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