treshold for therapy The question is not yes/no but which CT? Analytical Small number of trials Post hoc and subset analysis with lack of power

5 Prognosis of TNBC

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7 PATTERNS OF RELAPSE According to Molecular BC Subtype Bone Lung Liver Brain Pleura Luminal B Luminal A HER2 Normal Basal Smid M Cancer Res 2008

8 Curigliano G ESMO Masterclas 2015

9 Why targeting TNBC is important?

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11 Association of pcr and Survival in TNBC CTCneoBC Cortazar et al Lancet 2014

12 Biology of TNBC

13 Biology of TNBC not all TNBC are BLBC and vice versa

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15 pcr pcr in taxane treated patients

16 BASAL like LAR Mesenhimal like

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18 Abstract #528 The prognostic role of androgen receptor in earlystage breast cancer patients: A meta-analysis Ivana Božović Spasojević 1, Dimitrios Zardavas 1, Evandro de Azambuja 1, Lieveke Ameye 2, Christos Sotiriou 3, Martine Piccart 1, Marianne Paesmans 2 1 Breast Data Centre, Medical Oncology Department, Institut Jules Bordet, Brussels, Belgium 2 Data Centre, Institut Jules Bordet, Brussels, Belgium 3 Breast Cancer Translational Research Laboratory, Jules Bordet Institute, Brussels, Belgium

19 EVALUABLE ELIGIBLE SCREENING Flow chart of the study # of studies identified and screened n= 493 # of studies excluded n= 473 # of studies with reported AR status in correlation with clinical outcome n= 20 # of eligible studies excluded n=7 -Insufficient statistical information to estimate survival # of studies assessed for eligibility n=13 Total of 6525 patients Presented by:

20 AR Prognostic Impact in all BC Patients UNIVARIATE Analysis HR 95% CI p DFS (12 studies, N=5658) OS (12 studies, N=6525) p<0.001 for both MULTIVARIATE Analysis DFS (5 studies, N=3207) OS (6 studies, N=4671) p<0.001 for both Presented by:

21 AR Prognostic Impact within different BC subgroups UNIVARIATE analysis HR 95% CI p ER+ DFS (5 studies, N=2048) <0.001 OS (5 studies, N=3047) <0.001 ER- DFS (2 studies, N=316) OS (3 studies, N=620) HER2+/ER- DFS (3 studies, N=358) OS (3 studies, N=358) Triple negative DFS (5 studies, N=536) OS (4 studies, N=495) Presented by:

22 Targeted therapy

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24 663 pts TNBC

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26 Sikov et al. JCO 2014

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28 PARP Inhibitors In Breast Cancer Clear activity of PARP inhibitors as single agents in BRCA-associated breast cancer Triple negative breast cancer shares many features with BRCAassociated tumors Alterations in x-chromosomeinactivation Range of molecular markers Clinical behavior Genomic instability O Shaughnessy J, et al. ASCO Abstract 3..

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35 Conclusions 1. Inter and intra-tumoral heterogeneity of TNBC, may explain, at least in part, disappointing results from early trials with targeted agents in unselected TNBC. 2. PARP inhibition show promising efficasy in early stage clinical trials, however phase III trials are still lacking. 3. The absence of known predictive factors for bevacizumab efficacy renders recommendations on its use difficult. 4. Novel trials are underway with different targeted agents, PD1 pathway, antiandrogen

36 Thank you for your attention! Institute for Oncolgy and Radiology of Serbia Daily ChemoTherapy hospital Pasterova 14, Belgrade

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38 Back-up

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46 Liedke C, AIBCC 2015

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54 Neoadjuvant Bevacizumab in HER2 - BC Phase III NSABP-B40 Study dosing: q3w (4 cycles Docetaxel + 4 cycles AC) Patients with operable HER2-BC Chemo-naïve & primary tumors 2cm N = 1206 R A N D O M I Z E Bevacizumab Docetaxel AC Docetaxel Bevacizumab Xeloda +Docetaxel Xeloda +Docetaxel AC Bevacizumab Gemcitabine +Docetaxel AC AC AC S U R G E R Y Bevacizumab q3 wk x 10 Bevacizumab q3 wk x 10 Bevacizumab q3 wk x 10 End points: pcr rate AC, Adriamycin and cyclophosphamide Gemcitabine+Docetaxel Neoadjuvant treatment AC Adjuvant treatment Bear HD, Tang G, Rastogi P, J Clin Oncol, 2011; 29 (suppl) Abstract LBA1005

55 pcr* % Early signal in HR+ Bevacizumab regimens Docetaxel-AC 60 P= p= p= *pcr = breast + LN All BC Subtypes N=1180 ER+ ER-

56 A Note of CAUTION Which is correct? GeparQuinto Bevacizumab achieves higher pcr rates in TNBC NSABP-40 Bevacizumab achieves higher pcr rates in ER+

57 CBDCA

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73 Neoadjuvant results with bevacizumab very confusing and probably not helpful

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85 Biology of TNBC what is new?

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87 Elsamany et al. Med Oncol 2014

88 Meta-analysis

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93 Cytokeratins 5/6, P-catherin, EGFR

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