D coeffic adjuvant ct for t1ab jerusalem 2014

Adjuvant chemotherapy for T1ab breast cancer in 2014 ?

David Coeffic Cancer Ins@tute of Reims– Polyclinique

Courlancy

What we talk about ?

•  pT1ab (≤ 1 cm)

•  pN1 and pNmic are excluded

T1abN0 : is it a real problem in term of prognosis?

•  The number of clinical events could be jus@fied specific treatment ?

•  In other words, there is some clues that jus@fy to select predic@ve sub-‐type for treatment ?

Historic considera@on

We started, and it's a « shame », to be interested in T1abN0 from the @me there was a talk about Her2 !!

But several studies published in the last decade strongly support the fact that the metasta@c poten@al of breast tumors may be present a very early event, even though the primary breast tumor is not detectable by imaging (Engel, 2003 ; Van’t Veer, 2002 ; Schmidt-‐Ki:ler 2003 ; Husemann 2008 et Podsypanina 2008).

Press MF. et al. JCO 1997;15(8):2894-2904 Temps jusqu’à récidive (mois)

Pro

babi

lité

de s

urvi

e

Tumor size

Events exist !!!

§  Retrospective mulicentric study (US) §  382 tumoral sample (from surgery) §  N0 breast cancer §  Diagnosis < 1990 §  No adjuvant chemotherapy §  FISH analysis for HER2

We have found events in T1ab ! •  n = 965, 10 % of HER2+ •  More T1a than T1b are HER2+ •  No pa@ents received Chemotherapy or Trastuzumab •  Median follow-‐up: 6.2 years

Gonzalez-Angulo AM. et al – J Clin Oncol 2009

Time to diagnosis (months)

DFS

Time to diagnosis (months)

Met

asta

tic D

FS

Events exist, even with treatment !!

•  T1abc pN0 N = 2 026 -‐ T1a-‐b = 328 and T1c HR 1.71 (p = 0.01) DFS -‐ 67 % = adjuvant chemotherapy HR 2.03 (p = 0.003) OS -‐ Median Follow-‐up: 12.4 years

Chia S. et al. J Clin Oncol 2008;26:5697-‐5704

All patients

Time (years)

Surv

ie s

ans

réci

dive

(p

roba

bilit

é)

Patient without adjuvant chemotherapy

Time (years)

Surv

ie s

ans

réci

dive

(p

roba

bilit

é)

Events exist, even with treatment, even for HER2…

Popula@on T1a-‐b = 328, HER2+ : 10 % (n = 32)


T1a-b

Time (y)

DFS

OS

T1a-b

Time (y)

DFS

T1a-b, Without adjuvant chemotherapy

Time (y)

In conlusion

•  The number of event according to the retrospec@ve study is located between 5 and 10 % in no pretreated pa@ents

•  Events exist, even in pa@ents treated, confirming the requirement for op@mizing treatment

•  There is some prognos@c factors that seem obvious now, some of which are also predictors

Summary but not limited, prognos@c factors highlighted on retrospec@ve series, for DFS Red: posi@ve in mul@variate analysis, Yellow : posi@ve in univariate analysis

Author Journal

Year # Fol Feature

5- years

Her 2 + Triple N ER - Age Grade KI 67 Embol Node

Livi Cancer

2012 704 <35

Kwon BMC

2010 375 61 m

Monocentric T1Mic

3 M+ <35 1 Cut off

14 %

Cancello Breast

2011 1691 DFS =

92,5 %

Cut off 14 %

Theriault JCO

2012 1012 No treated < 35 vs

> 50

Hanrahan JCO

2007 51246 SEER registry <50 Grade

III > 6

Fisher JNCI

2001 235 Including T1c 50 ans

Wood Ann Surg

2002 282 Monocentric Nomogramme

2 M+ at 10

y Grade

cIII

Colleoni Ann Oncol

2004 425 Including T1 Mic Cut off

20 %

Kaplan 2009 110 4,2 y

DFS = 89 %

•  Age and prolifera@on are the major and universal prognos@c factors. •  Clinical Triple nega@ve is also a major factor •  Molecular factors that are predictors are somewhat interrelated

à To go further, it is urgent to have a more individualis@c approach based on molecular approach

« Doxa » of @me? For example, three paths :

•  NCCN 2014 •  Permanent publica@on screening •  Based on the level of evidence

•  Saint Gallen 2011 •  Scien@fic and intellectualized approach •  Only a consensus approach base on expert opinions

• French experts consensus 2011 (F Penault Llorca et al.) •  A consensus based on a exhaus@ve bibliographic screening

HER 2 néga@ve

HER2 posi@ve

Saint Gallen : a molecular approach

French expert reviews for tumors Her 2 +

** For grade 1 tumors and expressing strongly HR: request a review of HER2 status by FISH

Treatment of patients with breast cancer without lymph node involvement, HER2 is overexpressed

< 1 cm > 1 cm HR + ** HR - HR + ER-

All grade Chemotherapy + Trastuzumab §  < 35 ans or §  High proliferation (KI67, MI) or §  and/or grade 2-3 §  and/or embols +/- Hormonothérapie

Chemotherapy + Trastuzumab

Hormonotherapy Chemotherapy +

Trastuzumab

Chemotherapy + Trastuzumab

Penault-Llorca F et Coeffic D. Bull Cancer 2011; Jul;98(7):807-25.

A synthesis ? Size T1a T1b

Her 2+ RH - Her 2+ RH +

Luminal A Luminal B TN Her 2+ RH -

Her 2+ RH +

Luminal A

Luminal B

TN

NCCN 2014 No tt * HT*

HT *

HT * No tt * TZ + CT HT TZ+CT

HT CT according to Oncotype Dx


CT

Saint Gallen 2011

No tt HT HT HT CT TZ + CT HT TZ + CT

HT CT according to Oncotype Dx and UPA/P1


CT

French Consensus Penault Llorca 2011

TZ + CT HT TZ + CT according to age, KI67, MI,grade embols

No tt TZ +CT HT TZ + CT according to age, KI67, MI,grade embols

CT

INCA 2012 No answer No answer No answer No answer

* CT si Mic

Size T1a T1b



Her 2+ RH +

Luminal A

Luminal B

TN


HT *




CT

Saint Gallen 2011




CT




CT


Area of consensus

* CT si Mic

Size T1a T1b



Her 2+ RH +

Luminal A

Luminal B

TN


HT *




CT

Saint Gallen 2011




CT




CT


Area of disagreement

* CT si Mic

Problems are not yet solved!

•  The ques@ons that we will live •  Her2 tumors: should we take into account the size and / or

the HR status ?

•  TN: What are the predictors of efficacy to chemotherapy? For which sub-‐group?

•  Beyond the size, which predictors for chemotherapy in luminal ?

Her 2 + disease

Decision criterias in the « real life » for T1ab Her 2

Trastuzumab (n=93)

No Trastuzumab (n=112)

P value (Fisher test)

T1a T1b

16 (17%) 77 (83%)

36 (32%) 76 (68%)

0.016

Grade 1 Grade 2-3

3 (3%) 89 (97%)

17 (16%) 90 (84%)

0.004

HR + HR -

40 (43%) 53 (57%)

81 (72%) 31 (38%)

<0.001

MI =1 MI =2-3

24 (40%) 36 (60%)

58 (67%) 28 (33%)

0.001

Embols No Yes

72 (78%) 20 (22%)

95 (88%) 13 (12%)

0.085

* Log-‐rank test was used

Julien Peron. Study AERIO/UNICANCER, SABCS 2011.

HER 2 + as a prognos@c factor in T1ab ?

Retrospec@ve studies, Her 2 breast cancer T1, N0, M0.

Study Only T1a-b

# T1a T1b

HER2+ (%)

Median follow-up

(Y)

Adjuvant treatment

Press No 382 ? (Fish) ? No

Black No 27 47

100 5.6 ?

Joensuu No 49 264

12 9.5 No

Tavey No 230

6.9 6.5 ?

Chia No 103 225

6.4 12.4 67 %

Curigliano Yes 85 65

100 4.5 Yes

Gonzalez-Angulo Yes 323 642

10 6.2 No

Peron San Antonio 2011

Yes 52 153

100 ? 40 %

Rouanet San Antonio 2011

Yes 131 572

5,9 ? No

Events exist!!!

§  Retrospective Finnish study.

§  852 patients with pT1N0M0 breast cancer between 1991 and 1992.

§  Multivariate analysis §  Median Follow-up : 9,5

years. §  Only 5 % received

adjuvant chemotherapy

Joensuu H. et al. Clin. Cancer Res. 2003;9:923-930

Années de suivi Années de suivi

Années de suivi Années de suivi

Sur

vie

sans

mal

adie

à

dist

ance

S

urvi

e sa

ns m

alad

ie à

di

stan

ce

T1ab T1c

IHC

CISH

HER2 is a poor prognostic factor even when the tumor is small (T1ab, T1c).

HER2 expression is the major risk factor for recurrence in pT1a-‐b, NO breast cancer:

Clinical implicaAons from a French regional populaAon-‐based study of 703 paAents

Rouanet P, Roger P, Daures JP, Rousseau E, Romieu G, Mathieu A, Cretin J, Barneon G, Granier M, Maran-

Gonzalez A, Thibault S. Boissiere F, Bibeau F.

ONCO Languedoc-Roussillon Network

Disease Recurrence •  5-‐year DFS rates were 74% and 95% in pa@ents with HER2-‐posi@ve and

HER2-‐nega@ve tumors, respec@vely (p<0.0001)

•  According to the immunohistochemical phenotype DFS-‐5 years were •  95% for ER+/PR+/HER2-‐ (n=614/87%) •  91% ER-‐/PR-‐/HER2-‐ (n=47/6.7%) •  69% ER+/PR+/HER2+ (n=25/3.5%) •  81% ER-‐/PR-‐/HER2+ (n=17/2,4%)

•  In univariate analysis, HER2 posi@ve tumors (p=0.017), phenotype classifica@on (p=0.02) and adjuvant treatment (p=0.013) were significant prognos@c factors

•  In mul@variate analysis, only pa@ents with HER2+ tumors had higher risks of recurrence (hazard ra@o [HR], 2.41; 95% CI; [1.06-‐5.53]; p<0.05) than those with HER2-‐ tumors.

Benefit of Trastuzumab in T1N0 ?

Avantage AC-TH

Avantage AC-T

1.0 0.0 2.0

Node -‐

Node +

HR -‐

HR +

Tumor size < 2cm

Tumor size ≥ 2cm

AC-‐TH vs AC-‐T

1.0 0.0 2.0

Node -‐

Node +

HR -‐

HR +

Tumor size < 2cm

Tumor size ≥ 2cm

TCH vs AC-‐T

Avantage TCH

Avantage AC-‐T

BCIRG 006 : Subgroup analysis (OS)

Slamon et al. SABCS 2006

A french retrospec@ve pragma@cal study !

o  Mul@centric study

o  96 T1a-‐b, N0 invasive breast cancers o  Micro invasion and mul@focal tumor are excluded

o  Median size: 8 mm (2 – 10 mm)

o  25 (20 %) ≤ 5 mm

o  Adjuvant treatment: for « poor prognosis » (high grade and/or HR-‐) o  40 pa@ents were treated

o  90 % (37/40) of pa@ents received chemotherapy + trastuzumab

o  7 % (3/40) of pa@ents received trastuzumab alone.

Rodriguez et al. – ASCO 2009

Rodriguez et al. ASCO 2009

40 « poor prognosis » 56 « good prognosis »

No recurrence 9 % of recurrence

Trastuzumab

§  Recurrences only in the "Good prognosis" group: 9% vs 0% §  Recurrences could probably be avoided, perhaps, by an effective treatment in the "Good prognosis" group.

… pragma@cal results

Systemic Adjuvant Treatment Of T1a and T1b N0M0 HER2+ Breast Carcinomas; an

AERIO/UNICANCER Study Julien Péron1, Jean Sebastien Frenel2, Yann Vano3, Johanna Wasserman4,5,

Laurence Albiges-Sauvin4,6, Manuel Rodrigues4,7, Anne Vincent-Salomon7, Paul Cottu7 1Centre Léon Bérard , Lyon, France ; 2Centre René Gauducheau ,

Nantes, France ; 3Centre Antoine Lacassagne, Nice, France ; 4Association pour l’Enseignement et la Recherche des Internes en Oncologie ;

5Centre René Huguenin, Saint Cloud, France ; 6Institut Gustave Roussy, Villejuif, France ; 7Institut Curie, Paris, France

•  Trastuzumab/CT treatment led to a lower risk of recurrence (p=0.004)

•  Among 51 T1a tumors, 16 pa@ents received TZM/CT. One recurrence occurred among treated pa@ents and 3 among untreated pa@ents.

Californian registry on cause-‐specific mortality Pa@ents with breast cancer N0, T1a or T1b, HER2 +

Chew et al. J Clin Oncol 2010,28(suppl):abstract 583

All cases n = 20 188

2000 – 2004 n = 9 409

2005 – 2007 n = 10 779

HER2 Positive Negative

n (%) 3 196 (15.8)

16 992 (84.2)

n (%) 1 579 (16.8) 7 830 (83.2)

n (%) 1 617 (15) 9 162 (85)

Hormone receptors Weigh@ng factor in the management ?

Then what about the size (T1a) ?

Her + / HR +, good prognosis ?

•  T1abc pN0 N = 2 026 -‐ T1a-‐b = 328 and T1c HR 1.71 (p = 0.01) DFS -‐ 67 % = adjuvant chemotherapy HR 2.03 (p = 0.003) OS -‐ Median Follow-‐up: 12.4 years


All patients

Time (year)

DFS

No adjuvant treatment

Time (year)

T1/RH

Time (year)

DFS

Surv

ie s

ans

réci

dive

(p

roba

bilit

é)

No reason to consider a difference between T1a and T1b, why ?

•  Because the size is a con@nuous variable

•  Because the size is partly a subjec@ve variable

•  Because the limits of 5 mm or 10 mm were arbitrarily set

•  Finally, because there are few data in bibliography…

Rakkhit R. et al. SABCS 2008

T1ab HER2 + DFS

1A : DFS / HER + or - 1B : DFS

HR : HR + et HER - Triple negative HER2 : HER2+

Mul@variate analysis

Gonzalez-Angulo AM. et al – J Clin Oncol 2009

Survie sans récidive Survie sans récidive à distance

HR 95 % IC p HR 95 % IC p

HER2 positif vs négatif 2.68 (1.44 – 5) 0.002 5.30 (2.23 – 12.62) 0.0002

RH positif vs négatif 0.41 (0.23 – 0.72) 0.002 0.59 (0.25 – 1.37) 0.219

Âge et diagnostic 0.96 (0.94 – 0.98) 0.001 0.73 (0.32 – 1.7) 0.467

Grade 3 vs grade 1-2 1.34 (0.78 – 2.41) 0.320 0.97 (0.94 – 1) 0.080

Stade Ib versus Ia 1.59 (0.91 – 2.78) 0.103 1.47 (0.68 – 3.18) 0.329

Benefit of chemotherapy / Risk ?

Cardiotoxicity

Median follow-up Patients number

12-39 mois > 4000

2 ans 1056

39 mois 116

1 an 1677

2 ans 718

2 ans 1068

2 ans 579

3 ans 216

Treatment No Trastu

Docetaxel Carbopla@n + Trastu

9 weeks an@-‐micro tubules +

trastu follow by FEC x 3

Anthra then Trastu AC x 4 , then Trastu + Taxane

ICC NYHA

Grade 3 - 4

Control arm

BCIRG 006 FinHER HERA N-‐9831 BCIRG 006 N-‐9831 B31

3.5 4.1

2.5

1.6

0.6

0

0.4

0-‐0.8

0

1

2

3

4

256 paAents StraAficaAon

N+/N-‐

LVEF > 50%

Good safety profil, no grade 3/4 toxicity, except grade IV neutropeny

But stop treatment for 9 paAents due to FEV decrease

HercepAn 12 months 6 mg/kg /3 w

/ 3 w. 4 cycles

J1 J8 J15

75mg/m2

600mg/m2

HercepAn

C

T

Cycle 1, J1 ➔ 4 mg/kg 90 min, then 2 mg/kg/w

C

T

C

T

C

T

Jones SE et al. SABCS 2008, poster 2111

Phase II – docétaxel cyclophosphamide trastuzumab

Summary (1)

The risk of recurrence of breast cancer HER2 + for small tumors without lymph node involvement is

•  9-‐23 % at 5 years •  about 2.5 @mes greater than in disease-‐HER2 nega@ve

Summary (2)

•  Her 2 predictor of efficacy of trastuzumab? The answer is YES

•  Receptor status and size, weigh@ng factor of decision? Probably NO

•  It should probably take into account the risk-‐benefit ra@o and associated comorbidi@es in choosing treatment, but that does not prohibit an@ Her 2 treatment (and chemotherapy) for small tumors.

TN tumour

Preamble (valid for the remainder of the slides in forward and reverse)

No prospec@ve randomized clinical study reports the benefit of adjuvant chemotherapy for tumor size ≤ 10 mm and pN0 and whatever immunohistochemical subtype considered

About TN

•  All tumors "triple nega@ve" does not correspond to the "basal-‐like" phenotype defined by the classifica@on of Peru and Sorlie

•  « Basal Like » •  SBR = high, low differen@a@on •  High KI 67 •  CK 5-‐6 + and CK-‐17+, EGFR +, BRCA1 + / -‐

•  "Basal-‐like" between 58 and 67 years = 7% of breast tumors (1)

1. Sihto H, 2008, Clin Cancer Res

Associations of different TNBC subtypes.

Turner N C , and Reis-Filho J S Clin Cancer Res 2013;19:6380-6388

Click on image to magnify.

Basal-like 1: cell cycle, DNA repair and proliferation genes

Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R)

IM: immune cell processes (medullary breast cancer)

M: Cell motility and differentiation, EMT processes

MSL: similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers)

LAR: Androgen receptor and downstream genes, luminal features Lehmann et al JCI 2011

Summary of retrospec@ve series T1ab with more than 10% of TN

Author Year

Number of patients Follow-up Summary of data Multivariate analysis

Kaplan 2009

110 4,2 year 89 % TN X 6.6 risk of recurrence vs RH+ HER2-‐ ayer adjustemnt on size, age et adjuvant chemotherapy (Y or N)

Curigliano 2009

95 60 months 5 events, 0 M+ Her 2+

Kwon 2012

56 pt1ab

61 months

DFS-‐5 years 92.5% Only one metasta@c recurrence for a TN

Age <35 and TN are the only two parameters impacting DFS (HR= 4.91 et 4.96) no Her 2

Park (issue de Kwon) 2011

Only 33 TN

61 months

OS-5 years= 90 %

Ho 2012

Only 194 TN, with Tmic 113 adjuvant chemotherapy Often CMF

73 months DFS-‐5 years = 95% 11 metasta@c recurrence

Come-‐back to consensus Size T1a T1b



Her 2+ RH +

Luminal A

Luminal B

TN


HT *




CT

Saint Gallen 2011




CT




CT


In summary (1)

•  Global trend to provide chemotherapy for small TN but s@ll no consensus for T1a

•  Given the narrowness of the benefit of chemotherapy for T1ab, it should take the following precau@ons •  Consider any TN pT1ab low grade as suspect of not being a "basal-‐

like » •  Do not hesitate to ask a second look on histology •  Repeat IHC HER2 and HR •  Repeat evalua@on of SBR and growth factors

•  Remove histological subtype from TN known as good prognosis : adenoid cys@c carcinoma, androgene receptor +, apocrine

In summary (2) •  Rela@ve benefit of chemotherapy with taxanes and anthracyclines,

whatever the size and histologic subtype, is about 30% according to the Oxford meta-‐analysis updated in 2012

•  However, absolute benefit is depend on the risk of relapse, and the risk-‐benefit

•  It seems reasonable to give chemotherapy only for following profiles •  pT1B •  No major comorbidi@es •  Grade 3, high prolifera@on index

•  Regimen of chemotherapy will be dictated according to the bibliography (3 FEC 100-‐3 Doce etc…) or according to personal convic@on (4 TC, pla@num compounds)

Luminal subtype

Retrospec@ve data from NSABP 2001 J Natl Cancer Inst 1024 pa@ents pT1ab HR + Tam vs CT-‐TAM

< 50 y, HR -‐ HzR = 0,61

Benefit : 13%

0,39 x 38.8

DFS-‐8 years = trend for CT-‐TAM vs TAM alone Impac@ng parameters in mul@variate analysis Age (cut-‐off = 50 years) Size (1 cm vs < 1 cm)

< 50 y, N-‐, HR +

HzR = 0,64

Benefit : 10%

0,36 x 27.4

Oxford meta-‐analysis 2011

Prognosis approach does not allow a predic@ve vision

•  But, « honestly », chemotherapy may respond to laws of predictability, according to mechanisms of ac@on ? In absence of randomized prospec@ve study answering to our ques@on, is there a path to solve the problem..

L’approche de la sta@s@que modélisée Adjuvant Online

•  Un site web qui permet d’évaluer le pronostic individuel •  SG et SSR à 10 ans

•  Utilise le suivi des patientes traitées entre 1988 et 1992 et enregistrées sur le « Surveillance Epidemiology and End-Results Registry » (SEER).

•  10% des patientes USA traitées sur cette période •  Patientes de 36 à 59 ans avec enregistrement de la taille et du grade tumoral, du

statut hormonal et de l’atteinte ganglionnaire axillaire.

•  Evaluation statistique du bénéfice individuel des traitements médicamenteux adjuvants

•  Utilisation du bénéfice constaté de l’HT et de la CT adjuvante par la Méta-analyse de l‘Early Breast Cancer Trialists’ Collaborative Group •  TAM, CMF, AC, TT séquentiel avec Taxanes

•  Utilisation du bénéfice constaté des traitements adjuvants modernes dans les études adjuvantes randomisées récentes •  Taxanes, IA

AOL : unperfectly approach

•  No suitable for particular histology

•  Tubular, papillar, mucinous, medullary

•  No suitable for lobular

•  No suitable for T1ab N-

•  Under-estimation for efficacy of hormonotherapy

•  AOL! Ignores the prognosis value of: • Ki67, Mito@c Index

• HER2 • PR and Quan@ta@ve expression of ER

Je vous propose une simula@on d’AOL !

•  On par@ra du concept de Saint Paul : un gain addi@onnel de 5 % pour la récidive à 10 ans en plus de l’hormonothérapie

•  On fera varier les paramètres d'âge et de grade histologique, par tranche d’âge de 5 ans

•  On fera 3 simula@ons différentes basées sur l’état général

•  On re@endra comme conven@on •  Chimiothérapie : 3 FEC 100 – 3 TXT •  Hormonothérapie : TAM jusqu’à 45 ans, traitement séquen@el à 50 ans, traitement par IA exclusif au delà

Addi@onal benefit of chemotherapy over 10 years in risk of recurrence in addi@on to hormone therapy, according to age and histologic grade for a T1ab tumor with Adjuvant OnLine!

Age 30 y. TAM

35 y. TAM

40 y. TAM

45 y. TAM

50 y. TAM-IA

55 y. IA

60 y. IA

65 y. IA

70 y. IA

Grade 1 7,7 5,2 5,3 5,3 3,4 3,3 2,7 2,8 2,5

Grade 2 9,1 6,3 6,3 6,3 4 4 3,3 3,3 3,1

Grade 3 10,6 7,3 7,4 7,4 4,7 4,7 3,8 3,9 3,6

Good health, IK 100 %

Age 30 y. TAM

35 y. TAM

40 y. TAM

45 y. TAM

50 y. TAM-IA

55 y. IA

60 y. IA

65 y. IA

70 y. IA

Grade 1 7,7 5,3 5,2 5,1 3,2 2,7 2,7 2,5 2,2

Grade 2 9,1 6,2 6,2 6,1 3,8 3,1 3,1 3 3,7

Grade 3 10,6 7,3 7,4 7,3 4,6 4,6 3,7 3,5 3,2

Evolu@onnary Health state, depending on the age

Age 30 y. TAM

35 y. TAM

40 y. TAM

45 y. TAM

50 y. TAM-IA

55 y. IA

60 y. IA

65 y. IA

70 y. IA

Grade 1 7,5 4,9 4,9 4,5 2,2 2,3 1,4 0,7 0,4

Grade 2 8,9 6 5,7 5,5 3,1 2,8 1,7 1 0,4

Grade 3 10,3 7 6,6 6,4 3,7 3,2 1,9 1 0,4

Poor general condi@on, 2 significant comorbidi@es

Other approaches, other perspec@ves…

•  More personalized sta@s@cal approach: "No�ngham Prognos@c Index" taking into account the expression of HR and Her2 Oncotype Dx

•  Hormone therapy signatures •  UPA/P1

Oncotype DX®

16 cancer genes and 5 referent genes from three study

60

Paik et al. N Engl J Med. 2004;351:2817-2826.

Catégorie SR (0-100) Low risk RS < 18 Intermediate risk 18 < RS < 31 High risk RS ≥ 31

PROLIFERATION Ki-67

STK15 Survivin

Cyclin B1 MYBL2

OESTROGENES ER PR

Bcl2 SCUBE2

INVASION Stromelysine 3 Cathepsine L2

HER2 GRB7 HER2

REFERENCE Beta-actine

GAPDH RPLPO

GUS TFRC

GSTM1 BAG1

CD68

RS =

+ 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1

Oncotype DX® Validation Clinique: RS used as a continuous prognostic factor

• The recurrence score predicts the likelihood of beneficial effects of chemotherapy and the risk of recurrence at 10 years

61

Paik et al. N Engl J Med. 2004;351:2817-2826.

My SR is 30. What is the risk of recurrence in 10 years?

NSABP B-20: Many Small Tumors Have Intermediate to High Recurrence Score® Disease

Paik S, et al. J Clin Oncol. 2006;24:3726-3734.

33%

20% 19% 23% 21%

46%

N = 110 N = 318 N = 196 N = 24

Rec

urre

nce

Scor

e

≤1 cm 1.1-2 cm 2.1-4 cm >4 cm

Clinical tumor size

0

20

40

60

80

100 P=0.001

64% 56% 46%

16% 25% 30%

WSG-‐Plan B study (n=2551 )

Gluz O, et al. SABCS 2011 63

Risque intermédiaire risk (18-30)

Risque élevé (≥31)

Risque faible (<18)

Ki-67 <14 Ki-67 ≥14 Central grade

3%

36%

61%

19%

43%

38%

37%

63%

5%

39%

56%

30%

39%

31%

uPA/PAI-1 1 2 3 low high

Health & Medicine

D coeffic adjuvant ct for t1ab jerusalem 2014