Cancer 1989;63:181–187 Cancer 1983;52:1551–1557

Histopathology. 1991;19(5):403-410, J Clin Pathol. 2002 Feb;55(2):88-92, J Clin Oncol. 2007;25(10):1239-46

Modified SBR Grade3-5: Grade I - Well

6-7: Grade II - Moderate

8-9: Grade III – Poor

Significantly correlates

with DFS & OS

HG1 HG2 HG3

Sobretratamiento

Un 50% de las mujeres consideran que la quimioterapia merece la pena por un 1% de beneficio en supervivencia

«Es criminal dar quimioterapia a las mujeres con cáncer de mama que se curarían sin ella»

Diario MontañésANA ROSA GARCÍA | SANTANDER. 26 junio

NanoString Confidential. 7

Perou et al. Nature 2000

Sorlie et al. PNAS 2001

Microarrays

Pronóstico de los subtipos

van’t Veer et

al.

Nature 2002

MicroarraysPrimer test

genético

Paik et al.

NEJM 2004

Aplicabilidadde RT-qPCR

on FFPEOncotype Dx

S. XXI. Una nueva visión

NanoString Confidential. 8NanoString Confidential. 8

Oncotype Dx1,2 Mammaprint5PAM504Endopredict3

16+5 genes 70 genes50 genes8 genes

qPCR nCounter Microarray

N0/N1 N0

TAILORX MINDACT

NSABP-B14/20 ABCSG-6/8TransATAC, ABCSG-

8

1. Paik et al. NEJM 2004, 2. Paik et al. JCO 2006, 3. Parker et al. JCO 2009, 4. Dowsett et al. JCO 2013, 5.

van’t Veer et al. Nature 2002.

Genes

Tecnología

Validaciones

Clínicas

Retrospectivas

Validaciones

Clínicas

Prospectivas

Ha tener en cuenta…Han sido desarrollados en poblaciones heterogeneas

Han sido validados en estudios con una calidad diferente.

Debemos saber…La validación analítica

La validación clínica

La utilidad clínica

Estudios Prospectivos

Methods: TAILORx Design & Rationale for RS CutpointsEnrollment period: April 7 , 2006 to October 6 , 2010 (N=10,273 eligible)

14Sparano J A , and Paik S JCO 2008;26:721-728

Key Eligibility Criteria• Node-negative

• ER-pos, HER2-neg

• T1c-T2 (high-risk T1b)

• Age 18-75 years

• No PBI planned

Statistical Design• RS 11-25: non-inferiority

• 90% vs. <87% iDFS

• 835 DFS events

• RS < 11

• 95% vs. <93% DRFI at 10

years

• 75 DRFI events

Recurrence Score = 11 • 7.3% distant recurrence

rate at 10 years

• 95% CI 5%, 10%

Recurrence Score = 25 • 16.1% distant recurrence rate

at 10 years

• 95% CI 13%, 20%

Results: Patient Characteristics and Treatment

15

RS < 11 RS 11-25 P Value

No. eligible patients 1626 6897

Median age 58 years 55 years P<0.001

Post-menopausal 70% 64% P<0.001

Median tumor size 1.5 cm 1.5 cm N.S

Histologic grade

Low

Intermediate

High

34%

59%

7%

29%

57%

14%

P<0.001

ER Expression > 99% > 99% N.S.

PgR Expression 98% 92% P<0.001

Surgery

Lumpectomy

Mastectomy

68%

32%

72%

28%

P<0.001

• Endocrine therapy in low RS group: AI in 59%, tamoxifen in 34%, sequential tamoxifen-

AI in 1%, OFS plus other therapy (3%), or other/unknown (3%)

• Chemotherapy given to 6 patients in low RS group: (1 of whom recurred)

The results of a prospectively conducted clinical trial, the

Trial Assigning Individualized Options for Treatment

(TAILORx) in a specified low-risk cohort of women with

hormone-receptor–positive, HER2-negative, axillary node–

negative invasive breast cancer

93.8%99.3%

98.7%98.0%

PlanB: Design HER2-negative primary breast cancer

10.05.2017 19

� pT>2� G2-3� uPA/PAI-1↑� HR-� age <35 years

� Age<75 years � free margins� M0� pN+ � pN0 high risk

RANDOMIZATION

Doc75C600 x 6*

E90C600x4 �Doc100 x4*

RECURRENCE

SCORE

Endocrine therapy*0-3 LN and RS<11

0-3 LN and RS>11

or >/= 4 LN

HR+

HR-

• endocrine therapy and RT according to national guidelines• E: Epirubcin; Doc: Docetaxel; C: Cyclophosphamid

PlanB: Five-year disease-free survival in per-protocol population (n=2160)(no chemotherapy in pN0-1 RS 0-11)

10.05.2017 WSG GmbH 20

5-Y DFS 94%5-Y DFS 94%5-Y DFS 84%

5-Y DFS 94%5-Y DFS 95%5-Y DFS 88%

94%94%84%

N0 N1

Diagnóstico de cáncer de mama

primario invasivo (2004-2011)

N=379.103

HR-positivo, no metastásico

n=272.930

Ganglios negativos

n=184.190

Edad 40-84 años

n=169.158

Con resultado Recurrence Score

Ganglios negativos, edad 40-84 a

n=38.568

Ganglios positivos [N+(mic,1-3)]

n=57.491

Con resultado Recurrence Score

Ganglios positivos [N+(mic,1-3)]

n=4.691

Con resultado Recurrence Score

Ganglios negativos

n=40.134

Los resultados utilizando los puntos de corte del estudio TAILORx

son similares a los resultados utilizando los puntos de corte comerciales.

• Análisis de 9.201 pacientes con tumores G3 con seguimiento prospectivo

en el Registro SEER.

0% 20% 40% 60% 80% 100%

N0, ≤2 cm(n=5,655)

N0, >2 cm(n=2,523)

N+, ≤2 cm(n=556)

N+, >2 cm(n=467)

Estadio IBEstadio IB Estadio IIIAEstadio IIIAEstadio IIAEstadio IIA Estadio IIBEstadio IIB

Estadio según la

8ª edición.

Estadio pronóstico

usando T, N, M,

grado, RE, RP y HER2

Con un RS<11, todas estas pacientes son clasificadas como Estadio IA

• T1, Gr 1, PR-, N0, M0, RE+, HER2-

• T1, Gr 3, PR+, N0, M0, RE+, HER2-

• T2, Gr 1-2, PR+, N0, M0, RE+, HER2-

• T1, Gr 3, PR-, N0, M0, RE+, HER2-

• T2, Gr 1, PR-, N0, M0, RE+, HER2-

• T2, Gr 3, PR+, N0, M0, RE+, HER2-

• T2, Gr 2, PR-, N0, M0, RE+, HER2-

• T2, Gr 3, PR-, N0, M0, RE+, HER2-

8ª edición del Manual de Estadiaje del American Joint Committe on Cancer

NanoString Confidential. 26

NanoString Confidential. 27

Logistics MINDACT Mook,

Eur J Canc 2009

70 gene discoveryvan ‘t Veer Nature 2002,

van de Vijver NEJM, 2002

MammaPrint available to market - 2004Glas BMC Genomics, 2006

Delahaye Pers. Med 2013

Independent validation: TRANSBIG Buyse

JNCI 2006

RASTER Study Bueno – de Mesquita, Lancet Oncol 2007

Drukker, Int. Journal of Canc 2013

Pilot MINDACT 1st 800 patients Rutgers, Eur J Cancer 2011

MINDACT ResultsPrimary Endpoint analysisNEJM, august 2016

Agendia founded –July 2003

MammaPrint• Regulatory

• Reimbursement

• Guidelines

• Adoption

Validada en > de 12.000 pacientes

• Todos los grupos de edad• Tumores primarios pequeños• N0-N1 (1-3)• ER +/-• HER2 +/-• Fresco y Parafina

Diseño del estudio MINDACT (n = 6,693)N0, N1 (1 a 3 ganglios), T 1-3

Bajo riesgo clínico: SLE específica a 10 años > 88% si ER+ o > 92% si ER-

Características de los pacientes

• N 6.693p

• N0: 80% (4.225p) / N1: 20%

• HER2+: 10%

Características de los pacientes

• N 6.693p

• N0: 80% (4.225p) / N1: 20%

• HER2+: 10%

Grupos de riesgo

• cLow / gLow: 41% (2.700 p)

• cLow / gHigh: 9% (602 p)

• cHigh / g Low: 23% (1.540 p)

• cHigh / gHigh: 27% (1.800 p)

Características de los pacientes

• N 6.693p

• N0: 80% (4.225p) / N1: 20%

• HER2+: 10%

Grupos de riesgo

• cLow / gLow: 41% (2.700 p)

• cLow / gHigh: 9% (602 p)

• cHigh / g Low: 23% (1.540 p)

• cHigh / gHigh: 27% (1.800 p)

DMFS 5 años

• 97% (98,45 si N0)

• 95,4%

• 95%

• 91,7%

Características de los pacientes

• N 6.693p

• N0: 80% (4.225p) / N1: 20%

• HER2+: 10%

Grupos de riesgo

• cLow / gLow: 41% (2.700 p)

• cLow / gHigh: 9% (602 p)

• cHigh / g Low: 23% (1.540 p)

• cHigh / gHigh: 27% (1.800 p)

DMFS 5 años

• 97% (98,45 si N0)

• 95,4%

• 95%

• 91,7%

Con QT: 95,9%

Sin QT: 94,7%IC95% (92,5%-96,2%)

ESTUDIO POSITIVO(H0 92%)

Características de los pacientes

• N 6.693p

• N0: 80% (4.225p) / N1: 20%

• HER2+: 10%

Grupos de riesgo

• cLow / gLow: 41% (2.700 p)

• cLow / gHigh: 9% (602 p)

• cHigh / g Low: 23% (1.540 p)

• cHigh / gHigh: 27% (1.800 p)

DMFS 5 años

• 97% (98,45 si N0)

• 95,4%

• 95%

• 91,7%

Con QT: 95,8%

Sin QT: 95,0%

Adapted from Sorlie, T. et al. Proc. Natl Acad. Sci. USA 100, 8418–8423 (2003).

Plataformas Genómicas e información biológica

Parker JS, et al. J Clin Oncol. 2009;27(8):1160-1167.

ROR-C (tumor size and subtype model)

scores categorize intrinsic subtypes

• Decisiones en quimioterapia

Ganglios Negativos: Identifica un grupo (50%) de bajo riesgode recurrencia a 10 años (<4%)

Ganglos Positivos: Identifica un grupo (50%) de bajo riesgode recurrencia (<5%)

Neaoadyuvancia: Asociacion a respuesta a quimioterapia/trastuzumab.

Recurrencia Tardia: Predice recurrencia entre lo 5-10 añosen RH +

Radioterapia: Recurrencia Local: Predice recurrencia local

Prosigna

Prosigna Estudios Prospectivos• UK OPTIMA: Randomizes 4,500 HR+/N+ patients to test-directed chemotherapy vs.

standard of care (chemotherapy).

OPTIMAprelim study compared 5 tests including ODX

Prosigna selected by NHS as only test included in the OPTIMA main study

• ECOG EA1131: Randomizes patients with residual TN disease after neoadjuvant

chemotherapy to adjuvant carboplatin or standard of care.

• NeoPAL: French study randomizes Luminal B (and N+ Luminal A) patients to a

combination of Palbociclib + Letrozole vs chemotherapy.

• PRECISION: Dana Farber study where radiation will be omitted in Prosigna ‘Low Risk’

patients (Target local recurrence rate: <5% at 5years).

• EXPERT: ANZBCTG study where Prosigna ‘Low Risk’ patients are randomized to

breast irradiation after surgery.

• PAMELA: Evaluate the ability of the HER2-E subtype to predict pathological completeresponse (pCR) in the breast (ypT0-is) in all patients (ITT population) at the time ofsurgery.

HER2+

Breast Cancer

Stage I-IIIA

Adjuvant systemic treatment was at the

discretion of the treating physician

Trastuzumab 6 mg/kg every Trastuzumab 6 mg/kg every 3 weeks

Lapatinib 1000 mg/day

+ Letrozole or Tamoxifen if HR+

18 weeksN=150SURGERY

BaselinePAM50

Week 2PAM50

Week 6Ultrasoun

d

PAMELA

Intrinsic subtype at baseline vs. pCRBaseline samples (N=151)

Prat A, et al. San Antonio Breast Cancer Conference (SABCS); 2016; San Antonio, TX: Conference

Presentation.

DECISIONES DE ESTRATEGIA TERAPEUTICAS

GANGLIOS POSITIVOS

NEOADYUVANCIA

QT/RT/HT/TERAPIAS DIRIGIDAS

MUCHAS GRACIAS