nuevas perspectivas en hormonoterapia cÁncer de … · 117 san antonio breast cancer symposium -...
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NUEVAS PERSPECTIVAS en HORMONOTERAPIA CÁNCER DE MAMA
Mª José Echarri Gonzalez
Oncología Médica
Hospital Severo Ochoa
6/3/13
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INTRODUCCIÓN
Oestrogen
3000 BC 1500’s 1800’s
Cirugía
Sir George Beatson 1848–1933
HT
Beatson. Lancet 1896
Mejoría pacientes Ca. mama metastásico tras ooforectomía 1960s: descubrimiento receptor de estrógeno (ERα)
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>1 millon/año mujeres dx Ca. mama
WHO/IARC World Cancer Report 2003 Prat and Perou Molecular Biology 2010
Cómo tratamos al mayor grupo de Cáncer de mama?
700.000 Ca. Mama HR+
INTRODUCCIÓN
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-75% Ca. Mama infiltrantes son ER+ y/o PR+ -Definición: por IHQ > 1% celulas -Tamoxifeno: disminución riesgo recaída (40%) y mortalidad (30%) -IA tercera generación (“upfront”, secuencial, extendido): disminuyen más riesgo de recaída -Ambito metastásico: largas respuestas al tratamiento hormonal. Mayoría: supervivencia media < 3 años
-Biología receptor estrógeno: mecanismos resistencia a tratamientos hormonales
Eric P. Winer, SABCS 2011
INTRODUCCIÓN
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SABCS 2012 Saphner 1996
Recaídas tardías: 50% recaen 6-15 años tras el diagnóstico
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Grupo heterogéneo de pacientes
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FARMACOS DISPONIBLES Bloqueo del receptor
SERM (selective estrogen receptor modulators)
TAMOXIFENO
Reducción de síntesis
Inhibidores de aromatasa
- Esteroideos: EXEMESTANO
- No esteroideos: ANASTROZOL, LETROZOL
Ablación de función ovárica
OOFORECTOMÍA, RADIOTERAPIA,
ANÁLOGOS LHRH
Degradación del receptor
FULVESTRANT
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OPORTUNIDADES MEJORA
DEFINICIÓN ADYUVANCIA
NEOADYUVANCIA METÁSTASICO
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Recommendation
Optimal algorithm
for ER/PgR testing
Positive for ER or PgR if finding of ≥ 1% of tumor cell nuclei
are immunoreactive
Negative for ER or PgR if finding of < 1% of tumor cell
nuclei are immunoreactive in the presence of evidence that
the sample can express ER or PgR (positive intrinsic
controls are seen)
JCO June 1, 2010, Vol 28:16 Allred Mol Oncol 2010
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ADYUVANCIA Premenopausia Postmenopausia
Bifosfonatos
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JCO Feb 2008
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¿Necesitarán distinto tto
primeros 5 años?
¿ Necesitarán tto durante > 5 años
(terapia extendida)?
Elgene Lim Oncology Aug 2012
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94% vs 91% HR 0.68 p 0.001
Annals of Oncol 2008 Ingle
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Tamoxifeno x 5 años ?
Tamoxifeno x 5 años ?
Tamoxifeno x 5 años ?
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N= 1065 Postmenopausicas ER/PR POSITIVAS Estadio I-IIIA Endpoint 1º: cambio DMO a los 12 meses (columna) Endpoint 2º: SLP
LETROZOL 2.5 mg/24h x 5 años
Zoledrónico inmediata 4 mg/6 meses x 5 años
Zoledrónico retardada 4 mg/6 meses x 5 años
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NEOADYUVANCIA
CANCER DE MAMA cirujanos
operar
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-Valorar neoadyuvancia: facilitar cirugía conservadora; INFORMACIÓN PRONÓSTICA (pCR). -Tumores HR positivos y Ki67 bajo: NO RECOMIENDAN QT NEOADYUVANTE -Tratamiento neoadyuvante HORMONAL: pacientes postmenopáusicas, RRHH muy + puede ser opción (mantener hasta máxima respuesta o mínimo 4-8 meses): tasas respuesta clínica 36-74%
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Luminal: ER+,PR+ Her-2- CK8/18 +
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End point 1º: tasa respuesta clínica (Evaluación MRI)
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RR QT 66% vs HT 48% p 0.075 cRR QT 13% vs HT 6%
Toxicidad g3-4 47% QT vs 9% HT (hematologica, digestiva, NPF) p 0.001
61%
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Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for
premenopausal breast cancer (STAGE): a double-blind, randomised phase 3
trial
The Lancet Oncol Volume 13, Issue 4, April 2012, Pages 345–352
ER+ (> 10%), Her-2 – T2N0 M0 End point 1º: tasa respuesta clínica (exploración) Rama Tam: disbalance g3
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Efectos secundarios: mayor pérdida de DMO rama anastrozol
The Lancet Oncol Volume 13, Issue 4, April 2012, Pages 345–352
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SI NO ES CANDIDATA A QUIMIOTERAPIA ADYUVANTE…….
NO ES CANDIDATA A QUIMIOTERAPIA NEOADYUVANTE
Pre-m, Ki 67 alto, alto grado QT neoadyuvante?
Post-m, Ki 67 bajo, bajo grado HT neoadyuvante?
RR clínica: Tam: 36%, Letrozol 55-74%, Anastrozol 69%, Exemestano 63%
Eiermann W. Ann Oncol 2001; 12: 1527–32. Ellis MJ, ACOSOG Z1031. J Clin Oncol 2011; 29: 2342–49
ERA FIRMAS GÉNICAS
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TAMOXIFENO PREVIO IA 3ª
Tamoxifeno vs Andrógenos, DES, Acetato megestrol, IA 1-2ª generación: mismo efecto, mejor perfil toxicidad
Tamoxifeno vs otros SERMs (toremifeno, droloxifeno): mejor Tamoxifeno ORR y PFS
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TAMOXIFENO vs IA 3ª
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TAMOXIFENO vs IA 3ª
HR 0.87 p 0.001
IA 3º generación tratamiento estándar primera línea CMM
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RESISTENCIA
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MÁS ALLÁ TAM Y IA
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CMM postmenopausicas no tto hormonal previo
(1ª línea) ER +,PR + (n=587)
Endpoint: TTP Randomizacion 1:1
Fulvestrant 250 mg i.m. 1 vez/mes (cada 28 días) (n=313)
A
Tamoxifeno 20 mg/día (n=274)
FULVESTRANT 1ª línea
JCO 2004 Vol 22: 9
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TTP Fulvestrant 8.2
meses Tamoxifeno 8.3
meses HR 1.1 (p=0.39)
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HR 0.72
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CMM postmenopausicas ER +, PR + Tratamiento previo con un inhibidor aromatasa (IA) no esteroideo Endpoint: TTP N=693
Fulvestrant dosis carga 500 mg
i.m. Día 1, 250 mg día 14 y día
28 y posteriormente 250 mg
1vez/mes (cada 28 días) (n=351) A
Exemestano 25 mg/día
(n=342)
FULVESTRANT 2ª línea
JCO 2008 Vol 26;10
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TTP (meses) 3.7 Fulvestrant 3.7 Exemestano
HR 0.96 (IC 95% 0.81-1.13 p=0.65)
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Respondedor: Progresión tras ≥ 2 años de tto HT adyuvante o duración respuesta ≥ 24 semanas al tto HT 1ª línea
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CONFIRM: AE
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Fases III
FIRST: Fase II
FIRST: Fase II
CONFIRM: respondedoras menor beneficio?
CONFIRM: peor respondedoras mayor beneficio?
CONFIRM: peor respondedoras mayor beneficio?
CONFIRM: respondedoras menor beneficio?
FIRST: Fase II
Recaída precoz
Recaída precoz
Recaída tardía
Recaída tardía
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DOBLE BLOQUEO HORMONAL 1ª
CMM postmenopausicas (1ª línea) ER +,PR +
(n=514) Endpoint: TTP
Randomizacion 1:1
Fulvestrant 500 mg i.m. día1, 250 mg día 14 y 28 1vez/mes (cada 28 días) +
Anastrozol 1 mg/24h (n=258)
A
Anastrozol 1 mg/día (n=256)
JCO
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JCO
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JCO
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JCO
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DOBLE BLOQUEO HORMONAL 1ª
SWOG S0226
CMM postmenopausicas (1ª línea) ER +,PR + (n=
695) Endpoint: TTP
Randomizacion 1:1
Fulvestrant 500 mg i.m. día1, 250 mg día 14 y 28 1vez/mes (cada 28 días) +
Anastrozol 1 mg/24h (n=350)
A
Anastrozol 1 mg/día (n=345)
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SWOG S0226
No se permitía crossover
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SWOG S0226
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DOBLE BLOQUEO HORMONAL
MISMO ESQUEMA-DIFERENTES RESULTADOS
-Diferente población: americana vs europea (obesidad?) -Tratamiento previo Tamoxifeno? 69% vs 40% -Primera línea sin tratamientos hormonales previos? 30% vs 36% -IA previos: 1% vs no se especifica?
¿¿¿ PUEDE SER OPCIÓN 1ª LÍNEA ???
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Faslodex® Exemestano
IANE
IANE Placebo
+ +
Criterios de inclusión: • CMM post-M con RE+ y/o RP+
• Progresión con IANE: - Como tratamiento adyuvante
(>12 meses de tto) 18%
- Respuesta > 6 meses en 1ª línea para CMM (82%)
N= 723
Ensayo aleatorizado fase III: Faslodex® con o sin tratamiento continuado con un inhibidor de la aromatasa no esteroideo frente a exemestano en mujeres postmenopáusicas con cáncer de mama avanzado y RE+ o RPg+ que ha progresado a un IANE
Objetivos primarios: PFS • PFS con F+A frente a F • PFS con F frente a E
Faslodex®
DOBLE BLOQUEO HORMONAL 2ª
SLP: 4.8 meses SLP: 4.4 meses
SLP: 3.4 meses
EBCC 8 Vienna 2012
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TTP: 6 meses
Fulvestrant 250 mg/mes im +
Goserelina 3.6 mg sc
1vez/mes (n=26)
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mTOR inhibidores
Mutacion 20-25%
Perdida expresión 35%
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Progresión a Letrozol/anastrozol: ≤ 12 meses tras finalizar ady ≤ 1 mes tras finalizar tto 1ª línea
Sensible: Progresión tras ≥ 2 años de tto HT adyuvante o duración respuesta ≥ 24 semanas al tto HT 1ª línea
Endpoint 1º: SLP
2
1
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80% 2ª línea
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Abandono tto: 19% para E + E vs 4%
Duración tto: 17 semanas E + E vs 12 semanas E
Principal causa discontinuación:
PROGRESIÓN
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N= 57
N= 54
Endpoint 1º: tasa beneficio clínico
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70% 2ª línea
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RESISTENCIA PRIMARIA
RESISTENCIA SECUNDARIA
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32 meses
No alcanzado
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7% 22%
Duración tto: 6.5 meses T + E vs 4.8 meses T
Principal causa discontinuación:
PROGRESIÓN
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CMM postmenopausicas (1ª línea) ER +,PR + (n=
1112) Endpoint: PFS
Randomizacion 1:1
Temsirolimus 30 mg/día oral x 5 días cada 2 semanas + Letrozol 2.5 m/día
continuo (n=556)
A
Letrozol 2.5 mg/día (n=556)
HORIZON TRIAL
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mTOR inhibidores
TEMSIROLIMUS ORAL ≠ TEMSIROLIMUS IV
TEMSIROLIMUS ORAL ≠ EVEROLIMUS ORAL
(-) mTOR eficaces tras progresión a IA no esteroideo
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Dudas postBOLERO-2
-¿Qué pacientes son más sensibles a everolimus?: resistencia secundaria, todos?
-¿Es eficaz everolimus en primera línea?: BOLERO-4 (Phase II, Study of Everolimus Plus Letrozole in Postmenopausal Women With ER+ Metastatic Breast Cancer (Bolero-4): first line)
-¿Es necesario el exemestano?: BOLERO-6 (Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer. (BOLERO-6): after progression on letrozole or anastrozole)
-¿Exemestano + Everolimus es mejor que quimioterapia o Fulvestrant 500?
-¿Antes o después Fulvestrant?
-¿Everolimus sirve para pacientes Pre-menopáusicas? BOLERO-young
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Fases III
FIRST: Fase II
FIRST: Fase II
CONFIRM: respondedoras menor beneficio?
CONFIRM: peor respondedoras mayor beneficio?
CONFIRM: peor respondedoras mayor beneficio?
Recaída precoz
Recaída precoz
Recaída tardía
Recaída tardía
BOLERO-2 Exemestano + Everolimus
Exemestano + Everolimus
BOLERO-2
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BOLERO-2 Exemestano + Everolimus
Tamoxifeno
Exemestano + Everolimus
ILE corto
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ANTIANGIOGÉNICOS
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ER+/PR+ CMM primera línea (n~360)
Placebo + letrozol o tamoxifeno
Bevac.15mg/kg/3s
+ Letrozol o tamoxifeno
Bevacizumab en combinación con hormonoterapia CALGB 40503
Tratamiento hasta progresión
ANTIANGIOGÉNICOS
ClinicalTrials.gov Identifier: NCT00601900
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ANTIANGIOGÉNICOS
N= 20
N= 10
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INHIBIDOR DE IGF-1
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INHIBIDORES EGFR
No habían recibido tratamiento hormonal previo pero sí QT
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INHIBIDORES EGFR
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AntiHer-2 + Hormonoterapia
Menos eficaz que QT + AntiHer-2
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117
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Abstract S1-6
Results of a Randomized Phase 2 Study of
PD 0332991, a Cyclin-Dependent Kinase (CDK)
4/6 Inhibitor, in Combination with Letrozole vs
Letrozole Alone for First-Line Treatment of
ER+, HER2– Advanced Breast Cancer (TRIO-18)
RS Finn,1 JP Crown,2 I Lang,3 K Boer,4 IM Bondarenko,5 SO Kulyk,6 J Ettl,7 R Patel,8 T Pinter,9 M Schmidt,10 Y Shparyk,11 AR Thummala,12 NL Voitko,13 A Breazna,14
ST Kim,15 S Randolph,15 DJ Slamon1
1University of California Los Angeles, Los Angeles, CA, USA; 2Irish Cooperative Oncology Research Group, Dublin, Ireland;
3Orszagos Onkologiai Intezet, Budapest, Hungary; 4Szent Margit Korhaz, Onkologia, Budapest, Hungary; 5Dnipropetrovsk City Multiple-Discipline Clinical Hospital, Dnipropetrovsk, Ukraine; 6Municipal Treatment-and-
Prophylactic Institution, Donetsk, Ukraine; 7Technical University of Munich, Munich, Germany; 8Comprehensive Blood and Cancer Center, Bakersfield, CA, USA; 9Petz Aladar Megyei Oktato Korhaz, Gyor, Hungary; 10University Hospital
Mainz, Mainz, Germany; 11Lviv State Oncologic Regional Treatment and Diagnostic Center, Ukraine; 12Comprehensive Cancer Centers of Nevada, Henderson, NV, USA; 13Kyiv City Clinical Oncology Center, Ukraine; 14Pfizer Oncology, New
York, NY, USA; 15Pfizer Oncology, La Jolla, CA, USA
Presented at SABCS 2012; December 5, 2012; San Antonio, TX, USA
INHIBIDOR CICLO CELULAR
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118
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Rb as Master-Regulator of the R-point
118
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119
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Phase 2 Design
N = 66
1:1
Part 1
R
A
N
D
O
M
I
Z
A
T
I
O
N
PD 0332991
125 mg QDa +
Letrozole
2.5 mg QD
Letrozole
2.5 mg QD
Part 2
N = 99
1:1
ER+, HER2–
BC with
CCND1 amp
and/or
loss of p16
R
A
N
D
O
M
I
Z
A
T
I
O
N
PD 0332991
125 mg QDa +
Letrozole
2.5 mg QD
Letrozole
2.5 mg QD
a Schedule 3/1.
Stratification Factors
• Disease Site (Visceral vs Bone only vs Other)
• Disease-Free Interval (>12 vs ≤12 mo from end of
adjuvant to recurrence or de novo advanced disease)
ER+, HER2–
BC
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San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Baseline Characteristics (ITT) PD 991 + LET
(n = 84)
LET
(n = 81)
Median Age, years (range) 62 (41 – 89) 64 (38 – 84)
ECOG PS, n (%)
0
1
46 (55)
38 (45)
45 (56)
36 (44)
Disease Stage
Stage IIIB
Stage IV
Other
3 (4)
80 (95)
1 (1)
6 (7)
75 (93)
0
Disease Site
Visceral
Bone only
Other (Non-Visceral)
37 (44)
18 (21)
29 (34)
43 (53)
12 (15)
26 (32)
Disease-Free Interval, n (%)
>12 mos from adjuvant to recurrence
≤12 mos from adjuvant to recurrence
or de novo advanced disease
24 (29)
60 (71)
30 (37)
51 (63)
Prior Systemic Treatment, n (%)
None
Chemotherapy
Hormonal
Tamoxifen
Anastrozole
Letrozole
Exemestane
44 (52)
34 (40)
26 (31)
23 (27)
8 (10)
2 (2)
4 (5)
37 (46)
37 (46)
28 (35)
24 (30)
11 (14)
1 (1)
2 (2)
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San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Best Overall Response (ITT)
PD 991 + LET
(n = 84)
LET
(n = 81)
All randomized patients, n
Objective Response Rate, % (95% CI)
Complete Response, n (%)
Partial Response, n (%)
84
34 (24, 46)
0
29 (34)
81
26 (17, 37)
1 (1)
20 (25)
Patients with measurable disease, n (%)
Objective Response Rate, % (95% CI)
Complete Response, n (%)
Partial Response, n (%)
64 (76)
45 (33, 58)
0
29 (45)
65 (80)
31 (20, 43)
0
20 (31)
Stable Disease ≥24 weeks, n (%) 30 (36) 15 (18)
Clinical Benefit Rate, n (%)* 59 (70) 36 (44)
Stable Disease <24 weeks, n (%) 14 (17) 22 (27)
Progressive Disease, n (%) 3 (4) 17 (21)
Indeterminate, n (%) 8 (10) 6 (7)
* Complete response + partial response + stable disease ≥24 weeks.
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San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Progression-Free Survival PD 991 + LET
(n = 84)
LET
(n = 81)
Number of Events (%) 21 (25) 40 (49)
Median PFS, months
(95% CI)
26.1
(12.7, 26.1)
7.5
(5.6, 12.6)
Hazard Ratio
(95% CI)
0.37
(0.21, 0.63)
P value <0.001
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Time (Month)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
gre
ss
ion
-Fre
e S
urv
iva
l P
rob
ab
ilit
y
84 75 60 53 43 35 25 18 15 14 9 5 3 1 PD991+LET 81 57 38 29 22 17 11 6 5 4 3 3 1 1 LET
Number of patients at risk
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San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Most Common Treatment-Related
AEs ≥10% (AT)
PD 991 + LET
(n = 83)
LET
(n = 77)
Grade 1/2 Grade 3 Grade 4 Grade 1/2 Grade 3 Grade 4
Neutropenia 19 46 5 1 1 0
Leukopenia 24 14 0 0 0 0
Anemia 19 4 1 0 0 0
Fatigue 17 2 0 13 0 0
Alopecia 18 0 0 3 0 0
Hot flush 17 0 0 10 0 0
Arthralgia 16 0 0 10 0 0
Nausea 12 2 0 1 0 0
Thrombocytopenia 11 1 0 0 0 0
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San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center - December 4-8, 2012
Conclusions
• The combination of PD 0332991 and letrozole compared with
letrozole alone continues to show statistically significant
improvement in median PFS in patients with ER+/HER2– breast
cancer
• These results confirm the preclinical observations made with
PD 0332991 in breast cancer models
• The combination is generally well tolerated, with uncomplicated
neutropenia as the most frequent adverse event
• A randomized phase 3 study is planned to start in early 2013
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CONCLUSIONES
-Opciones de mejora en todos los escenarios -Amplia pero heterogénea población Ca. Mama -Adyuvancia: tratamiento extendido (recaídas tardías): qué y a quién -Neoadyuvancia: comportamiento biologico in situ, retraso ensayos QT neoadyuvante -Mejores opciones de tratamiento CMM ER+ -Avances: aprobación nuevos fármacos (Fulvestrant 500 mg, mTOR (-)): mejora y “complicación” decisión tratamiento -Promesas: inhibidores ciclos celular