Individual	
  prognosis	
  and	
  predic1ve	
  
biomarkers.	
  	
  
Pr	
  Frédérique	
  PENAULT	
  LLORCA,	
  
France	
  
Prognosis	
  	
  
T	
  
N	
  
M	
  
Classical	
  prognosis	
  and	
  predic2ve	
  factors	
  
•  Age	
  
•  Grade	
  	
  
•  Histological	
 ...
Grade I
Grade II
Grade III8,9
SBR	
  grade	
  modified	
  	
  
by	
  Elston	
  and	
  Ellis	
  
•  Standardiza2on	
  of	
  ...
Group 3 - Average prognosis
Medullary, classical lobular,
lobular mixed
Group	
  1	
  -­‐	
  Excellent	
  prognosis:	
  Tu...
18	
  Histological	
  types	
  in	
  breast	
  cancer	
  and	
  only	
  4	
  
molecular	
  groups!	
  	
  
RE neg RE pos
C Perou & T Sorlie
Towards	
  a	
  simplified	
  taxonomy	
  of	
  breast	
  cancer?	
  «	
  defini2on	
  of	
...
Intrinsic	
  classifica2on	
  easily	
  	
  
translated	
  by	
  IHC	
  
HER2	
  +	
  
Basal	
  
Triple	
  nega1ve	
  
ER&P...
Predic1on	
  	
  
Surrogate	
  defini2on	
  of	
  intrinsic	
  
subtypes	
  of	
  breast	
  cancer	
  
«basal-­‐like»	
  
•  ER	
  and	
  PgR...
T	
  
N	
  
M	
  
Classical	
  prognosis	
  and	
  predic2ve	
  factors	
  
•  Age	
  
•  Grade	
  	
  
•  Histological	
 ...
HER2	
  
Nega1ve	
  predic1ve	
  value	
  
(<5% chance to respond to
anti-estrogens or trastuzumab)
HIGH	
  95%	
  
Posi1v...
Ki67	
  why?	
  
•  Defini2on	
  of	
  luminal	
  A	
  and	
  B	
  
•  Decision	
  of	
  CT	
  for	
  ER+,	
  Grade	
  II	
...
•  At	
  present,	
  the	
  enormous	
  varia2on	
  in	
  analy2cal	
  
prac2ce	
  markedly	
  limits	
  the	
  value	
  o...
MOLECULAR	
  SIGNATURES	
  
T	
  
N	
  
M	
  
Yes	
  ,	
  we	
  have	
  molecular	
  
biology	
  !	
  
•  Age	
  
•  Grade	
  	
  
•  Histological	
  ...
Centralized tests
MammaPrint
(Agendia, NL)
HR+ ET HR - / HER2- , T < 5cm, N ≤ 3
Fresh frozen=> FFPE
DNA array
70 GENES
CELL CYCLE/ PROLIFERA...
MammaPrint – RESULTATS
UNE BONNE SEPARATION GLOBALE A BAS/HAUT RISQUE
MAIS SANS CAPACITE DE RECONNAÎTRE
LES TUMEURS DE TRE...
80	
  genes	
  
56	
  GENES	
  
70	
  GENES	
  
Where	
  are	
  the	
  proofs	
  
Formalin	
  fixed,	
  paraffin	
  included	...
OncotypeDX
(Genomic Health, USA)
HR+ / HER2- , T1-3, N-/N+
FFPE specimens
qRT-PCR
21 GENES
PROLIFERATION, OESTROGENE,
HER2...
Decentralized tests
EndoPredict
(Sividon, GE)
HR+ / HER2- , T1-2, N0
FFPE
qRT-PCR
7 GENES SIGNATURE
PROLIFERATION, OESTROGENES
« LOCAL » TEST
...
Prosigna (PAM50)
(NanoString Technology, USA )
IDENTIFICATION OF « MOLECULAR3 SUBTYPES »
(LumA, LumB, HER2-enrichi, Basal)...
Conclusion	
  
•  Accurate	
  pathology	
  tes2ng	
  is	
  essen2al	
  for	
  individual	
  
pa2ent	
  selec2on	
  and	
  ...
Conclusion	
  	
  
•  For	
  the	
  2me	
  being	
  pathology	
  cannot	
  be	
  safely	
  
replaced	
  by	
  molecular	
 ...
Source:	
  Weigelt,	
  Reis-­‐Filho	
  &	
  Swanton,	
  Ann.	
  Oncol.	
  	
  2012;Suppl	
  10:x211	
  
?	
  
?	
  
Frédérique Penault Llorca : individual prognostic and predictive biomarkers
Frédérique Penault Llorca : individual prognostic and predictive biomarkers
Frédérique Penault Llorca : individual prognostic and predictive biomarkers
Frédérique Penault Llorca : individual prognostic and predictive biomarkers
Frédérique Penault Llorca : individual prognostic and predictive biomarkers
Frédérique Penault Llorca : individual prognostic and predictive biomarkers
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Frédérique Penault Llorca : individual prognostic and predictive biomarkers

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Frédérique Penault Llorca : individual prognostic and predictive biomarkers

  1. 1. Individual  prognosis  and  predic1ve   biomarkers.     Pr  Frédérique  PENAULT  LLORCA,   France  
  2. 2. Prognosis    
  3. 3. T   N   M   Classical  prognosis  and  predic2ve  factors   •  Age   •  Grade     •  Histological  subtypes   •  ER/PR  and  HER2  status   •  Ki67  +/-­‐  mito2c  index   •  Vascular  invasion   •  Tumor  margins   Oldies   but   goldies    
  4. 4. Grade I Grade II Grade III8,9 SBR  grade  modified     by  Elston  and  Ellis   •  Standardiza2on  of  tumor   grading   •  France  2011:  Gr  I  25%,  Gr  II   50%,  Gr  III  25%     •  Lack  of  reproducibility  
  5. 5. Group 3 - Average prognosis Medullary, classical lobular, lobular mixed Group  1  -­‐  Excellent  prognosis:  Tubular,   invasive  cribriform,  mucinous     Group  2  -­‐  Good  prognosis   Tubular  mixed,  mixed  ductal  NST  and  special   type  like  adenoid  cys1c,  secretory   Group 4 - Poor prognosis Ductal NST, solid lobular, mixed ductal NST and lobular, micropapillary 18  Histological  types  :     morphology  maOers!      
  6. 6. 18  Histological  types  in  breast  cancer  and  only  4   molecular  groups!    
  7. 7. RE neg RE pos C Perou & T Sorlie Towards  a  simplified  taxonomy  of  breast  cancer?  «  defini2on  of   intrinsic  subtypes  has  proven  efficient  in  defining  prognosis  for  breast  cancer   pa2ents  »    
  8. 8. Intrinsic  classifica2on  easily     translated  by  IHC   HER2  +   Basal   Triple  nega1ve   ER&PgR  -­‐,    HER  2  -­‐   ER /PgR+ HER2 -, Ki 67 < ER /PgR + HER2 -, Ki 67 > Luminal  A   Luminal  B   15 % 15 % 60 % CK 8, 18, 19 CK 5/6, 14, 17 EGFR, P53, ckit Pcad Normal  like   EE 2-3 EE 3 EE 1-2-3 HER2+   ER/  PgR+   Claudin  Low  
  9. 9. Predic1on    
  10. 10. Surrogate  defini2on  of  intrinsic   subtypes  of  breast  cancer   «basal-­‐like»   •  ER  and  PgR  absent   •  HER2  nega2ve   •  Approximately  80%  overlap  between  «  triple   nega2ve  »  and  intrinsic  «  basal-­‐like  »   •  But  «  triple  nega2ve  »  also  include  good   prognosis  special  types  such  as  medullary  and   adenoid  cys2c  carcinoma     •  Staining  for  basal  kera2n  is  considered   insufficiently  reproducible  for  general  use    
  11. 11. T   N   M   Classical  prognosis  and  predic2ve  factors   •  Age   •  Grade     •  Histological  subtypes   •  ER/PR  and  HER2  status   •  Ki67  +/-­‐  mito2c  index   •  Vascular  invasion   •  Tumor  margins   Oldies   but   goldies    
  12. 12. HER2   Nega1ve  predic1ve  value   (<5% chance to respond to anti-estrogens or trastuzumab) HIGH  95%   Posi1ve  predic1ve  value   30-­‐50%   Breast  Cancer   ER/PGR   What  is  the  level  of  predic2on   accuracy  clinically  useful?  
  13. 13. Ki67  why?   •  Defini2on  of  luminal  A  and  B   •  Decision  of  CT  for  ER+,  Grade  II  tumors  
  14. 14. •  At  present,  the  enormous  varia2on  in  analy2cal   prac2ce  markedly  limits  the  value  of  Ki67     •  An  interna2onal  panel  of  inves2gators  with  substan2al   exper2se  in  the  assessment  of  Ki67  and  in  the   development  of  biomarker  guidelines  was  convened  to   consider  evidence  for  poten2al  applica2ons.  
  15. 15. MOLECULAR  SIGNATURES  
  16. 16. T   N   M   Yes  ,  we  have  molecular   biology  !   •  Age   •  Grade     •  Histological  subtypes   •  ER/PR  and  HER2  status   •  Vascular  invasion   •  Tumor  margins  
  17. 17. Centralized tests
  18. 18. MammaPrint (Agendia, NL) HR+ ET HR - / HER2- , T < 5cm, N ≤ 3 Fresh frozen=> FFPE DNA array 70 GENES CELL CYCLE/ PROLIFERATION SIGNAL TRANSDUCTION INVASION, METASTASIS, ANGIOGENESIS « CENTRALIZED » TEST RECENTLY ADAPTATED TO FFPE Group of genes (« signatures ») EARLY RECURRENCE (Dg < 5 ans) PROGNOSTIC GOOD SIGNATURE : LOW RISK POOR SIGNATURE : HIGH RISK HR +&   HR-­‐  
  19. 19. MammaPrint – RESULTATS UNE BONNE SEPARATION GLOBALE A BAS/HAUT RISQUE MAIS SANS CAPACITE DE RECONNAÎTRE LES TUMEURS DE TRES BON OU DE TRES MAUVAIS PRONOSTIC attendre les résultats de l’étude MindAct (MicroArray in Node-Negative Disease May Avoid ChemoTherapy)
  20. 20. 80  genes   56  GENES   70  GENES   Where  are  the  proofs   Formalin  fixed,  paraffin  included  samples     Redundant  genes?   Valida2on  of    blue,  target  et  theraprint?   ?  
  21. 21. OncotypeDX (Genomic Health, USA) HR+ / HER2- , T1-3, N-/N+ FFPE specimens qRT-PCR 21 GENES PROLIFERATION, OESTROGENE, HER2, INVASION (16 GENES) + REFS (5 GENES) « CENTRALIZED » TEST (recurrence score) RS Late recurrence (10 years) Benefit from adjuvant TT PROGNOSTIC AND PREDICTIVE LOW RISK : + HORMONOTHERAPY / - CHEMOTHERAPY INTERMEDIATE RISK : DISCUSSION LOW RISK : + HORMONOTHERAPY / + CHEMOTHERAPY
  22. 22. Decentralized tests
  23. 23. EndoPredict (Sividon, GE) HR+ / HER2- , T1-2, N0 FFPE qRT-PCR 7 GENES SIGNATURE PROLIFERATION, OESTROGENES « LOCAL » TEST (SPECIAL EQUIPMENT IS REQUIRED) SCORE OF RECURRENCE EP SCORE LATE AND EARLY RECURRENCES (5 & 10 YEARS) PROGNOSIS LOW RISK HIGH RISK UBE2C BIRC5 DHCR7 STC2 AZGP1 IL65T RBBP8 MGP
  24. 24. Prosigna (PAM50) (NanoString Technology, USA ) IDENTIFICATION OF « MOLECULAR3 SUBTYPES » (LumA, LumB, HER2-enrichi, Basal) FFPE DNA ARRAY WITH BARCODES (1 gene = 1 barcode) 50 GENES « LOCAL » TEST (SPECIAL EQUIPMENT IS REQUIRED) LATE AND EARLY RECURRENCES (5 & 10 YEARS) PROGNOSIS LOW RISK (ROR) Intermediate risk HIGH RISK (ROR)
  25. 25. Conclusion   •  Accurate  pathology  tes2ng  is  essen2al  for  individual   pa2ent  selec2on  and  treatment  design  (subtypes  /  IHC   based  intrinsic  classifica2on/grading)   •  Tissue  prepara2on  is  the  KEY  for  accurate  biomarkers   evalua2on     •  Gene  signatures  may  provide  increased  confidence  for   treatment  decision   –  Oncotype  Dx®  is  recommended  by  St  Gallen’s  Panel  of  experts   (also  by  ASCO,  NCCN)   –  The  other  signatures  are  either  recommended  to  a  lesser   extend  or  very  promizing   •  However,  even  using  gene  signatures,  there  will  be  cases   for  which  treatment  decision  will  not  be  straighjorward  
  26. 26. Conclusion     •  For  the  2me  being  pathology  cannot  be  safely   replaced  by  molecular  assays   •  Advantages  of  combining  two  approaches   should  be  discussed   – The  target  popula2on  will  be  the  ER+,  HER2-­‐,  N-­‐   (Luminal  Breast  Cancer)  and  not  grade  3   •  Predic2ve  tests  are  awaited!  
  27. 27. Source:  Weigelt,  Reis-­‐Filho  &  Swanton,  Ann.  Oncol.    2012;Suppl  10:x211   ?   ?  

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