Can we predict it ?

Late metastasis

Joseph  Gligorov  MD,  PhD  ESO  Advanced  Breast  Cancer  Task  Force  

APHP-­‐HUEP-­‐Tenon,  Paris  InsDtut  Universitaire  de  Cancérologie  

Université  Pierre  &  Marie  Curie,  Sorbonne  Universités  

Conflict  of  interest  

•  Amgen®  •  Genomic  Health®  

•  Eisai®  •  Roche-­‐Genentech®  •  Nanostring  ®  •  Novar;s  ®  

Clinical  trials  support,  advisory  boards,  speaker  

DEFINITIONS  AND  IMPORTANCE  

Defini;ons  &  importance  •  Late:          

•  Metastasis:    .  micro  mets  ?            .  macro  mets  ?            .  the  way  we  detect  the  mets  ?  

 •  Importance:  .  Is  it  frequent  ?  

         .  Is  it  life  threatening  ?            .  Is  breast  cancer  mortality  s;ll  important  as  a            main  risk  of  early  death  aNer  a  long  period            of  follow-­‐up  ?  

0                    2                              5                                                  10                                                  15              years  ?  

Defini;ons  &  importance  •  Late:          

•  Metastasis:    .  micro  mets  ?            .  macro  mets  ?        .  Clinical  events            .  Local  or  distant  mets  ?  

 •  Importance:  .  Let’s  see  the  datass  it  frequent  ?  

         .  Is  it  life  threatening  ?            .  Is  breast  cancer  mortality  s;ll  important  as  a            main  risk  of  early  death  aNer  a  long  period            of  follow-­‐up  ?  

0                    2                              5                                                  10                                                  15              years  

FREQUENCY  OF  LATE  METASTATIS    

Influence  of  chemo  and  pN  status  

Influence  on  mortality  

Conclusion  1  •  According  to  EBCTCG  publica;on    

–  Overall  breast  cancer  popula;on  treated  in  adjuvant  seXng  with  tamoxifen  present  an  absolute  risk  of  late  recurrence  aNer  5  years  between  10-­‐15%  

–  This  risk  is  higher  in  pN+  popula;on  who  do  not  receive  chemotherapy  (#  20%)  compared  to  pN0  with  or  without  chemotherapy  (7  to  8%)  

•  The  influence  of  adjuvant  tamoxifen    –  is  s;ll  clear  between  5  to  10  years  in  ER  &  PR  posi;ve  disease  –  Is  less  clear  aNer  5  years  in  PR  &/or  ER  poor  disease  

•  Risk  of  late  recurrence  clearly  impact  mortalit  

MORE  RECENT  DATA  

Influence  of  histological  type  

Pestalozzi et al., J Clin Oncol 26:3006-3014.2008

Prat A, Perou CM. Molecular Oncology 2011

Clinical-­‐pathological  characterisDcs    of  the  current  intrinsic  subtypes  of  breast  cancer  

Informa;ons  from  neoadjuvant  data  

Luminal  A   Luminal  B/HER2-­‐   Luminal  B/HER2+++  

HER2+++  non  luminal   Triple  nega;ve   ?  

Rates  of  distant  recurrences  and  breast-­‐specific  survival  in  TNBC  and  other  breast  cancers.  

RFS OS

Dent R et al. Clin Canc Res 2007

HR+  HR-­‐  

Time  to  distant  recurrence   Smoothed  hazard  rate  curves  for  risk  of  recurrence  

Clearly  in:    

 -­‐pN+  populaDon,    

 -­‐  premenopausal  women  at  Dme    of  tamoxifen  

 

ITT    :  intent-­‐to-­‐treat    COX  :  cox  regression  model  IPCW  :  inverse  probability  of  censoring  weighted  SCC  :  Shao,  Chang,  Chow  model  

Conclusion  2  •  Histological  type  might  influence  the  risk  of  late  relapse  

•  Intrinsic  subtypes  might  also  influence  the  risk  of  late  relapse  and  par;cularly  according  to  the  efficacy  of  systemic  treatments  –  Chemotherapy  for  TNBC  –  an;HER2  treatments  for  HER2  posi;ve  BC  

•  the  main  popula;on  for  which  the  iden;fica;on  of  a  late  risk  of  relapse  remains  the  most  important  is  the  HR  posi;ve  popula;on  

•  We  have  possible  treatment  op;ons  to  propose  to  the  pa;ents  

CAN  WE  PREDICT  LATE  METASTASIS  ?  

New  considera;ons  

•  Target  popula;on  is  HR  posi;ve  popula;on  

•  Predic;ng  late  metastasis:  2  informa;ons  – Prognos;c:  improving  OS  

– Predic;on:    •  defining  popula;on  s;ll  sensi;ve  to  endocrine  treatment  

•  Trying  to  find  new  targets  to  prevent  late  relapse  

ROR  score  was  calculated  using  the  test  variables  that  include:  •  Pearson  correlaDons  with  prototypical  gene  expression  profiles  for  the  four  intrinsic  Subtypes    •  ProliferaDon  score  •  Pathologic  tumor  size  

OP   pN0   pN+  

transATAC  study:  PAM50  vs  Oncotype  Dx  vs  IHC4  (RE,  RP,  HER2,Ki67)      

Clinical  variables  

Sestak  I  et  al,  JNCI  2013  

Trans ATAC & ABCSG-8 Distant recurrence – post 5 years

San Antonio Breast Cancer – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013

Courtesy of Sestak I et al.

Cha

nge

in L

Rχ2

Sta

tistic

94.1

67.9

0 10 20 30 40 50 60 70 80 90

100

CTS ROR Univariate Multivariate

HR (95% CI ) for IQR

Univariate

CTS Nodal status, grade, tumour size, age, treatment

1.96 (1.73 - 2.21) ROR score (PAM 50) 2.69 (2.12 - 3.43)

61.4

35.3

Multivariate*

1.80 (1.57 - 2.06) 2.07 (1.63 - 2.64)

*When added to other score

10 20 30 40 50 60 70 80 90

100

0

Luminal A vs Luminal B according to PAM50

San Antonio Breast Cancer – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013

HR (95% CI) P-value

Luminal A (N=1530 (71.6%)) - -

Luminal B (N=542 (25.4%)) 2.89 (2.07- 4.02) <0.0001

0 5

10

15

5 6 7 8 9 10 Follow-up time [years]

Luminal B Luminal A

Dis

tant

recu

rren

ce (%

)

4.1%

12.9%

0 5

10

15

Courtesy of Sestak I et al.

E-module in Oncotype Dx is predictive of late reccurence

Among women with tumours most sensitive to oestrogen, with a high E-module score, the recurrence rate more than doubled from 5.7% in the first five years to 13.6% in the subsequent five years. However, if they had a low E-module score, there was little difference in recurrence rates between the first five years and the next five years: 10.3% versus 12.3%.”

Dowsett M et al. EBCC 2014

Breast  Cancer  Index:  •  Molecular  Grade  Index  •  HOXB13/IL17BR  

The  predic;ve  value  of  the  marker  seems  depedent  of  the  previous  treatment  exposure  …  

Sgroi  et  al.  Lancet  Oncol  2013  

Endopredict  clinicalscore  was  calculated  using:  •  ProliferaDon  associated  genes  •  HR  associated  genes  •  Clinical  parameters  (tumour  size  &  nodal  status)  

Dubsky  P  et  al.  BJC  2013  

ER  pathway  seems  to  be  the  “driver”…  

Mikempergher  L  et  al.  Mol  Oncology  2013  

Conclusion  3  

•  Clinical  parameters  s;ll  remains  crucial  for  evalua;ng  the  risk  of  late  relapse  (pN,  pT)  

•  ER  pathway  ac;va;on  seems  to  be  crucial  also  and  maight  help  to  “predict”  the  benefit  of  prolonged  endocrine  treatment  in  popula;ons  at  risk  of  late  relapse  

•  New  approaches  and  signatures  might  help  us  to  find  new  tools  in  pa;ent  at  risk  of  late  relapse  and  not  candidate  for  prolonged  endocrine  treatment  

THANKS