Enfermedad con Expresión de Receptores hormonales

Enfermedad con Expresión de

Receptores hormonales

Mª Isabel Gallegos Sancho

Hospital General de Segovia

Enfermedad Precoz

Postmenopaúsica: INHIBIDOR DE AROMATASA 5 años

Premenopáusica: TAMOXIFENO 10 años

Premenopáusica- Postmenopaúsica: TAMOXIFENO-

INHIBIDOR AROMATASA

¿Qué sabemos del IA de inicio en la mujer

premenopáusica?

Randomized comparison of adyuvant aromatase inhibitor (AI)

exemestano (E) plus ovarian fuction suppression (OFS) vs tamoxifen

(T) plus OFS in premenopausal women with hormone receptor-positive

(HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and

SOFT trials( Abstract LBA1).

SESION PLENARIA Asco 2014

¿ Papel del IA en las premenopaúsicas?

ESTUDIOS TEXT Y SOFT

TEXT TRIAL= TAMOXIFEN AND EXEMESTANE TRIAL

Tamoxifen + OFS x 5 y

Exemestane+ OFS x 5 y

• Premenopausicas

• Triptorelina 3,75 mg mensual con el tto endocrino. Bilateral

ooforectomía o RT ovárica al menos 6 meses tras el

análogo.

• Si QT: iniciaban el análogo concomitante con la QT. El tto

endocrino al finalizar la QT.

• Si no QT, rand 12 sem tras cirugia

• Tto endocrino 6-8 semanas dp el análogo.

N= 2672

ESTUDIOS TEXT Y SOFT

SOFT TRIAL= SUPPRESSION OF OVARIAN FUNCTION

TRIAL

Tamoxifen x 5 y

Tamoxifen + OFS x 5 y

Exemestane+ OFS x 5 y

• Premenopausicas

• Si QT ady o neoad, eran randomizadas 8

meses tras QT.

• Pudieron recibir tto endocrino oral antes de

la randomización.

• Si no QT, rand 12 sem tras cirugia

N= 3066

Estratificación: QT adyuv/ neoady previa

Afectación/ no ganglionar

Objetivo Primario: SLE

Objetivo Secundario: ILE, ILRecurrencia,SG,

CARACTERISTICAS DE LAS PACIENTES

• Mediana de edad: 43 a

• 42.6% no recibió QT/ 57.4% si QT ( TEXT: 34.3 % dp de la random y SOFT:

23.2% antes )

• 41.7% SOFT recibió tamoxifeno antes de la randomización una media de 4m

• Ganglios positivos: 42.2%

RESULTADOS DE EFICACIA

SLE: 91.1% vs 87,3% HR: 0.72

ILE: 92.8% vs 88,8%

HR: 0.66 *

RECURRENCIA A

DISTANCIA : 93.8% vs 92

HR: 0.78

EFECTOS ADVERSOS

• La incidencia grado 3/ 4 es similar ( 30.6% vs 29.4%).

• Sofocos, musculoesqueléticos, hipertensión.( grado 3/4)

• Osteoporosis ( T score - 2.5) 13.2 % vs 6.4% ( grado 1-4)

• Fracturas, musculoesqueléticos,, sequedad vaginal, disminución de la libido,

dispareunia con Exemestano//

• Eventos tromboembólicos, incontinencia, sudoración con Tamoxifeno//.

• Céncer ginecológico: 7 y 9 pacientes ( 2 y 5 endometriales).

• Depresión en torno a un 50% ámbos grupos ( 3-4: 4.1%).

• Cese precoz del tto 16% grupo Exemestano vs 11% Tamoxifeno.

• ABSTRACT 557: Diferente perfil de E.2º, no variación en calidad de vida.

Conclusiones:

1. Exemestano ( E) +Castración ovárica ( CO) comparado con Tamoxifeno + CO,

incrementa de forma significativa la SLE, ILE, ILR a distancia.

2. Es una nueva opción para las mujeres premenopáusicas RH+ con cáncer de

mama precoz.

3. No hay diferencias en Supervivencia Global.

4. El perfil de efectos secundarios está dentro de lo esperado.

5. Nos falta por conocer los resultados del SOFT de la rama de tamoxifeno solo.

6. ¿ Cuánto tiempo es el realmente suficiente y a que coste?

Tamoxifeno 10 años?

Tamoxifeno 5 años, seguido de IA 5 años?

IA 5 años + Castracción ovárica?

¿Algo más en la premenopáusica?

Effect of obesity on prognosis in pre-menopausal, ER+ early breast cancer

EBCTCG data on 80000 patients in 70 trials Hongchao PAN & Richard GRAY

University of Oxford, UK

for the Early Breast Cancer Trialists’ Collaborative Group

(EBCTCG)

ASCO 2014

La Obesidad es un

factor adverso

independiente,

relacionado con

MORTALIDAD POR

CANCER DE MAMA EN

MUJER

PREMENOPAUSICA.

Lancet Oncol 2014

¿Diferencias en cuanto a los IA en

adyuvancia en mujer postmenopaúsica?

MA.27

Exemestano 25

mg

Anastrozol 1 mg 7576 pts

Postmenop

Cancer mama precoz

497 pts, DMO 25 sem tras randomizacion

300 pts T score -2 o mayor

197 pts T score menor de -2

147

Exemestano

153

Anastrozol

101

Exemestano

96

Anastrozol

• Calcio 1000 mg/d y Vitamina D 800 UI/d

• Bifosfonatos si T score -2.

OBJETIVO PRIMARIO: PORCENTAJE DE CAMBIO DE DENSIDAD

OSEA A LOS 2 AÑOS EN COLUMNA Y CADERA

NO

DIFERENCIAS

SIGNIFICATIVAS

ENTRE LOS IA A

LOS 2 AÑOS

“No cambios en la práctica clínica; sí seguridad del tto en

mujeres con osteopenia o osteoporosis cd se usan

concomitantemente con bifosfonatos”

Effects Of Bisphosphonate Treatment On

Recurrence And Cause-specific Mortality

In Women With Early Breast Cancer:

A Meta-analysis Of Individual Patient Data

From Randomised Trials

R Coleman, M Gnant, A Paterson, T Powles, G von Minckwitz,

K Pritchard, J Bergh, J Bliss, J Gralow, S Anderson, D Cameron,

V Evans, H Pan, R Bradley, C Davies, R Gray.

Early Breast Cancer Trialists’ Collaborative Group

(EBCTCG)’s Bisphosphonate Working Group.

¿ Algo más en la postmenopáusica?

San Antonio Breast Cancer Symposium, December 10-14 2013

Breast Cancer Recurrence: Postmenopausal Women*

Distant Recurrence Bone Recurrence

1564 events 508 events

Non Bone Recurrence

1056 events

Significantly Greater Effect on Bone than Other Distant Recurrence

* Includes induced menopause and women aged >55 if unknown

Bifosfonatos en la mujer postmenopausica.

Los bifosfonatos adyuvantes reducen las metástasis óseas y

aumentan la supervivencia en las mujeres postmenopáusicas.

34 % reducción en riesgo de recurrencia en hueso p= 0,00001.

17% reducción en riesgo de muerte por cáncer de mama p= 0,004.

No reduce significativamente el riesgo de recurrencia fuera del

hueso.

La reducción del riesgo es independiente de del RE, estado

ganglionar y recibir o no QT.

4 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrclinonc

ratio of 0.71, 95% CI 0.58–0.88 for ≥10 years). Overall,

10 years of tamoxifen treatment was associated with an

increased risk of endometrial cancer and pulmonary

embolism, but no increase in stroke, and a decreased

incidence of ischaemic heart disease. Other smaller trials

that assessed long-term treatment with tamoxifen had

previously reported conflicting results.63–65 If the results

of the ATLAS trial are confirmed by ongoing trials (for

example, ATTOM66), 10 years of adjuvant tamoxifen will

become an interesting option for premenopausal women.

Extended hormone therapy in ER-positive breast

cancer effectively decreases late recurrences; thus, pro-

viding an example of how tumour dormancy can be tar-

geted in the clinic.61 However, we do not yet have the

optimal tools to select the patients who will benefit from

extended adjuvant hormone therapy.

Large tumour size and positive lymph-node status are

associated with increased late relapse rates in postmeno-

pausal women who have received 5 years of tamoxifen.67

Moreover, it has been suggested that women who were

premenopausal at diagnosis,68 whose tumours measured

>2 cm,53 and who had node-positive53,54 and ER-positive/

PR-positive disease52,69 derived more benefit from

extended aromatase inhibitor treatment after 5 years of

tamoxifen. It should be noted that in the ATLAS trial,

there was no significant heterogeneity in risk reduc-

tion after 10 years of tamoxifen according to patient

character istics, including tumour size and nodal status.62

Nevertheless, currently, most postmenopausal women at

high risk of relapse are treated upfront with an aroma-

tase inhibitor, and women with less-poor prognosis are

treated with 2–3 years of tamoxifen followed by 2–3 years

of aromatase inhibitor treatment.

Recently, data from the ABCSG-8 and the TransATAC

studies showed that classic clinicopathological character-

istics and three gene signatures (Breast Cancer IndexSM,

EndoPredict® and PAM50-ROR) are independent predic-

tors of late recurrence, with most information provided

by the clinicopathological characteristics.70–73 On the one

hand, using clinicopathological characteristics and these

signatures, the investigators were able to predict which

women with low risk of late relapse could be spared the

toxicity of extended hormone therapy.70–73 On the other

hand, positive lymph-node status is already used to select

women who might benefit from extended hormone

therapy. We believe that validation of these signatures

in completed or ongoing trials of extended adjuvant

hormone therapy, as well as a better understanding of

the biology of dormant disseminated tumour cells,74–76

will help us better tailor extended adjuvant endocrine

treatment in the future.

Adjuvant bisphosphonatesPreclinical studies have suggested that bisphosphonates

have antitumour effects, mainly by interrupting a vicious

cycle of growth factors and cytokines between occult

tumour cells and osteoclasts in the bone marrow micro-

environment (Figure 2).77–79 Moreover, the bisphospho-

nate zoledronic acid reduced the incidence of bone

marrow disseminated tumour cells in women receiving

chemotherapy.80,81 Subgroup analyses from several trials

raise the hypothesis that bisphosphonates might decrease

recurrences in women with early stage breast cancer in

the presence of a low-oestrogen environment (either

premenopausal women undergoing chemical ovarian

ablation or postmenopausal women).79

The AZURE trial showed that the addition of 5 years

of zoledronic acid to standard systemic treatment did not

improve disease-free survival (DFS) or overall survival in

the overall population, but improved DFS (hazard ratio

[HR] = 0.75, 95% CI 0.59–0.96, P = 0.02) and overall sur-

vival (HR = 0.74, 95% CI 0.55–0.98, P = 0.04) in women

who were postmenopausal at least 5 years before study

entry.82 The ABCSG-12 trial showed that, in premeno-

pausal women, zoledronic acid every 6 months for 3 years

improved DFS (HR = 0.64, 95% CI 0.46–0.91, P = 0.01)

when added to hormone therapy.83 In an updated analysis

there was an overall survival benefit from the addition of

zoledronic acid, mainly in women over 40 years of age.84

In the ZO-FAST study, immediate use of zoledronic acid

resulted in increased DFS compared to delayed zole-

dronic acid treatment in postmenopausal women with

early stage breast cancer who were receiving letrozole

(HR = 0.66, P = 0.03),85 and in the NSABP B34 trial, the

addition of the oral bisphosphonate clodronate improved

the recurrence-free interval only in patients who were

over 50 years old (HR = 0.75, 95% CI 0.57–0.99).86

A formal meta-analysis of available or ongoing trials

(such as, NATAN87) is warranted to investigate inter-

actions between benefit from bisphosphonates and

factors such as age and menopausal status. Although

Osteoclastprecursor

Osteoblast

OPG RANKL

Osteoclast

Bonematrix

Tumourcells

Bone-derivedgrowth factors(TGF-β, FGFs,IGFs, PDGF,BMPs), Ca2+

Boneresorption

PTHrP

RANKLantibody

Bisphosphonates

PTHrPIL-8

IL-11

Figure 2 | Vicious cycle of occult tumour cells and osteoclasts in breast

cancer.77–79 Bone marrow disseminated tumour cells that have escaped dormancy

produce factors (for example, PTHrP) that promote the formation and activation of

osteoclasts. Osteoclast activation results in bone resorption and thus release

of factors by bone matrix, such as TGF-β, which stimulate tumour cell proliferation.

Bisphosphonates and denosumab can interrupt this vicious cycle. Abbreviations:

BMPs, bone morphogenetic proteins; FGFs, fibroblast growth factors; IGFs, insulin-

like growth factors; IL, interleukin; OPG, osteoprotegerin; PDGF, platelet derived

growth factor; PTHrP, parathyroid hormone-related peptide; RANKL, receptor

activator of nuclear factor-κB ligand; TGF-β, transforming growth factor-β.

REVIEWS

© 2013 Macmillan Publishers Limited. All rights reserved

Enfermedad Avanzada

NO PREVIO

TTO

ENDOCRINO

PREVIAMENTE

TAMOXIFENO/ IA

PREVIAMENTE

TAMOXIFENO/ IA

FULVESTRANT

Pre

TAMOX/ IA + SO

Post

IA

IA/ TAMOX

FULVESTRANT

IA + EVEROLIMUS

PROGESTAGENOS

ESTROGENOS

QT

• 50-60% responden a 1ª línea

• 25% son resistentes ( RESISTENCIA PRIMARIA)

• Practicamente todos progresan al tto ( RESISTENCIA

SECUNDARIA).

• Beneficio clínico previo, mejor predictor de eficacia.

ESTRATEGIAS UTILIZADAS PARA REVERTIR LA

RESISTENCIA

Combinación de

tratamientos hormonales

versus monoterapia

723 pts

Progresión a

IA previo

Fulvestrant 250 mg +

Anastrozol 1mg

Fulvestrant 250 mg +

Placebo

Exemestano 25 mg

ESTUDIO

SOFEA

Estratificación: AI adyuvante / 1ª Línea

OBJETIVO PRIMARIO: PFS

Stephen RD Johnston, Lancet Oncol 2013

ESTRATEGIA DE COMBINACIÓN : ¿ En

progresión a Inhibidor de Aromatasa?

•IA adyuvante: ( 17—22%)

•IA < 1 año: ( 18- 20%)

•IA 1-2 años: ( 26- 35%)

•IA > 2 años: (27-31%)

4,4 m vs 4,8

4,8 m vs 3,4

NO HAY DIFERENCIAS CON LA

COMBINACIÓN DE FULVESTRANT +

ANASTROZOL TRÁS PROGRESION

A IA

Images are not actual patients.

SoFEA: Patients Derive Clinical Benefit With Additional

Endocrine Therapy After Progressing After a Nonsteroidal

Aromatase Inhibitor

Fulvestrant + Anastrozole

(n = 250)Fulvestrant

(n = 250)Exemestane

(n = 250) P valuea P valueb

PFS (mo) 4.4 4.8 3.4 .98 .56

OS (mo) 20.2 19.4 21.6 .61 .68

ORR (%) 7.4 6.9 3.6 .82 .10

Phase 3 study; N = 750

Postmenopausal women with HR+ advanced

breast cancer

Progressed after nonsteroidal AI therapy in

adjuvant or first-line metastatic setting

Primary endpointPFS

Secondary endpoints

OS, ORR, safety

Fulvestrant 250 mg/mo+ Anastrozole 1 mg/d

Fulvestrant 250 mg/mo

Exemestane 25 mg/d

AI, aromatase inhibitor; HR, hormone receptor; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

a Fulvestrant + anastrozole versus fulvestrant alone. b Fulvestrant alone versus exemestane alone.

Johnston S, et al. Lancet Oncology. 2013 July 29 Epub.

• ESTUDIO SWOG SO226: Fulvestrant +

Anastrozol vs Anastrozol.

SLP: 15 m vs 13.5 m HR= 0.80

Mehta et al NEJM 2012

¿ Que sabíamos de la

combinación? 1ª Línea

• ESTUDIO FACT: Fulvestrant + Anastrozol vs

Anastrozol

SLP: sin diferencias.

Bergh JCO 2012

Interpretaciones: “ La combinación de tratamientos hormonales con diferentes

mecanismos de acción, probablemente no mejores los resultados, y por lo tanto el tto secuencial continúe siendo el

estándar de nuestras pacientes”

Aman U Buzdar

Anderson Center, Houston

“ Quizás tumores Luminales A( sin resistencias 1ª), y tumores no previamente expuestos a tto endocrino ( sin

resistencias 2ª), se pueda explorar en estudios prospectivos la terapia de combinación hormonal”

Angelo di Leo

Instituto Toscano de Tumores


RESISTENCIA

Combinación de

tratamientos hormonales

con terapia antiangiogénica

Bevacizumab+ Exemestano

• AROBASE: A phase III trial of exemestano and bevacizumab as maintenance therapy in patients with metastatic brest cancer treated

in first line with paclitaxel and bevacizumab- A Gineco study.

Olivier Tredan, Département d’Oncologie Médicale, Centre Léon Bérad, Lyon, France

ASCO-2014

¿Qué sabemos de las

Resistencias Secundarias?

Activación de la cascada PI3K/ AKT/ mTor

Activación de factores de crecimiento/ receptores

( HER)

Pérdida o inactivación del propio RE o de su

cascada

Musgrove EA, Nat Rev Cancer. 2009;9:631-643

Desacoplamiento del Ciclo celular

PI3K

AKT

PTEN

mTOR

RAS

RAF

MEK

MAPK

ER target gene transcription

P P

EGFR HER2

E

E

ER

E

TKI

mTOR Inhibitors Everolimus Sirolimus Temsirolimus

Aromatase Inhibitor Nonsteroidal AIs

Anastrozole Letrozole

Steroidal AIs Exemestane

Selective Estrogen Receptor Modulators Tamoxifen Toremifene

ER Downregulator Fulvestrant

HDAC Inhibitor Entinostat

Combinación terapia antiestrogénica+ terapia

dirigida en tumores RE+

CDK 4/6 Inhibitor PD 0332991

Cell

Cycle

Transcription

Silencing

ER

E

ER

E


RESISTENCIA


phase III trial showed improved PFS when trastuzumab

was added to anastrozole in patients with ER-positive/

HER2-positive metastatic breast cancer (HR = 0.63, 95%

CI 0.47–0.84, P = 0.0016).109

ER and PI3K/ AKT/ mTOR crosstalk

Crosstalk between the ER and the PI3K/AKT/mTOR

signalling pathways has been associated with endocrine

resistance.107 The mTORC1 complex integrates signals

from growth factors (for example, insulin-like growth

factor), the presence of nutrients (amino acids), energy

signals through the AMP-activated kinase, and various

stress signals (such as hypoxia and DNA damage) to

promote cell growth and division by increasing mRNA

translation and inhibiting autophagy.110 Genes from

the PI3K/AKT/mTOR pathway are the most frequently

mutated in luminal breast cancer; PI3K mutations are the

most prevalent mutations and are identified in around

40% of cases.30,33,35,111

Interestingly, the majority of PI3K mutations in

ER-positive tumours have been identified in the alpha

catalytic subunit (PIK3CA).36 Moreover, preclinical data

have demonstrated a synthetic lethal interaction when

PIK3CA inhibition is combined with oestrogen depri-

vation in breast cancer cell lines,112 suggesting that this

is a very promising approach to be tested in the clinic.

However, gene-expression profiling and reverse-phase

protein array data have shown that PIK3CA mutations

in non-metastatic, ER-positive breast cancer are not

associated with AKT/S6K pathway activation,33,113,114

as observed in cases that have PTEN loss in triple-

negative breast cancer. Therefore, whether the approach

of combined PI3K inhibition and endocrine treatment

is effective in early stage breast cancer remains to be

d emonstrated in future clinical studies.

Currently, there are numerous types of agents t argeting

the PI3K/AKT/mTOR pathway, including the following:

pan-PI3K inhibitors (such as, BKM-120, GDC-0941

and XL147); isoform-specific PI3K inhibitors (for

example, the PI3Kα inhibitors BYL719, GDC-0032 and

INK111; the PI3Kβ inhibitors GSK2636771, TGX-221

and KIN-193; and the PI3Kδ inhibitor CAL-101); dual

PI3K–mTOR inhibitors (such as, BEZ235, XL765,

GDC-0890 and GSK1059615); AKT inhibitors (includ-

ing ATP-competitive inhibitors such as GSK690693 and

GDC-0068 or allosteric inhibitors such as MK-2206);

and mTOR inhibitors (including allosteric inhibitors

such as the rapalogues sirolimus, temsirolimus, ridaforo-

limus and everolimus or mTOR catalytic inhibitors such

as the INK128, AZD8055, AZD2014 and OSI-027).115,116

The most promising results for targeting the crosstalk

between ER and the PI3K/AKT/mTOR pathway have

come from combining everolimus with endocrine therapy

in patients with metastatic breast cancer in the BOLERO II

phase III clinical trial.117 This trial randomly assigned 724

postmenopausal women with ER-positive/HER2-negative

breast cancer that was resistant to anastrozole or letro-

zole to either exemestane plus everolimus or exemestane

plus placebo in a 2:1 ratio. Of note, 84% of the women

participating in the study had previously been sensitive

to endocrine therapy. Everolimus improved median PFS

when added to exemestane (HR = 0.36; 95% CI 0.27–0.47;

P <0.001). However, the increased efficacy came at the cost

of increased toxicity, namely higher incidence of grade 3

or 4 stomatitis, hyperglycaemia, fatigue, anaemia and

pneumonitis. Based on this study, the FDA and European

Medicine Agency (EMA) approved everolimus in combi-

nation with exemestane for the treatment of women with

ER-positive/HER2-negative breast cancer with recurrence

or progression after receiving letrozole or anastrozole.

PI3K/ AKT/ mTOR

PIK3CA mutation 40%PTEN mutation/ loss 18%INPP4B loss 12%AKT1 mutation 3%

Pan-PI3K inhibitor sIsoform-speci c PI3K

inhibitorsDual PI3K–mTOR inhibitor s

AKT inhibitorsmTOR inhibitors

CDK4/ 6

11q13 ampli cation 37%CCND1 ampli cation 40%CDK4 ampli cation 19%CDKN1B, CDKN2A,CDKN2B loss 11%RB1 mutation 1%

CDK4/ 6 inhibitors

p53–MDM2

TP53 mutation 22%MDM2 gain 22%

MDM2 inhibitors

FGFR1

8p11–12 ampli cation 10%FGFR1 ampli cation 10%

Tyrosine kinase inhibitor sFGFR monoclonal antibodies

FGF-trap

HDAC

MLL3 mutation 7%HypermethylatedLuminal B ‘subtype’ 8%

HDAC inhibitors

E2F mTOR MAPK

Transcription

No transcription

RTK

PI3K

AKT

mTORC1

PTEN

INPP4B

4EBP1

S6K

mTORC2

Cyclin D1CDK4/ 6

Rb

MDM2

p53

FGFR1

PI3K

AKT

RAS

MEK

Figure 3 | Genomic and epigenomic landscape, pathways and drugs to reverse endocrine resistance in oestrogen

receptor-positive breast cancer. Data on genomic and epigenomic landscape are derived from next-generation sequencing

studies30–35 and from a study combining gene-expression profiling and copy number aberration data.29 Pink denotes gene or

protein activation and blue denotes gene or protein suppression in breast cancer. Abbreviations: HDAC, histone deacetylase;

RTK, receptor tyrosine kinase.

REVIEWS


Inhibidores de la vía

PI3/AKT/ mTor

ESTUDIO BOLERO-2

Baselga J et al, New Engl J Med 2012

ORIGINAL RESEARCH

Everol im us Plus Exem estane in Postm enopausalPat ien ts w i th HR+ Breast Cancer: BOLERO-2 FinalProgression-Free Survival Analysis

Denise A. Yardley • Shinzaburo Noguchi • Kathleen I. Pritchard • Howard A. Burris III • Jose Baselga •

Michael Gnant • Gabriel N. Hortobagyi • Mario Campone • Barbara Pisti l l i • Martine Piccart •

Bohuslav Melichar • Katarina Petrakova • Francis P. Arena • Frans Erdkamp • Wael A. Harb •

Wentao Feng • Ayelet Cahana • Tetiana Taran • David Lebwohl • Hope S. Rugo

To view enhanced content go to www.advancesintherapy.com

Received: September 18, 2013 / Published online: October 25, 2013

Ó The Author(s) 2013. This art icle is published with open access at Springerl ink.com

ABSTRACT

Int rodu ct ion: Effect ive treatmen ts for

hormone-receptor-posit ive (HR? ) breast cancer

(BC) following relapse/progression on

nonsteroidal aromat ase inhibitor (NSAI)

therapy are needed. Init ial Breast Cancer Trials

of OraL EveROl imus-2 (BOLERO-2) trial data

demonstrated that everolimus and exemestane

signifi cantly prolonged progression-free

survival (PFS) versus placebo plus exemestane

alone in this patient population.

Methods: BOLERO-2 is a phase 3, double-blind,

randomized, international trial comparing

everolimus (10 mg/day) plus exemestane

(25 mg/day) versus placebo plus exemestane in

postmen opausal women with HR? advanced BC

with recurrence/progression during or after

Port ions of the data have been presented previously:

Piccart-Gebhart MJ, Noguchi S, Pritchard KI, Burris HA,

Rugo HS, Gnant M, et al. Everolimus for postmenopausal

women with advanced breast cancer: Updated results of

the BOLERO-2 phase III trial [abstract]. Presented at the

48th Annual Meeting of the American Society of Clinical

Oncology; June 1–5, 2012; Chicago, IL. Abstract 559.

Electron ic supplem entary m aterial The onlineversion of this art icle (doi:10.1007/s12325-013-0060-1)contains supplementary material, which is available toauthorized users.

D. A. Yardley (& ) H. A. Burris III

Sarah Cannon Research Inst itute and Tennessee

Oncology, PLLC, Nashvil le, TN 37203, USA

e-mail: [email protected]

S. Noguchi

Department of Breast and Endocrine Surgery, Osaka

University, Suita, Osaka 565-0871, Japan

K. I. Pritchard

Sunnybrook Odette Cancer Centre and the

University of Toronto, Toronto, ON M4N 3M5,

Canada

J. Baselga

Memorial Sloan-Kettering Cancer Center, New York,

NY 10065, USA

M. Gnant

Department of Surgery, Comprehensive Cancer

Center, Medical University of Vienna, 1090 Vienna,

Austria

G. N. Hortobagyi

The University of Texas MD Anderson Cancer

Center, Houston, TX 77030, USA

M. Campone

Institut de Cancerologie de l ’Ouest, Rene

Gauducheau, Centre de Recherche en Cancerologie,

44805 Nantes Saint Herblain, France

Enhanced content for Advances in Therapy

articles is available on the journal web site:

www.advancesinth erapy.com

123

Adv Ther (2013) 30:870–884

DOI 10.1007/s12325-013-0060-1

Yardley. ADV Ther 2013

7.8 m vs 3.2 m

11 m vs 4.1 m HR= 0.38

p< 0.0001

BOLERO-2 (18 m): Beneficio en SLP consistente en

todos los sugbrupos, tanto revisión local como central.

• The effect of EVE+EXE treatment was consistent among prospectively defined

subgroups by local investigator and central review

0 0.2 0.4 0.6 0.8 1 1.2 1.4

Hazard Ratio and 95% CI

0.38 11.00 4.10

0.32 11.33 3.94

0.50 10.84 4.17

0.41 13.86 4.17

0.38 9.40 4.11

0.33 13.83 4.14

0.36 5.72 1.61

0.39 22.18 4.21

0.37 10.91 3.94

724

449

275

137

275

274

38

106

618

N

All

Local Central

Age group

< 65

≥ 65

Region

Asia

Europe

North America

Other

Japanese patients

Japan

Non-Japan

Median PFS, mo

HR EVE+EXE PBO+EXE

0.45 7.8 3.2

0.38 8.31 2.92

0.59 6.83 4.01

0.60 8.48 4.14

0.45 7.16 2.83

0.38 8.41 2.96

0.40 4.53 1.48

0.58 8.54 4.17

0.42 7.16 2.83

Favors EVE+EXE

0.42 13.86 4.17

0.38 10.91 4.14

0.15 NA 1.45

0.39 12.45 4.21

0.35 10.91 2.79

0.43 13.14 4.14

0.37 11.01 4.11

0.27 16.59 5.82

0.46 8.31 2.89

0.43 9.56 4.07

0.19 19.52 6.51

143

547

34

435

274

184

523

318

406

573

151

Race

Asian

Caucasian

Other

Baseline ECOG performance status

0

1, 2

PgR status

Negative

Positive

Presence of visceral metastasis No

Yes

Bone only lesions at baseline

No

Yes

0.62 8.48 4.14

0.42 7.36 2.96

0.25 6.93 1.41

0.48 8.25 4.11

0.39 6.93 2.76

0.51 6.93 2.83

0.41 8.08 3.32

0.41 9.86 4.21

0.47 6.83 2.76

0.48 6.90 2.83

0.33 12.88 5.29

Favors PBO+EXE

N

Median PFS, mo

HR EVE+EXE PBO+EXE

0 0.2 0.4 0.6 0.8 1 1.2 1.4

Hazard Ratio and 95% CI

Favors EVE+EXE Favors PBO+EXE Abbreviations: EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival.

Yardley DA, et al. Adv Ther. 2013;30:870-884.

33

0.40 10.91 4.14

0.37 11.04 4.14

0.39 10.91 4.11

0.38 15.01 6.80

0.38 10.91 4.11

0.39 17.97 7.00

0.38 11.01 4.11

0.24 11.10 6.80

114

610

620

104

653

71

691

33

Sensitivity to prior hormonal therapy

No

Yes

Only received prior adjuvant therapy*

No

Yes

Only received prior adjuvant hormonal

therapy with chemotherapy*

No

Yes

Only received prior adjuvant hormonal

therapy without chemotherapy*

No

Yes

0.55 6.83 2.83

0.43 8.05 3.94

0.46 7.00 2.96

0.40 11.70 4.17

0.46 7.06 2.96

0.40 12.29 4.17

0.45 7.59 3.19

0.37 11.10 4.12

Subgroup analysis of PFS by local investigator review (yellow) and central review (blue).

*Does not include patients who received neoadjuvant therapy.

Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EVE, everolimus; EXE, exemestane; HR, hazard ratio; NSAI, nonsteroidal aromatase inhibitor;

PBO, placebo; PFS, progression-free survival ; PgR, progesterone receptor.

Yardley DA, et al. Adv Ther. 2013;30:870-884.

0 0.2 0.4 0.6 0.8 1 1.2 1.4 Hazard Ratio and 95% CI

0.38 11.00 4.10

0.24 19.52 6.51

0.53 8.28 4.17

0.35 8.48 2.83

0.44 10.58 5.55

0.35 11.27 4.07

0.35 13.83 4.21

0.42 7.13 2.83

0.46 9.95 4.21

0.32 12.02 3.32

724

219

232

271

231

493

538

186

326

398

N

All

Number of organs involved

1

2

Prior chemotherapy

No

Yes

Prior chemotherapy

for metastatic disease

No

Yes

Prior use of hormonal therapy

other than NSAI

No

Yes

Median PFS, mo

HR EVE+EXE PBO+EXE

0.45 7.8 3.2

0.40 11.50 4.37

0.52 6.70 3.45

0.41 6.93 2.56

0.53 6.97 3.45

0.41 8.18 3.19

0.46 8.31 4.07

0.38 6.11 2.69

0.52 7.00 4.11

0.39 8.11 2.76

Favors EVE+EXE Favors PBO+EXE

≥ 3

Local Central N

Median PFS, mo

HR EVE+EXE PBO+EXE

0 0.2 0.4 0.6 0.8 1 1.2 1.4 Hazard Ratio and 95% CI

Favors EVE+EXE Favors PBO+EXE

34

BOLERO-2 (18 m): Beneficio en SLP consistente en todos

los sugbrupos, tanto revisión local como central.

BOLERO-2 (18-m ): Everolimus + Exemestano aumenta la

Tasa de Respuestas y de Beneficio Clínico

P < 0.0001

Pe

rce

nt P < 0.0001

Yardley. ADV Ther 2013

0

20

40

60

Pro

bab

ility

of

Even

t, %

80

100

Time, wk Time, wk

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114

EVE+EXE

PBO+EXE

Patients at risk

271 240 192 157 128 107 88 72 52 38 25 22 16 12 11 7 5 4 1 0

135 108 66 44 32 23 18 14 11 8 4 4 3 1 0 0 0 0 0 0

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120

EVE+EXE

PBO+EXE

Patients at risk

214 196 174 147 129 114 97 86 72 53 41 28 19 12 11 6 5 4 1 1 0

104 82 66 52 35 27 21 16 10 7 6 4 2 2 1 1 1 0 0 0 0

A B C

HR=0.47 (95% CI, 0.37-0.60)

Kaplan-Meier medians EVE+EXE: 6.83 mo

PBO+EXE: 2.76 mo

HR=0.41 (95% CI, 0.31-0.55)

Kaplan-Meier medians EVE+EXE: 9.86 mo

PBO+EXE: 4.21 mo

Censoring times

EVE+EXE (n/N=122/214)

PBO+EXE (n/N=84/104)

Censoring times

EVE+EXE (n/N=188/271)

PBO+EXE (n/N=116/135) 0

20

40

60

80

100

Time, wk

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108

EVE+EXE

PBO+EXE

Patients at risk

105 95 88 75 72 65 53 47 41 30 20 13 7 6 5 3 2 1 0

46 35 30 24 19 14 12 10 5 3 1 1 1 0 0 0 0 0 0

EVE+EXE (n/N=48/105)

PBO+EXE (n/N=33/46)

Censoring Times

EVE+EXE: 12.88 mo

Kaplan-Meier medians

PBO+EXE: 5.29 mo

HR=0.33 (95% CI, 0.21-0.53)

M Campone et al.

European Journal of Cancer 2013

Everolimus + Exemestane Placebo + Exemestane

Pts Events %

Median

PFS,

mo Pts Events %

Median

PFS,

mo Hazard Ratio

(95%Cl)

Pts with visceral

disease at baseline 271 188 69.4 6.83 135 116 85.9 2.76 0.47 (0.37,

0.60)

ECOG PS = 0 167 114 68.3 6.83 84 70 83.3 2.79 0.54 (0.40,

0.73)

ECOG PS ≥ 1 100 71 71 6.77 48 43 89.6 1.45 0.35 (0.23,

0.52)

M Campone et al. European Journal of Cancer 2013

Everolimus + Exemestano aumenta SLP en pacientes que progresan tras tto adyuvante

Beck et al. Breast Cancer Res Treat 2014

Subgroup EVE+EXE (N = 100)

PBO+EXE (N = 37)

Any adjuvant therapy, %a 100 37

Adjuvant endocrine therapy only, %a 26 9

Adjuvant endocrine therapy + chemotherapy, %a 74 28

Pritchard, Clinical Breast Cancer Dec 2013

<70 años

8,11 m vs 4.01m

HR= 0.44

> 70 años

6.77 m vs 1.51 m

HR= 0.45

BOLERO-2 (39-m): Supervivencia Global

232

109

248

113

266

120

279

130

292

145

311

153

330

162

347

170

373

182

399

194

414

201

429

211

448

220

471

232

485

239

EVE+EXE

PBO+EXE

No. at risk

HR = 0.89 (95% CI, 0.73-1.10) Log-rank P = .1426

Kaplan-Meier medians EVE+EXE: 30.98 months PBO+EXE: 26.55 months

Censoring times

11

5

23

8

39

18

58

28

91

41

118

56

154

77

196

98

216

102

0

0

1

1

Piccart M , et al. EBCC 2014

¿ Cúal es la 2ª línea tras progresión a

IA no esteroideo?

Bachelot et al. Breast Cancer Res Treat 2013


RESISTENCIA

Inhibidores Ciclinas


phase III trial showed improved PFS when trastuzumab

was added to anastrozole in patients with ER-positive/

HER2-positive metastatic breast cancer (HR = 0.63, 95%

CI 0.47–0.84, P = 0.0016).109

ER and PI3K/ AKT/ mTOR crosstalk

Crosstalk between the ER and the PI3K/AKT/mTOR

signalling pathways has been associated with endocrine

resistance.107 The mTORC1 complex integrates signals

from growth factors (for example, insulin-like growth

factor), the presence of nutrients (amino acids), energy

signals through the AMP-activated kinase, and various

stress signals (such as hypoxia and DNA damage) to

promote cell growth and division by increasing mRNA

translation and inhibiting autophagy.110 Genes from

the PI3K/AKT/mTOR pathway are the most frequently

mutated in luminal breast cancer; PI3K mutations are the

most prevalent mutations and are identified in around

40% of cases.30,33,35,111

Interestingly, the major ity of PI3K mutations in

ER-positive tumours have been identified in the alpha

catalytic subunit (PIK3CA).36 Moreover, preclinical data

have demonstrated a synthetic lethal interaction when

PIK3CA inhibition is combined with oestrogen depri-

vation in breast cancer cell lines,112 suggesting that this

is a very promising approach to be tested in the clinic.

However, gene-expression profiling and reverse-phase

protein array data have shown that PIK3CA mutations

in non-metastatic, ER-positive breast cancer are not

associated with AKT/S6K pathway activation,33,113,114

as observed in cases that have PTEN loss in triple-

negative breast cancer. Therefore, whether the approach

of combined PI3K inhibition and endocrine treatment

is effective in early stage breast cancer remains to be

d emonstrated in future clinical studies.

Currently, there are numerous types of agents t argeting

the PI3K/AKT/mTOR pathway, including the following:

pan-PI3K inhibitors (such as, BKM-120, GDC-0941

and XL147); isoform-specific PI3K inhibitors (for

example, the PI3Kα inhibitors BYL719, GDC-0032 and

INK111; the PI3Kβ inhibitors GSK2636771, TGX-221

and KIN-193; and the PI3Kδ inhibitor CAL-101); dual

PI3K–mTOR inhibitors (such as, BEZ235, XL765,

GDC-0890 and GSK1059615); AKT inhibitors (includ-

ing ATP-competitive inhibitors such as GSK690693 and

GDC-0068 or allosteric inhibitors such as MK-2206);

and mTOR inhibitors (including allosteric inhibitors

such as the rapalogues sirolimus, temsirolimus, ridaforo-

limus and everolimus or mTOR catalytic inhibitors such

as the INK128, AZD8055, AZD2014 and OSI-027).115,116

The most promising results for targeting the crosstalk

between ER and the PI3K/AKT/mTOR pathway have

come from combining everolimus with endocrine therapy

in patients with metastatic breast cancer in the BOLERO II

phase III clinical trial.117 This trial randomly assigned 724

postmenopausal women with ER-positive/HER2-negative

breast cancer that was resistant to anastrozole or letro-

zole to either exemestane plus everolimus or exemestane

plus placebo in a 2:1 ratio. Of note, 84% of the women

participating in the study had previously been sensitive

to endocrine therapy. Everolimus improved median PFS

when added to exemestane (HR = 0.36; 95% CI 0.27–0.47;

P <0.001). However, the increased efficacy came at the cost

of increased toxicity, namely higher incidence of grade 3

or 4 stomatitis, hyperglycaemia, fatigue, anaemia and

pneumonitis. Based on this study, the FDA and European

Medicine Agency (EMA) approved everolimus in combi-

nation with exemestane for the treatment of women with

ER-positive/HER2-negative breast cancer with recurrence

or progression after receiving letrozole or anastrozole.

PI3K/ AKT/ mTOR

PIK3CA mutation 40%PTEN mutation/ loss 18%INPP4B loss 12%AKT1 mutation 3%

Pan-PI3K inhibitor sIsoform-speci c PI3K

inhibitorsDual PI3K–mTOR inhibitor s

AKT inhibitorsmTOR inhibitors

CDK4/ 6

11q13 ampli cation 37%CCND1 ampli cation 40%CDK4 ampli cation 19%CDKN1B, CDKN2A,CDKN2B loss 11%RB1 mutation 1%

CDK4/ 6 inhibitors

p53–MDM2

TP53 mutation 22%MDM2 gain 22%

MDM2 inhibitors

FGFR1

8p11–12 ampli cation 10%FGFR1 ampli cation 10%

Tyrosine kinase inhibitor sFGFR monoclonal antibodies

FGF-trap

HDAC

MLL3 mutation 7%HypermethylatedLuminal B ‘subtype’ 8%

HDAC inhibitors

E2F mTOR MAPK

Transcription

No transcription

RTK

PI3K

AKT

mTORC1

PTEN

INPP4B

4EBP1

S6K

mTORC2

Cyclin D1CDK4/ 6

Rb

MDM2

p53

FGFR1

PI3K

AKT

RAS

MEK

Figure 3 | Genomic and epigenomic landscape, pathways and drugs to reverse endocrine resistance in oestrogen

receptor-positive breast cancer. Data on genomic and epigenomic landscape are derived from next-generation sequencing

studies30–35 and from a study combining gene-expression profiling and copy number aberration data.29 Pink denotes gene or

protein activation and blue denotes gene or protein suppression in breast cancer. Abbreviations: HDAC, histone deacetylase;

RTK, receptor tyrosine kinase.

REVIEWS


7

Rb as Master-Regulator of the R-point

7

palbociclib

Finn, AACR 4 / 2014, San Diego USA

Estudio Fase II: Palbociclib +/- Letrozol

14

Phase 2 Study Design

ER+, HER2– Locally Recurrent or Metastatic Breast Cancer

N=66

1:1

Part 1

• Post-

menopausal

• ER+, HER2–

BC status

• No prior

treatment for

advanced

disease

R

A

N

D

O

M

I

Z

A

T

I

O

N

Palbociclib

125 mg QDa +

Letrozole

2.5 mg QD

Letrozole

2.5 mg QD

Part 2

N=99

1:1

• Post-

menopausal

• ER+, HER2–

BC with

CCND1

amplification

and/or loss

of p16

• No prior

treatment for

advanced

disease

R

A

N

D

O

M

I

Z

A

T

I

O

N

Palbociclib

125 mg QDa +

Letrozole

2.5 mg QD

Letrozole

2.5 mg QD

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)

aSchedule 3/1

Key Eligibility Criteria

• Measurable disease (RECIST 1.0) or bone-only disease

• ECOG PS of 0 or 1

• Adequate blood counts and organ function

• No prior/current brain metastases

Finn, AACR 4/ 2014, San Diego USA

Palbociclib +/- Letrozol : EFICACIA



Palbociclib +/- Letrozol

20

PFS Subgroup Analysis

0 . 062 0 . 125 0 . 25 0 . 50 1 . 0 2 . 0 4 . 0

Hazard Ratio ( log scale )

Time from End of Adju . Trt to Dis . Recur . Ms

Time from End of Adju . Trt to Dis . Recur . > 12 Ms

Time from End of Adju . Trt to Dis . Recur . Ms or De Novo

Prior Systemic Therapy : No

Prior Systemic Therapy : Yes

Previous Antihormonal Therapy : No

Previous Antihormonal Therapy : Yes

Previous Chemotherapy : No

Previous Chemotherapy : Yes

Disease Site : Other

Disease Site : Bone Only

Disease Site : Visceral

Baseline ECOG : 1

Baseline ECOG : 0

Age ≥ 65

Age < 65

Part 2

Part 1

All patients

15

25

59

44

40

57

27

71

13

30

17

37

38

46

37

47

50

34

84

14

30

51

37

44

53

28

65

16

26

12

43

36

45

39

42

49

32

81

Number of Patients

PAL + LET LET Population In favor of PAL + LET In favor of LET

≤12

≤12


Palbociclib +/- Letrozol

Palbociclib: Efectos adversos


Conclusiones y Reflexiones en Enfermedad Avanzada:

• La combinación de ttos hormonales ( Fulvestrant+ IA) tras fracaso a IA, no demuestra beneficio.

• De seguir explorando esta opción, ¿ debería plantearse en un contexto naïve hormonal?.

• Everolimus + Exemestano es una opción clara para pacientes R a IA no esteroideo.

• Beneficio claro para todas las pacientes, incluso en aquellos con enfermedad visceral.

• Beneficio para las que progresan precozmente trás ady/ neady ( hormonoresistencia).

Conclusiones y Reflexiones en Enfermedad Avanzada:

• Se exploran otras dianas: Inhibidor deacetilasa Histona, Receptor de Andrógenos, etc…

• A día de hoy no tenemos biomarcadores. • Inhibir la vía pasa por más agentes que inhibir mTor. • Se exploran pan- PI3K inhibidores : BKM-120 con

fulvestrant : Estudios BELLE .

• Palbociclib es el primer inhibidor CDK4/CDK6 que aumenta SLP en primera línea.

• En marcha los fase III ( Estudio PALOMA-2 –letrozol y PALOMA- 3-Fulvestrant).

GRACIAS

Documents

Enfermedad con Expresión de Receptores hormonales