HORMONOTERAPIA EN CANCER DE MAMA

HORMONOTERAPIA EN CANCER DE MAMA DR MARCO ANTONIO GARCIA HERNANDEZ R3OMTEMARIO

PERSPECTIVA HISTORICAHay relacin entre la funcin ovrica y el cncer de Mama?

Thomas William Nunn (1882) inform por primera vez un casoDe regresin espontnea meses despus de la menopausia

Albert Schinzinger (1889) propuso ooforectoma quirrgicaEn el tratamiento y como profilaxis contra la recurrencia local ~

George Thomas Beatson (1896) inform de dos pacientesCon remisin en enfermedad inoperable despus de ooforectoma *Sex Hormone Receptors in Breast Cance. Nina DAbreo, Alexander A. Hindenburg. Vitamins and Hormones, Volume 93. 2013

~ No fue adoptada como practica * La castracin fue popularmente utilizada para prolongar la lactancia y crea que el tumor mamario tendra una degeneracin grasa despus de la ooforectoma lo que ocurra con las vacas. En su estudio el dio a los paciente extractos de glndulas tiroideas por lo que no pudo precisar cual de las dos intervenciones era la causa de la regresin tumoral. 3PERSPECTIVA HISTORICAStanley Boyd, que haba observado el trabajo de Beatson Inform los resultados de 54 pacientes con ooforectoma Entre ellos la primera ooforectoma adyuvante, en 1897

Fue el primero en sentenciarLa relacin de la funcin ovrica y el cncer de mamaUn tercio se beneficiabaLa mayora recae a los 6-12 meses *

En la dcada de 1950 , Charles HugginsReintrodujo la ooforectoma en combinacin con adrenalectomaEn enfermedad localmente avanzado y metastsica

Sex Hormone Receptors in Breast Cance. Nina DAbreo, Alexander A. Hindenburg. Vitamins and Hormones, Volume 93. 2013

* Hubo un gran periodo de descanso sobre todo por las complicaciones de la ooforectoma y por la introduccin de la RT en 1905 como mtodo de castracin.4PERSPECTIVA HISTORICAIdentificacin del 17-b estradiol (E2) Establece las bases para el desarrollo de estrgenos sintticos

Sir Alexander Haddow (1944) introdujo la primera terapia Utiliz estrgenos de origen (trifeniletileno) no esteroideo en dosis altas Una aparente paradoja al efecto de la ablacin ovrica

En los aos 60, se descubre un antiestrogeno (trifeniletileno) no esteroideoEfecto anti estrgeno en presencia de estrgenos exgenos *Efecto uterotrofico a dosis mas latas ~

TAMOXIFEN

Primer terapia blanco aprobada para el cncer de mama metastsico Sex Hormone Receptors in Breast Cance. Nina DAbreo, Alexander A. Hindenburg. Vitamins and Hormones, Volume 93. 2013

Al mismo tiempo, desde la primera mitad del siglo XX, hubo un creciente inters por los mtodos no quirrgicos de la supresin hormonalEn los aos 20 se demostr en ratas con oforectoma el efecto de una sustancia extrada del los folculos ovricos que posteriormente se supo que era Estradiol* Inihibia la cornificacion vaginal, la implantacin del vulo no se sabia si por inhibir la produccin o por inhibir la absorcin por algunos receptores~ Comportamiento importante para el reconocimiento posterior de la modulacin selectiva ER

5RECEPTOR DE ESTROGENO A finales de 1950, Elwood Jensen sintetizo 6,7 - (3H)-estradiol

Estrgeno altamente especfico

Demostr que estradiol (marcado) era afn a algunos tejidos El tero, la vagina, y la pituitaria anterior *

Extrajo una protena que se une al estradiol citoslico ~Receptor de estrgeno ER Sex Hormone Receptors in Breast Cance. Nina DAbreo, Alexander A. Hindenburg. Vitamins and Hormones, Volume 93. 2013

* Pero no a msculo, corazn y pulmones~ Demostrando el efecto trfico en el tero y que este poda ser inhibido al disminuir el consumo por un antiandrogeno, dando evidencia que era un verdadero receptor

6SINTESIS DE ESTROGENOS

HORMONOTERAPIA ADYUVANTE

Relevance of breast cancer hormone receptors and otherfactors to the effi cacy of adjuvant tamoxifen: patient-levelmeta-analysis of randomised trialsEarly Breast Cancer Trialists Collaborative Group (EBCTCG)

Lancet 378:771, 2011

En las pacientes con RHs positivos, la HT adyuvante tiene un impacto grande en la SG. El metaanlisis , recientemente actualizado, demuestr que, despus de 5 aos de tamoxifeno, la reduccin del riesgo de recurrencia fue del 0.53 en los primeros 5 aos y del 0.8 en los 5 aos siguientes. Sin embargo, la reduccin del riesgo de los aos 10-14 es de solamente 0.97, indicando que no existen beneficios o prdidas adicionales despus de los 10 primeros aos.La mortalidad por cncer de mama es reducida en aproximadamente un tercio en los primeros 15 aos despus del diagnstico (HR de 0.71 en los primeros 5 aos, 0.66 en los 5 aos siguientes y 0.68 de los aos 10-149Early Breast Cancer Trialists Collaborative Group (EBCTCGLancet 378:771, 2011

La reduccin del riesgo es sustancial, incluso en los casos con expresin marginal de RE, siendo independiente de la expresin de RP, edad, comprometimiento ganglionar y del uso de QT.

10Tiempo de Inicio de HormonoterapiaN= 1558PosmpT1-3N1-N2RH +MRM o LumpectomiaRT adyuvanteSWOG-8814- INT-0100N= 381 Tamoxifeno N= 590FAC - TamoxifenoN= 587FAC TFAC x 6 cada 4 semanasCiclofosfamida: 100 mg/m2 VO x 14ADR: 30 mg/m25-FU: 500 mg/m2SLE2 primarioMuerte SGEALancet 2009; 374: 205563Secuencial o Concomitante

Si existe indicacin para QT, la hormonoterapia debe ser administrada solamente despus del final de aquella. 11Tiempo de Inicio de HormonoterapiaLancet 2009; 374: 205563Tiempo( aos)Tiempo( aos)

Diferencia: 7%Diferencia: 7%Supervivencia libre de enfermedad (%)

Diferencia: 6%Supervivencia Global ( %) Mayor Beneficio:T< 5 cm Edad: < 65 aos N+= 4Favorece a Terapia Secuencial

BENEFICIO DE HORMONTERAPIA ADYUVANTETamoxifeno > ObservacinSupervivencia Libre de RecurrenciaMortalidad

QT + TMX > TMX

Beneficio hasta 10 aos de tratamiento: Beneficio en SLR y Mortalidad por Cncer< Incidencia de Ca Mama Contra lateral > Incidencia de Ca tero

Secuencial > ConcomitanteDiferencia en SLR: 7 % Diferencia el SG: 6 %

HORMONOTERAPIA EN PREMENOPAUSICASTAMOXIFENO

La separacin entre pacientes en la premenopausia y en la postmenopausia es tambin crtica en la eleccin de la hormonoterapia.Las pacientes deben ser orientadas para informar al mdico, en el caso que no estn presentes los sntomas tpicos de la menopausia, como calores o sequedad vaginal. Los niveles de estradiol en pacientes en tratamiento con un IA deben estar < 10 pmol/L14Tamoxifen After Adjuvant Chemotherapy for Premenopausal Women With Lymph NodePositive Breast Cancer: International Breast Cancer Study GroupTrial 13-93N= 1294 Pre - Qx previa. N+RH (+ )( -) (?)QT. ADR. 60 mg/m2CFA 600 mg/m2CFA 100 mg/m2 VO 1-14MTX 40 mg/m2 IV D1 y D 8 5-FU 600 mg/m2 IV D1 y D8 Gpo 1N= 622Gpo 2N=624TMX 20 mg x 5 aosGpo 2N=624

J Clin Oncol 24:1332-1341.2006

Supervivencia libre de enfermedadTiempo en aosTamoxifen After Adjuvant Chemotherapy for Premenopausal Women With Lymph NodePositive Breast Cancer: International Breast Cancer Study GroupTrial 13-93Mujeres menores de 40 aos, RE +HR: 0.59; 95% CI, 0.46 to 0.75

Tiempo en aos RE (-)J Clin Oncol 24:1332-1341.200641%

Tamoxifen After Adjuvant Chemotherapy for Premenopausal Women With Lymph NodePositive Breast Cancer: International Breast Cancer Study GroupTrial 13-93Supervivencia libre de enfermedadTiempo (aos)Amenorrea > 15 mesesMayor Beneficio > 35 aos vs < 3595 vs 42 % p=0.000111% recuperacin 18- 36 mes80 %65%Tamoxifeno: Beneficio en SLR diferencia 5 a. 13 %Mujeres con RE (-) : Deletreo ?Amenorrea :Impacto en SLR > 35 aosDiferencia 15 % a 5 a J Clin Oncol 24:1332-1341.2006

Beneficio en pacientes con amenorrea inducida por QT en pacientes con RH positiv17A randomized placebo-controlled study of tamoxifen after adjuvant chemotherapy in premenopausal women with early breast cancer (National Cancer Institute of CanadaClinical Trials Group Trial, MA.12)Annals of Oncology 21: 283290, 2010N= 672pT1-4p N1-2QX previaT>1 cmPLV G3RH +: 75%RH- 11%RH ?: 14 %CMF: 45%FEC: 22%AC: 33%

Tamoxifeno vs Placebo

SG(%)SLE(%)Tiempo ( Aos)SLR 5 (78 vs 71% HR=0.77 p=0.056) SG 5 (86 vs82% HR:0.78 p=0.12)Anlisis de subgrupoRE/RP+SLE: 80 vs 73% (HR0.82 p=0.05)SG: 90 vs 85% (HR=0.83 , p=0.04)

PREMENOPAUSICASUPRESIN OVRICA

El uso de la supresin ovrica es tema controvertido 19

Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials Lancet 2005; 365: 16871717Recurrencia: 4 .3 %Mortalidad por Cncer: 3.2 %Tiempo (aos)Tiempo (aos)

Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trialsLancet 2007; 369: 171123Valorar el uso de Agonistas LHRH en tratamiento adyuvante: 16 estudiosnica modalidad de tratamientoVs QT + QT+TamoxifenoQT+TMXVs QT+TMXRE y RP + Edad : 40 45TT > 2 cm . 50%N+2 aos: Goserelina: 143Triptorelina: 2Leuprorelina: 1CMF: 66%Antra: 32 % No taxanosRecurrencia Muerte despues de la Recurrencia

Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trialsLHRH vs Ninguna terapia sistmicaRecurrenciaMuerte despues de la RecurrenciaLancet 2007; 369: 171123

Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials

RecurrenciaLHRH vs LHRH + TAM

Muerte despues de la RecurrenciaLancet 2007; 369: 171123

23

Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trialsRecurrenciaMuerte despues de la RecurrenciaDoble Bloqueo Hormonal Lancet 2007; 369: 171123

La adicin de supresin ovrica con anlogo de LHRH para aquellas tratadas con QT y tamoxifeno no reduce de forma significativa la recidiva (15.9% de reduccin, p=0.37) o la muerte despus de recidiva (32.6% de reduccin, p=0.4), segn el metaanlisis de 2007.

Un anlisis de subgrupo, el cual incluysolamente pacientes con menos de 40 aos, mostr una reduccin de riesgo de recidiva del 32%, pero no alcanz significancia estadstica (p=0.12).

24

QT(TAM +-)Agregar LHRHRecurrenciaUse of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trialsRecurrenciaLancet 2007; 369: 171123QT + TAM + LHRHQT vs LHRH12%Recurrencia (%)Tiempo ( aos)Tiempo ( aos)

QT ( TAM + - ) LHRH15%

PREMENOPAUSICAINHIBIDORES DE AROMATASA

Endocrine Therapy plus Zoledronic Acidin Premenopausal Breast Cancer. ABCSG-12N= 1803PremenoEC I IIRH +< 10 N+N= 451Goserelina + TAMN= 451Goserelina + TAM + Ac. ZoledronicoN= 453Goserelina + AnastrozolN= 450Goserelina + Anastrozol + Ac. Zoledronico1:1:1:1SLE SLPSGDensidad seaN Engl J Med 2009;360:679-91.

El papel del cido zoledrnico como agente antineoplsico en la adyuvancia es, en el momento, altamente controvertido. Utilizando un diseo factorial 2 x 2, el estudio austraco ABCSG-12 evalu especficamente el papel de este medicamento en la adyuvancia y en pacientes premenopusicas.

Explotando dos preguntas: 1) si el anastrozol en adicin a la supresin ovrica con goserelina es superior al tamoxifeno ms goserelina, ambos administrados por 3 aos; y 2) si el cido zoledrnico (4 mg, IV, de 6/6 meses, por 3 aos) tiene la capacidad de reducir la recidiva del cncer de mama.27

Caractersticas EdadEstado GanglionarEC Grado Histolgico Expresin de los receptores Estrgeno Expresin de los receptores ProgesteronaQT preoperatoria

Endocrine Therapy plus Zoledronic Acidin Premenopausal Breast Cancer. ABCSG-12EventosGlobalRecurrenciaLocoregional

DistanciaMets Oseas

Cncer de mama contra lateralSegundo Primario

MuerteGlobal

Sin recurrencia previa TAM vs Anastrozol Sin Diferencias en SLENo impacta en SG y SLR

La actualizacin de este estudio despus de seguimiento mediano de 62 meses mostr que el anastrozol no fue superior al tamoxifeno. La adicion de zometa redujo el RR de recurrencia 34%, redujo los eventos de recaida locorregional, metstasis a distancia (seas y no seas) y cncer en la mama contralateral. En el seguimiento mediano de 84 meses, no hubo aumento de toxicidad renal u osteonecrosis de mandbula asociada al rgimen de cido zoledrnico y en un anlisis exploratorio los beneficios del bisfosfonato parecen restringirse a la poblacin de pacientes con ms de 40 aos29CONCLUSIONES PREMENOPAUSICAS:Tamoxifeno: Tratamiento estandarMayor beneficio en menores de 40 aos con RE +

Supresin Ovrica:Agonistas LHRH > Observacin QT + TMX + LHRH beneficio en SLR y Mortalidad (p=0.004)

Inhibidores de Aromatasa: No ofrecen beneficio vs TamoxifenoTerapia combinada con agonistas LHRH

30ADYUVANCIA POSMENOPAUSICAS

Long-Term Benefits of 5 Years of Tamoxifen: 10-Year Follow-Up of a Large Randomized Trial in Women at Least 50 Years of Age With Early Breast Cancer. Cancer Research UK J Clin Oncol 29:1657-1663. 2011N=3449T: 1-3N: 0-1Pos Qx - RT DRAmTT: 2 cm 1987 -1997N= 1724 20 mg Tamoxifeno x 2 aosN= 172520 mg Tamoxifeno x 5aosRecurrenciaSupervivenciaEventosCardiovascularesTamoxifeno 5a HRpRecurrencias0.830.003Muerte Especfica0.910.22Muerte post-recada0.860.03Ca Mama Contralat0.700.03Ca Endometrial1.100.56

CONCLUSIONESTamoxifeno 5 aos > 2 aos17% Menos Recurrencias9% Menos Muertes (SD)Menos muertes x Eventos CV (50-59a)Menos Ca Mama Contralateral

Muerte x Ca mama

INHIBIDORES DE AROMATASA

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trialN= 9366

Edad m: 64 aIMC: 27 N (-) 60 %N (+) 30 % TTm. < 2 cm : 63 %RH +: 83 %Qx: 47 % RT: 63 %QT. 22 %

N = 3125Anastrozol 1 mg N= 3116TamoxifenoN= 3125Anastrozol + Tamoxifeno1:1:1SLETiempo a la recurrencia(contralateral)Supervivencia GlobaRecurrencia a distancial

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial

1er eventoLocalDistanciaCa mama ContralateralInvasivoDuctalIn situMuertes

Total

2 Evento DistanciaMuerte

Total de muertesDistribucin de eventos por grupo de tratamientoLancet 2002; 359: 213139ParmetroEventosHRPSLE735 vs 8240.860.003Contra lateral62 vs 960.620.003T. a recurrencia456 vs 5580.790.0002Muerte por cncer284 vs 3200.870.09Recurrencia a distancia352 vs 4080.850.02Seguimiento a 10 aos IA vs TAMLancet Oncol 2010; 11: 113541

Subgrupos beneficiados:

Todos los pacientesTamao del tumor

Grado del tumor

Receptores de estrgenos

RH

EdadHisterectomiaHRTCiruga definitiva

Axila

Radioterapia

QT previa

IMCEstado ganglionar

65a

THR

Sin RTSin QT

2 cm: 36 %N+: 41 % N-: 57%RE/RP +: 63%RE +/RP -: 20 %CC + RT: 53% MT + RT: 18 %MT RT: 25 %QT: 25 %Sin QT : 74 % SLESLEN= 4922 N Engl J Med 2005;353:2747-57.

39VariableLet vs TamHRpSLE76 vs 72%0.820.002SG85 vs 81%0.790.0006SLE sistmica88 vs 85%0.790.003SL falla local84 vs 81%0.800.002

Anlisis por desenlaceRecurrencia (%) Tiempo ( aos )A Comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast CancerThe Breast International Group (BIG) 1-98 Collaborative GroupT> 2 cm Edad: > 65 aos N: + QX: Mastectomia QT : + R: (-) HR: 0. 75 ( IC 0.61 -0.88) pP 0.001N Engl J Med 2005;353:2747-57.

40Assessment of letrozole and tamoxifen alone and insequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 81 years median follow-up

N = 619EventoLetrozol Tamoxifen(n=2463) (n=2459)

Total de pxDFSIPCWITTSGIPCWITTRecurrencia DistanciaIPCWITTIntervalo libre Ca MamaIPCWITT

Recurrencia (%) Tiempo ( aos )SVLE 8 aos (76 vs 72%)Ltz vs Tmx HR 0.82 (p4 Ganglios (+)No HT previaNo QT previa

TAM EXE ExemestanoValor de PTrastornos SNC no especificados678 / 14 % 813 /17%0.0004Insomnio504 / 10 %654 / 13%0.0001Dislipidemia136 / 3%230 /5%0.0001Incremento de Peso422/9%350/7%0.005Osteoporosis274/6%495/10%0.0001Dolores articulares1500/ 31%1730/36%0.0001Fracturas166/3%249/5%0.0001Anormalidades endometriales191/4%19/1%0.0001Bochornos1945/40%1703/ 35%0.0001Eventos Cardiovasculares143/3%182/4%0.038Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trialLancet 2011; 377: 32131

Conclusiones:Inhibidores de aromatasa vs Tamoxifeno: 5 aDisminucin de la recurrencia local Disminucin de la mortalidad por cncer:Beneficio a 10 aos:Recurrencia local: Diferencia Recurrencia contra lateral: HR 0. 62 ( p=0.0003)Tiempo a la recurrencia: HR. 0.79 (p=0.0002) Mayor beneficioTumores mayores de 2cmAfeccin ganglionarEventos adversos a considerar:Artralgias : 22 27%Fracturas: 5 10 %Dislipidemias: 52 %Tamoxifeno: Riesgo de Ca de endometrio HR: 1.10

TERAPIA SWITCH

Anastrozol EstudionEstrategiaResultadosComentariosITA

J Clin Oncol. 2005;23(22):5138.548 mujeresRE+G+Tamoxifeno 20mg/d/5aos (n=225) vs Tam 2 3 aos -> Anastrazol 1mg/d 2 3aos Med. Seguimiento:36m(tam vs secuencialidad)Recurrencia: 32 vs 22Segundos primarios: 10 vs 5Muerte sin recurrencia: 3 vs 0SLE: HR0.35 p=0.001Toxicidad grave; 33 vs 28 (p=0.04)- Eventos endometriales: 17 vs 1 (p=0.002)- No diferencia en tasa de fracturasARNO 95

J Clin Oncol. 2007;25(19):2664.979 mujeresT1-3N0-2ResecadasTamoxifeno 20 - 30mg/d por 2 aos Aleatorizacin:Anastrazol 1mg/dTamoxifeno 20 30mg 3 aos

Med Seg: 30m-Reduccin relativa del 34% en recurrencia (HR0.66, p=0.049)2.6% Reduccin absoluta en recurrencia

- 47% incremento relativo en SG (HR:0.53, p=0.045)Beneficio absoluto en mortalidad 1.2% Toxicidad: EventosCarcinoma endometrial: 0 vs 2 Eventos trombticos; 0 vs 6Fracturas: 10 vs 10ABCSG-8

J CliinOncol2012 :Jan 23371475% G-T1 75%Tamoxifeno 20mg/d por 2 aos

Switch ANA 3 aos vs tamoxi 3 aosMed. Seguimiento 60 meses

SLR: HR:0.80 (p=0.60)

SG: HR: 0.92 (p=0.16)Anlisis Exploratorio; Beneficio de 22% en SLR; RE/RP+ (HR0.78, p=0.002)

Eventos trombticos; 1 vs 3.2%Ca de endometrio; 0.5 vs 1.6%

Meta-Analysis of Breast Cancer Outcomes in Adjuvant Trials of Aromatase Inhibitors Versus TamoxifenLancet Oncol 2006; 7: 99196

Tiempo al eventoProporcin con primer evento (%)Supervivencia libre de eventos: (055 [042071]; p exemestano 25mg/d (n=4868)VsExemestano 25mg/d (n=4898)Mediana de seguimiento; 70.1m

SLE a 5aos; 85% secuencial vs 86% exemestano (HR=0.97; p=0.22)SG a 5aos: 91 vs 91% p>0.99Anlisis de seguridad:

Sntomas ginecolgicos; 20 vs 11% Trombosis venosa; 2 vs 1%Alteraciones endometriales; 4 vs 1%

A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women with Primary Breast Cancer. Intergroup Exemestane StudyN= 4742Edad m: 64 aosN (-): 50 %N +: 43 %RH +: 81% Qx previa: 98%QT previa: 32 % Tamoxifeno 20 30 mg 2 aos Tamoxifeno 20 30 mg 2 - 3 aos Examestano 25 mg 2 3 aos 0 aos4 aosSupervivencia libre de enfermedad1998 - 2003N Engl J Med 2004;350:1081-92.

A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women with Primary Breast Cancer. Intergroup Exemestane StudyPacientes vivos libres de enfermedad (%)Aos despues de la aleatorizacion End PointHR ( 95% CI)Valor de PSLE0.67 (0.56-0.82) 6 months after stopping adjuvant AIs or responding for 6 months to AIs in the metastatic setting.No cross-over was planned.The primary endpoint of the TAMRAD study was clinical benefit rate (CBR) at 6 months, and secondary endpoints were time to disease progression, overall survival, objective response rate, toxicity, and translational studies.CBR at 6 months was defined as the percentage of all patients with a complete response (CR), partial response (PR), or stable disease at 6 months.For measurable lesions, tumour response was assessed according to Response Evaluation Criteria in Solid tumours (RECIST, v1.0).For nonmeasurable bone lesions, CR was defined as complete lesion disappearance (ie, complete disappearance of uptake on bone scan and by computed tomography [CT]) and normalization of CA15-3 levels; progressive disease was defined as the appearance of 1 or more new lesions or unequivocal progression of an existing lesion.tumour assessments: CT scans at baseline and every 2 months until the 6-month visit, then every 3 months until 18 months.Scans were assessed locally, and radiologic reports were reviewed centrally by a medical expert.Safety assessments, performed monthly until the 6-month visit, then every 3 months until 18 months, including adverse event (AE) monitoring (assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events, v3.0), laboratory tests, vital signs, and physical exams.Although no formal statistical between-group comparison was planned, Fishers exact test was used to compare between-group CBRs, and the log-rank test was used to compare the survival curves for exploratory purposes. Translational studies into progression-free survival based on biomarker expression were also conducted as exploratory analyses.

0.00.10.20.30.40.50.60.70.80.91.00612182430Probabilidad ProgresinMesesResistencia primariaTAM: 3.8 mesesTAM + RAD: 5.4 mesesHR = 0.70 (0.40-1.21)p = NS (anlisis exploratorio) Resistencia secundariaTAM: 5.5 mesesTAM + RAD: 14.8 mesesHR = 0.46 (0.26-0.83) p = 0.0087 (anlisis exploratorio)0.00.10.20.30.40.50.60.70.80.91.00612182430Probabilidad PregresinMesesTAM TAM + RAD Tiempo a la Progresin como Funcin de la Resistencia Hormonal IntrnsecaRandomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study.J Clin Oncol. 2012;22(30):2718-2724

As shown in the slide, patients with primary hormone resistance did not appear to gain much benefit from the addition of RAD to tamoxifen. On the other hand, patients who previously responded to aromatase inhibitors and then became resistant may be a population for which this approach is most promising.

7576Resistencia PrimariaN (%) de eventosTAM: 15 (54%)TAM + RAD: 12 (46%)HR = 0.73 (0.34-1.55)p = 0.41 (anlisis exploratorio)Resistencia SecundariaN (%) de eventosTAM: 16 (55%)TAM + RAD: 4 (15%)HR = 0.21 (0.07-0.63)p = 0.002 (anlisis exploratorio)TAM TAM + RAD Supervivencia Global en funcin de la Resistencia Hormonal IntrnsecaRandomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study.J Clin Oncol. 2012;22(30):2718-2724

76These results were confirmed on the last update of the survival analysisonly patients with secondary hormone resistance seem to have a strong benefit from treatment with everolimus.77Incidencia, n (%)TAM n = 57TAM + EVEn = 54GradoCualquiera3/4Cualquiera3/4Eventos Adversos ms comunes (EAs) Fatiga Estomatitis Rash Anorexia Diarrea Nusea Vmito Pneumonitis Tromboembolia Dolor30 (52.6)4 (7.0)4 (7.0)10 (17.5)5 (8.8)20 (35.1)7 (12.3)2 (3.5)4 (7.0)49 (90.7) 6 (10.5)00 2 (3.5)002 (3.5)2 (3.5)4 (7.0)10 (18.5) 39 (72.2)30 (55.6)24 (44.4)23 (42.6)21 (38.9)19 (35.2)9 (16.7)9 (16.7)5 (8.8)44 (81.5)3 (5.6)6 (11.1)2 (3.7)4 (7.4)1 (1.9)2 (3.7)01 (1.9)3 (5.6)5 (9.3)Reduccin de dosis por EA0 (0)11 (20) Discontinuacin de tratamiento por EA4 (7.0)12 (22)Bachelot T, et al. J Clin Oncol. 2012;22(30):2718-2724Bourgier C, et al. ECCO-ESMO 2011; Abstract 5005

Eventos Adversos

77In the TAMRAD trial, adverse events (AEs) were consistent with those previously reported for tamoxifen (TAM) and everolimus (EVE) and were mostly of grade 1 or 2 severity.The most common nonhematologic AEs were pain, fatigue, stomatitis, rash, anorexia, and diarrhea, a profile that is consistent with previous safety data obtained in monotherapy studies of EVE and shows that the safety profile of TAM + EVE is predictable and manageable.The frequency of grade 3 or 4 nonhematologic AEs were comparable between the treatment arms (P = 0.2).The most frequently reported hematologic AEs were decreased hemoglobin (69% TAM + EVE vs 35%, TAM) and decreased lymphocyte (48% vs 21%) and leukocyte (54% vs 18%) counts.A total of 11 patients in the combination arm required dose reductions due to drug-related AEs. Main reasons for dose reductions were stomatitis, rash, thrombocytopenia, and pneumonitis. Subsequently, 3 of the 11 patients permanently discontinued treatment with EVE.Permanent treatment discontinuations due to drug-related AEs were:TAM: venous thrombosis (n=2), pulmonary embolism (n=1), and asthenia (n=1).TAM + EVE: venous thrombosis (n = 2), acute renal insufficiency (n = 1), cardiac failure (n = 1), and hemorrhagic risk (n = 1).Overall serious adverse event rates were 32% in each group.

Conclusion:Tamoxifeno + Everolimus:Mejora el tiempo a la progresin:14 m vs 5.5 m : 46% disminucin el riesgo

Mejora la supervivencia global:Reduce 55 % riesgo de muerte HR, 0.45; 95% CI, 0.24 to 0.81

Mayor beneficio en pacientes con resistencia secundaria

Toxicidad;Fatiga, Rash , anorexia y diarrea manejables

EVE 10 mg/d+EXE 25 mg/d (n = 485)Placebo+EXE 25 mg / d (n = 239)2:1 N = 724Postmenopusicas RH+Recurencia o progresin IAMets: Higado ( 30%) Hueso (70%) Pulmon ( 10%)PLE: > 24 m+ 3 terapias previasObjetivos:Primario: SLP (evaluacin local y central)Secundario: SG, TRG, CV, seguridad, marcadores seos, FC N Engl J Med 2012;366:520-9. Everolimus in Postmenopausal Hormone-ReceptorPositive Advanced Breast Cancer(BOLERO-2)

79BOLERO-2 (Study Y2301) a randomised Phase III study evaluating everolimus in combination with exemestane was conducted in post-menopausal women with ER positive refractory ABC (with recurrence or progression following prior therapy with letrozole or anastrozole).

724 women were randomized in a 2:1 ratio to receive either everolimus or matching placebo in addition to open-label exemestane.

Randomization was stratified by documented sensitivity to prior hormonal therapy (yes vs. no) and by the presence of visceral metastasis (yes vs. no). Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease 24 weeks) to at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence.

The primary endpoint for the trial was PFS evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on the investigators (local radiology) assessment. Supportive PFS analyses, were based on an independent central radiology review.

Secondary endpoints included overall survival (OS), Overall Response Rate (ORR), Clinical Benefit Rate (CBR), Safety, change in Quality of Life (QoL) and time to ECOG PS deterioration. Additional endpoints included changes in bone turnover markers at 6 and 12 weeks.

Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. No cross-over after disease progression was allowed.

0204060Supervivencia libre de progresion (%)80100ABTtiempo ( semanas9 06121824303642485460667278849096102108114EVE + EXEPBO + EXE188/271Events/Patients (n)116/135EVE + EXEPBO + EXE6.83 mesesMedian PFS2.76 mesesEVE + EXEPBO + EXEHR = 0.47 (95% CI = 0.37, 0.60)HR = 0.41 (95% CI = 0.31, 0.55)9.86 mesesMedian PFS4.21 meses0204060801000612182430364248546066727884909610210811412000Censoring TimesEVE + EXEPBO + EXE122/214Events/Patients (n)84/104Censoring TimesSLP en pacientes con (A) y sin (B) involucro visceralCampone M, et al. EMSO 2012; abstract 324PD (poster)BOLERO-2 ResultadEverolimus in Postmenopausal Hormone-ReceptorPositive Advanced Breast Cancer(BOLERO-2)Ttiempo ( semanas9 Supervivencia libre de progresion (%)

Abbreviations: CI, confidence interval; EVE, everolimus (10 mg/day); EXE, exemestane (25 mg/day); HR, hazard ratio; PBO, placebo; PFS, progression-free survival.

80020406080100Time, wk06121824303642485460667278849096102108EVE + EXEPBO + EXENumber of Patients Still at Risk1059588757265534741 30 20 137653210463530241914121053111000000Progression-Free Survival, %EVE + EXEPBO + EXE48/105Events/Patients (n)33/46EVE + EXEPBO + EXE12.88 mesesMedian PFS5.29 mesesHR = 0.33 (95% CI = 0.21, 0.53)Censoring TimesPacientes con metstasis seas nicas Campone M, et al. EMSO 2012; abstract 324PD (poster).BOLERO-2

Everolimus in Postmenopausal Hormone-ReceptorPositive Advanced Breast Cancer(BOLERO-2)

Baselga J, et al. N Engl J Med. 2012;366(6):520.Piccart M, et al. ASCO 2012; abstract 559 (poster).Everolimus in Postmenopausal Hormone-ReceptorPositive Advanced Breast Cancer(BOLERO-2)

EVE + EXE(n=482), %PBO + EXE(n=238), %Todos los gradosGrado 3Grado 4Todos los gradosGrado 3Grado 4Estomatitis598011< 10Erupcin3910600Fatiga364< 12710Diarrea332< 119< 10Disminucin del apetito301012< 10Nusea29< 1< 12810Neumonitis no infecciosa1530000Hiperglucemia145< 12< 10Everolimus in Postmenopausal Hormone-ReceptorPositive Advanced Breast Cancer(BOLERO-2)Baselga J, et al. N Engl J Med. 2012;366(6):520.Piccart M, et al. ASCO 2012; abstract 559 (poster).

La estomatitis es un AE comn en el estudio BOLERO-2, y se inform en el 59% de los pacientes tratados con EVE (8% de grado 3, 0% de grado 4) [Hortobagyi2011, pg18/Table]Sin embargo, los eventos fueron generalmente de bajo grado y manejable con reduccin de dosis establecida en los protocolos

Referencia:[Hortobagyi2011] Hortobagyi GN, Piccart M, Rugo H, et al. Everolimus for postmenopausal women with advanced breast cancer: updated results of the BOLERO-2 trial. Presentation at 34rd San Antonio Breast Cancer Symposium, San Antonio, TX. 2011:1-26.83Conclusiones:Everolimus + Exemestano:

Impacto en supervivencia libre de progresin:

Beneficio en metstasis no viscerales 9 vs 4 mesesEn metstasis viscerales: 6.8 v 2 mMetstasis seas nicas: 12.8 vs 5.2 meses

Todos los grupos con beneficio

Eventos adversos:Estomatisis, fatiga, rash, anorexia y diarrea.

Pendientes reporte de resultados de Supervivencia Global