Role of the mTOR Pathway in Endocrine Therapy- Resistant Breast … · 2012. 3. 15. · Modified from W. Sellers at SABCS 2009. PTEN loss HER2 PI3K PTEN Growth Factors RAS PDK1 PTEN

Role of the mTOR Pathway in Endocrine Therapy-

Resistant Breast Cancer

Ana M. GonzalezAna M. Gonzalez--Angulo, M.D.Angulo, M.D.Associate ProfessorAssociate Professor

Breast Medical OncologyBreast Medical OncologySystems BiologySystems Biology

Sao Paulo, Brazil, 3/2012Sao Paulo, Brazil, 3/2012

PI3K PI3K pathwaypathway

Meric-Bernstam and Gonzalez-Angulo, J Clin Oncol 2009

adaptoradaptoradaptoradaptor

RasRas

PIP2PIP2

PIP3PIP3

RTKRTK

RacRacRacRac

TuberinTuberinTuberinTuberin

IKKIKKIKKIKK

eNOSeNOSeNOSeNOS

PTENPTENPTENPTEN

NF NF κκκκκκκκBBNF NF κκκκκκκκBB

p53p53p53p53 Mdm2Mdm2

p85p85p85p85

p110p110

PDK1PDK1AKTAKT

PI3K pathwayPI3K pathway

Cell SurvivalCell SurvivalCell SurvivalCell Survival Cell CycleCell CycleCell CycleCell Cycle Cell GrowthCell GrowthProtein SynthesisProtein Synthesis

Cell GrowthCell GrowthProtein SynthesisProtein Synthesis

p27p27 KIP1KIP1

Ribosomal S6Ribosomal S6Ribosomal S6Ribosomal S6MycMyc

Cyclin D1Cyclin D1FasFas--ligandligandFasFas--ligandligand

p130p130 Rb2Rb2p130p130 Rb2Rb2

TuberinTuberinTuberinTuberin

HamartinHamartinHamartinHamartin

GSKGSK--33GSKGSK--33ForkheadForkheadForkheadForkhead

BimBimBimBim

BclBcl--XLXLBclBcl--XLXL

BadBadBadBad

mTORmTORmTORmTOR

S6K1S6K1S6K1S6K1

RhebRhebRhebRheb

4E4E--BP1BP14E4E--BP1BP1

1414--33--331414--33--33

PI3K PI3K pathway: metabolismpathway: metabolism

Gonzalez-Angulo and Meric-Bernstam, Clin cancer Res 2009

PI3K PI3K pathway: angiogenesispathway: angiogenesis

Stoeltzing, Meric-Bernstam, Ellis, Cancer Cell 2006

PI3K Pathway: genetic target in PI3K Pathway: genetic target in breast Cancerbreast Cancer

HER2HER2

PI3KPI3K

LKB1LKB1PTENPTEN

RASRAS

Growth Growth FactorsFactors

GeneGene % Mutation% Mutation % Amp/Del% Amp/Del

HER2HER2 22 2525INPP4BINPP4B

AKTAKT

TSCTSC1/21/2

mTORmTOR

S6KS6K

Tumor suppressor geneTumor suppressor geneOncogeneOncogene

AMPKAMPK

HER2HER2 22 2525

PIK3CAPIK3CA 2525 1616

KRASKRAS 44

PTENPTEN 44 88

INPP4BINPP4B 55 (TN)55 (TN)

AKT1AKT1 33

Modified from W. Sellers at SABCS 2009Onc*Base and Beroukhim et al, Nature 2010

PI3K pathway: distinct cancer statesPI3K pathway: distinct cancer statesAre there distinctive dependences?Are there distinctive dependences?

Modified from W. Sellers at AACR 2011

PIK3CA mutationsPIK3CA mutations

HER2HER2

PI3KPI3K

PTENPTEN


RASRAS

PDK1PDK1

PIK3CA MutationsPIK3CA MutationsDO NOT invariable activate AKTDO NOT invariable activate AKTDO NOT invariable require AKTDO NOT invariable require AKTDO require PIK3C alphaDO require PIK3C alpha

mTORmTOR

S6KS6K

AKTAKT

TSC1/2TSC1/2

PDK1PDK1

Vasudevan et al, Cancer Cell 2009Wee et al, PNAS 2008Modified from W. Sellers at SABCS 2009

PTEN lossPTEN loss

HER2HER2

PI3KPI3K

PTENPTEN


RASRAS

PDK1PDK1

PTEN loss leads toPTEN loss leads toConstitutive AKT activationConstitutive AKT activationAKT dependence (AKT1)AKT dependence (AKT1)PIK3C Beta dependencePIK3C Beta dependence

mTORmTOR

S6KS6K

AKTAKT

TSC1/2TSC1/2

PDK1PDK1

Vasudevan et al, Cancer cell 2009Nakamura et al, MCB 2000Jia et al, Nature 2008Modified from W. Sellers at SABCS 2009

RTK activationRTK activationLeads to PIK3C Alpha dependenceLeads to PIK3C Alpha dependence

RTK activationRTK activation

If HER2 signaling depends on If HER2 signaling depends on alpha, why PTEN loss creates alpha, why PTEN loss creates trastuzumabtrastuzumab resistance?resistance?

PTEN loss can convert alpha to PTEN loss can convert alpha to beta dependencebeta dependence

Zhao et al, PNAS 2008Jia et al, Nature 2008Wee et al PNAS 2008Modified from W. Sellers at SABCS 2009

Resistance to endocrine therapy in ER+ breast Resistance to endocrine therapy in ER+ breast cancer is dependent upon PI3K signalingcancer is dependent upon PI3K signaling

LTED cells exhibit LTED cells exhibit increased PI3K/increased PI3K/mTORmTORpathway activationpathway activation

PI3K pathway inhibition suppresses PI3K pathway inhibition suppresses LTED cell growth, and prevents LTED cell growth, and prevents the emergence of hormonethe emergence of hormone--independent cellsindependent cells

Miller et al, J Clin Invest 2010

Resistance to endocrine therapy in ER+ breast Resistance to endocrine therapy in ER+ breast cancer is dependent upon PI3K signalingcancer is dependent upon PI3K signaling

Miller et al, J Clin Invest 2010

Frequency of mutations in the Frequency of mutations in the PIK3CA, PIK3CA, and and AKT1AKT1genes in 547 human breast cancers and 41 breast genes in 547 human breast cancers and 41 breast

cancer cell linescancer cell lines

Tumor subtypeTumor subtype MutationMutation

PIK3CAPIK3CA catalytic catalytic domain*domain*

PIK3CAPIK3CA other other †† PIK3CAPIK3CA totaltotal AKT1AKT1 E17KE17K

All human breast tumorsAll human breast tumors 73/547 (13.3%)73/547 (13.3%) 44/547 (8.0%)44/547 (8.0%) 117/547 (21.4%)117/547 (21.4%) 6/418 (1.4%)6/418 (1.4%)

Human breast HRHuman breast HR++ 48/232 (20.7%)48/232 (20.7%) 32/232 (13.8%)32/232 (13.8%) 80/232 (34.5%)80/232 (34.5%) 6/232 (2.6%)6/232 (2.6%)

ER+PR+ER+PR+ 39/186 (21%)39/186 (21%) 22/186 (11.8%)22/186 (11.8%) 61/186 (32.8%)61/186 (32.8%) 6/186 (3.2%)6/186 (3.2%)

ER+PRER+PR-- 9/41 (22%)9/41 (22%) 10/41 (24.4%)10/41 (24.4%) 19/41 (46.3%)19/41 (46.3%) 0/41 (0%)0/41 (0%)

Stemke-Hale, Gonzalez-Angulo et al, Cancer Res 2008

ER+PRER+PR-- 9/41 (22%)9/41 (22%) 10/41 (24.4%)10/41 (24.4%) 19/41 (46.3%)19/41 (46.3%) 0/41 (0%)0/41 (0%)

ERER--PR+PR+ 0/5 (0%)0/5 (0%) 0/5 (0%)0/5 (0%) 0/5 (0%)0/5 (0%) 0/5 (0%)0/5 (0%)

Human breast HER2Human breast HER2++ 13/75 (17.3%)13/75 (17.3%) 4/75 (5.3%)4/75 (5.3%) 17/75 (22.7%)17/75 (22.7%) 0/75 (0%)0/75 (0%)

Human breast TNHuman breast TN 12/240 (5.0%)12/240 (5.0%) 8/240 (3.3%)8/240 (3.3%) 20/240 (8.3%)20/240 (8.3%) 0/111 (0%)0/111 (0%)

All breast cancer cell linesAll breast cancer cell lines 7/41 (17.1%)7/41 (17.1%) 9/41 (22%)9/41 (22%) 16/41 (39%)16/41 (39%) 0/41 (0%)0/41 (0%)

Breast cancer cell lines HR+Breast cancer cell lines HR+ 1/12 (8.3%)1/12 (8.3%) 3/12 (25%)3/12 (25%) 4/12 (33.3%)4/12 (33.3%) 0/12 (0%)0/12 (0%)

Breast cancer cell lines HER2+Breast cancer cell lines HER2+ 2/10 (20%)2/10 (20%) 4/10 (40%)4/10 (40%) 6/10 (60%)6/10 (60%) 0/10 (0%)0/10 (0%)

Breast cancer cell lines Breast cancer cell lines TNTN 4/19 (21%)4/19 (21%) 2/19 (10.5%)2/19 (10.5%) 6/19 (31.6%)6/19 (31.6%) 0/19 (0%)0/19 (0%)

mTOR

PI3K pathway activationPI3K pathway activation

Courtesy of S. Johnston

TamTamTemsirolimusTemsirolimusControlControl

WTWTMCFMCF--77

Tam + TemsirolimusTam + Temsirolimus

TemsirolimusTemsirolimus Reverses TAM resistance in Reverses TAM resistance in AktAkt--Expressing Breast Cancer by Restoration of Expressing Breast Cancer by Restoration of

Apoptotic ResponseApoptotic Response

MyrAkt1MyrAkt1MCF7MCF7

MCFMCF--77

De Graffenried et al, Clin Cancer Res 2004

TamTamTemsirolimusTemsirolimusControlControl

WTWTMCFMCF--77

Tam + TemsirolimusTam + Temsirolimus

TemsirolimusTemsirolimus Reverses TAM resistance in Reverses TAM resistance in AktAkt--Expressing Breast Cancer by Restoration of Expressing Breast Cancer by Restoration of

Apoptotic ResponseApoptotic Response

MyrAkt1MyrAkt1MCF7MCF7

MCFMCF--77

De Graffenried et al, Clin Cancer Res 2004

RAD001 Added to Letrozole Causes RAD001 Added to Letrozole Causes GI Accumulation and Increased ApoptosisGI Accumulation and Increased Apoptosis

1515

2020

2525

Apo

ptot

ic c

ells

(%)

Apo

ptot

ic c

ells

(%)

Vehicle 1Vehicle 1

Vehicle 2Vehicle 20.2 0.2 nMnMRAD001RAD001

2 2 nMnMRAD001RAD001

54%54%

53%53%60%60%

p p < 0.05 (Friedman test)< 0.05 (Friedman test)

MCF7 cells overexpressingMCF7 cells overexpressingaromatase enzymearomatase enzyme

00

55

1010

00 22 00 22 00 22Apo

ptot

ic c

ells

(%)

Apo

ptot

ic c

ells

(%)

RAD001RAD001

100nM 100nM LetLet

500nM 500nM LetLet

Adapted from S. JohnstonBoulay et al. Clin Cancer Res 2005

60%60%

66%66%

73%73%

100 nM Let100 nM Let

MCF7 Cells overexpressingMCF7 Cells overexpressingaromatase enzymearomatase enzyme

Randomised Phase II study of Randomised Phase II study of LetrozoleLetrozole ±± TemsirolimusTemsirolimus in MBCin MBC

1.0

0.9

Probability of Progression-Free Survival

0.5

0.6

0.7

0.8

RRRR CBRCBRLL 45%45% 69%69%L+10TL+10T 33%33% 57%57%L+30TL+30T 40%40% 80%80%

Probability of Progression-Free Survival

0.0

0.1

0.2

0.3

0.4

0.5

0 2 4 6 8 10 12 14 16 18 20

Months to Progressive Disease/Death

10 mg TEMSR + 2.5 mg LET, daily schedule

30 mg TEMSR + 2.5 mg LET, intermittent schedule

2.5 mg LET alone, daily schedule

Baselga et al, SABCS 2005

Phase III Study of Letrozole Phase III Study of Letrozole ±±TemsirolimusTemsirolimus in ER+ MBCin ER+ MBC

0.70.7

0.60.6

0.80.8

0.90.9

1.01.0

--fr

ee s

urviva

lfr

ee s

urviva

l

Median PFS (mo)Median PFS (mo) 9.29.2 9.29.2

LetrozoleLetrozole

(n=489)(n=489)

Letrozole +Letrozole +TemsirolimusTemsirolimus

(n=493)(n=493)

HR (95% CI) = HR (95% CI) = 0.920.92 (0.75, 1.13)(0.75, 1.13)

Chow et al. SABCS 2006, abstract 6091

00 22 44 66 88 1010 1212 1414 1616 1818

Time (months)Time (months)

0.60.6

0.50.5

0.20.2

0.10.1

00

0.40.4

0.30.3

Prog

ress

ion

Prog

ress

ion--

�� No specific patient selection!No specific patient selection!

RAD001 RAD001 iincreasesncreases tumor tumor pp--AktAkt in in patientspatients

--th

erap

yth

erap

y

daily continuous oral dose daily continuous oral dose weekly oral dose weekly oral dose

PhasePhase I I pharmacodynamicpharmacodynamic studystudy

Tabernero et al. J Clin Oncol. 2008

pre

pre--

onon--th

erap

yth

erap

y

5mg/day5mg/day 10mg/day10mg/day 20mg/week20mg/week 50mg/week50mg/week

Akt

PTEN

PIP2 PIP3

TSC1TSC2

PI3K PDK1IRS1

IGF1RFeedback loopFeedback loop

Rheb GDP

mTOR mTORraptorrictor

4EBP1

Rheb GTP

S6K

S6

Ki67Proliferation

eIF4E-F-G


Akt

PTEN

PIP2 PIP3

TSC1TSC2

PI3K PDK1

IGF1R

IRS1

Feedback loopFeedback loop

Rheb GDP

mTOR mTORraptorrictor

4EBP1

Rheb GTP

S6K

S6

Ki67Proliferation

eIF4E-F-G

everolimus


•• Newly diagnosed, untreated patients with ERNewly diagnosed, untreated patients with ER++ localized breast localized breast cancer likely to benefit from hormonal therapycancer likely to benefit from hormonal therapy

•• Palpable tumor: Palpable tumor: > 2 cm diameter> 2 cm diameter

RRAANN Letrozole 2.5 mg/dLetrozole 2.5 mg/d

RAD001 10 mg/dRAD001 10 mg/d

N = 138N = 138SSCC

Phase II Phase II neoadjuvantneoadjuvant everolimuseverolimus(RAD001) breast cancer study(RAD001) breast cancer study

Tumor samples Tumor samples (surgery)(surgery)

NNDDOOMMIIZZEE

Letrozole 2.5 mg/dLetrozole 2.5 mg/dRAD001 10 mg/dRAD001 10 mg/d

Letrozole 2.5 mg/dLetrozole 2.5 mg/dPlaceboPlacebo

16 weeks16 weeks

SurgerySurgery

Tumor biopsiesTumor biopsies(pretreatment)(pretreatment)

Tumor biopsies Tumor biopsies (day 15)(day 15)

SSCCRREEEENN

N = 132N = 132

Baselga et al. J Clin Oncol 2009

Results: efficacy summaryResults: efficacy summary

Everolimus +Everolimus +LetrozoleLetrozolen = 138n = 138

Placebo +Placebo +LetrozoleLetrozolen = 132n = 132 PP

Overall Response (CR + PR), %Overall Response (CR + PR), %

n = 138n = 138 n = 132n = 132 PPPalpationPalpation(primary end point)(primary end point) 68.168.1 59.159.1 .062*.062*

UltrasoundUltrasound 58.058.0 47.047.0 .035*.035*

*1*1--sided chisided chi--square level of significance is 10%.square level of significance is 10%.


Results:Results:Major Major pharmacodynamicpharmacodynamic changes at day 15changes at day 15

--2020

00

2020

4040

Chang

e in

H S

core

(% P

ositive f

or K

i67)

Chang

e in

H S

core

(% P

ositive f

or K

i67)

CyclinD1CyclinD1 pS6pS6235235PRPR Ki67Ki67 pS6pS6240240ERER

pAktpAkt

Reduction in pS6240 and pS6235 reveals everolimusReduction in pS6240 and pS6235 reveals everolimus--treated patientstreated patients

--140140

--120120

--100100

--8080

--6060

--4040

--2020

Chang

e in

H S

core

(% P

ositive f

or K

i67)

Chang

e in

H S

core

(% P

ositive f

or K

i67)

Everolimus + letrozoleEverolimus + letrozole

LetrozoleLetrozole


Cell cycle response (KiCell cycle response (Ki--67) correlates with clinical 67) correlates with clinical response: role of PIK3CA mutationsresponse: role of PIK3CA mutations

Reduction in KiReduction in Ki--67 at Day 15 67 at Day 15

Patients with PIK3CA Patients with PIK3CA exonexon 9 9 mutmutless responsive to less responsive to letrozoleletrozole as as sensitive to sensitive to everolimuseverolimus + + letrozoleletrozole

00

PIK3CA e9PIK3CA e9mutant onlymutant only

PIK3CA e20PIK3CA e20mutant onlymutant only

PIK3CA PIK3CA wt onlywt only

6060

8080

Day 15 Day 15 KiKi--67 score correlated 67 score correlated with clinical responsewith clinical response

--120120

--100100

--8080

--6060

--4040

--2020

EEverolimusverolimus + + letrozoleletrozoleLetrozoleLetrozole

Ki6

7d15

Ki6

7d15

CRCR PRPR NCNC PD PD

00

2020

4040

6060


TAMRAD SchemaTAMRAD SchemaRandomized Phase IIRandomized Phase IIMetastatic patients with prior exposure to AIMetastatic patients with prior exposure to AI

A : Tamoxifen, 20 mg/d (TAM)A : Tamoxifen, 20 mg/d (TAM)

•• Stratification: Primary or secondary hormone resistanceStratification: Primary or secondary hormone resistance•• Primary: Relapse during adjuvant AI; progression within 6 Primary: Relapse during adjuvant AI; progression within 6

months of starting AI treatment in metastatic settingmonths of starting AI treatment in metastatic setting•• Secondary: Late relapse (≥ 6 months) or prior response Secondary: Late relapse (≥ 6 months) or prior response

and subsequent progression to metastatic AI treatmentand subsequent progression to metastatic AI treatment•• No crossover plannedNo crossover planned

B : Tamoxifen 20 mg/d + RAD001 10 mg/d (TAM + RAD) B : Tamoxifen 20 mg/d + RAD001 10 mg/d (TAM + RAD)

Bachelot M, et al SABCS 2010

Time to ProgressionTime to Progression

Hazard Ratio (HR) = 0.53; 95% CI (0.35Hazard Ratio (HR) = 0.53; 95% CI (0.35--0.81)0.81)Exploratory logExploratory log--rank: rank: P = P = 0.00260.0026

TAM: 4.5 mo.TAM: 4.5 mo.TAM + RAD: 8.6 mo. TAM + RAD: 8.6 mo.

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0Pr

obab

ility

of

Sur

viva

lPr

obab

ility

of

Sur

viva

l TAM TAM

TAM + RAD TAM + RAD

MonthMonth

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626 2828

Prob

ability

of

Sur

viva

lPr

obab

ility

of

Sur

viva

l

Patients at riskPatients at riskTAM + RAD: n = TAM + RAD: n =

TAM : n = TAM : n = 54545757

45454444

39393030

34342424

28282222

25251313

19191111

121266

7711

1100

0000

26261616

161677

9922

1100


Time to Progression as a Function Time to Progression as a Function of Intrinsic Hormone Resistanceof Intrinsic Hormone Resistance

•• PrimaryPrimary hormone hormone resistance (n = 54)resistance (n = 54)

–– TAM: 3.9 mo.TAM: 3.9 mo.

–– TAM + RAD: 5.4 mo.TAM + RAD: 5.4 mo.

–– HR = 0.74 (0.42HR = 0.74 (0.42--1.3)1.3)

TAM TAM

TAM + RAD TAM + RAD

0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.91.01.0

Prob

ability

of

Sur

viva

lPr

obability

of

Sur

viva

l

–– HR = 0.74 (0.42HR = 0.74 (0.42--1.3)1.3)

•• Secondary hormone Secondary hormone resistance (n = 56)resistance (n = 56)

–– TAM: 5.0 mo.TAM: 5.0 mo.

–– TAM + RAD: 17.4 mo. TAM + RAD: 17.4 mo.

–– HR = HR = 0.38 (0.210.38 (0.21--0.71) 0.71)

0.00.000 66 1212 1818 2424 3030

Prob

ability

of

Sur

viva

lPr

obability

of

Sur

viva

lPr

obability

of

Sur

viva

lPr

obability

of

Sur

viva

l

MonthsMonths

0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.91.01.0

MonthsMonths

00 66 1212 1818 2424 3030


Adverse EventsAdverse Events

Incidence, n (%)TAM

n = 57TAM + RAD

n = 54

Grade Any 3/4 Any 3/4

Most Common Adverse Events (AE)FatigueFatigueStomatitisStomatitisRashRashAnorexiaAnorexia

30 (52.6)4 (7.0)3 (5.3)

10 (17.5)

6 (10.5)0

1 (1.8)2 (3.5)

40 (74.1)40 (74.1)28 (51.9)28 (51.9)21 (38.9)21 (38.9)24 (44.4)24 (44.4)

3 (5.6)6 (11.1)3 (5.6)5 (9.3)AnorexiaAnorexia

DiarrheaDiarrheaNauseaVomitingPneumonitisThromboembolicPain

10 (17.5)5 (8.8)

19 (33.3)7 (12.3)2 (3.5)4 (7.0)

48 (84.2)

2 (3.5)00

2 (3.5)2 (3.5)4 (7.0)

11 (19.3)

24 (44.4)24 (44.4)21 (38.9)21 (38.9)18 (33.3)9 (16.7)9 (16.7)7 (13.0)42 (77.8)

5 (9.3)1 (1.9)2 (3.7)

01 (1.9)3 (5.6)5 (9.3)

Dose reduction due to AEDose reduction due to AE 0 (0)0 (0) 15 (28) 15 (28)

Treatment discontinuation due to AETreatment discontinuation due to AE 4 (7.0)4 (7.0) 3 (5.6)3 (5.6)

Bachelot et al SABCS 2010

2 2

11

Everolimus 10 mg/day +Everolimus 10 mg/day +Exemestane 25 mg/day Exemestane 25 mg/day

(N = 485)(N = 485)

Placebo +Placebo +Exemestane 25 mg/day Exemestane 25 mg/day

BOLEROBOLERO--2 Schema2 Schema

N = 724 N = 724

Postmenopausal Postmenopausal ER+ HER2ER+ HER2-- ABC ABC refractory to refractory to letrozoleletrozole or or

PFSPFS

OSOSORRORR

Bone MarkersBone MarkersSafetySafetyExemestane 25 mg/day Exemestane 25 mg/day

(N = 239)(N = 239)

�� Stratification:Stratification:

1.1. Sensitivity to prior hormonal therapySensitivity to prior hormonal therapy

2.2. Presence of visceral disease Presence of visceral disease

�� No crossNo cross--overover

letrozoleletrozole or or anastrozoleanastrozole

Bone MarkersBone MarkersSafetySafety

PKPK

Baselga et al. N Engl J Med 2012

BOLEROBOLERO--2 Primary Endpoint: PFS 2 Primary Endpoint: PFS Local AssessmentLocal Assessment

8080

6060

100100

Prob

ability

of

Eve

nt (%)

Prob

ability

of

Eve

nt (%)

HR = 0.43 (95% CI: 0.35HR = 0.43 (95% CI: 0.35––0.54)0.54)

EVE + EXE: 6.9 monthsEVE + EXE: 6.9 months

PBO + EXE: 2.8 monthsPBO + EXE: 2.8 months

Log rank Log rank PP value = 1.4 x 10 value = 1.4 x 10 --1515

EverolimusEverolimus 485485 398398 294294 212212 144144 108108 7575 5151 3434 1818 88 33 33 00PlaceboPlacebo 239239 177177 109109 7070 3636 2626 1616 1414 99 44 33 11 00 00

Time (weeks)Time (weeks)

00 121266 1818 2424 3030 3636 4848 60604242 5454 72726666 7878

4040

2020

00

Prob

ability

of

Eve

nt (%)

Prob

ability

of

Eve

nt (%)

Everolimus + Exemestane (E/N=202/485)Everolimus + Exemestane (E/N=202/485)Placebo + Exemestane (E/N=157/239)Placebo + Exemestane (E/N=157/239)


BOLEROBOLERO--2 Primary Endpoint: PFS 2 Primary Endpoint: PFS Central AssessmentCentral Assessment

HR = 0.36 (95% CI: 0.27HR = 0.36 (95% CI: 0.27––0.47)0.47)

EVE + EXE: 10.6 MonthsEVE + EXE: 10.6 Months

PBO + EXE: 4.1 MonthsPBO + EXE: 4.1 Months

Log rank Log rank PP value = 3.3 x 10 value = 3.3 x 10 --1515

8080

6060

100100

Prob

ability

of

Eve

nt (%)

Prob

ability

of

Eve

nt (%)

Time (weeks)Time (weeks)

00 121266 1818 2424 3030 3636 4848 60604242 5454 72726666 7878

4040

2020

00

Prob

ability

of

Eve

nt (%)

Prob

ability

of

Eve

nt (%)

Everolimus + Exemestane (E/N=114/485)Everolimus + Exemestane (E/N=114/485)Placebo + Placebo + ExemestaneExemestane (E/N=104/239)(E/N=104/239)

EverolimusEverolimus 485485 385385 281281 201201 132132 102102 6767 4343 2828 1818 99 33 22 00PlaceboPlacebo 239239 168168 9494 5555 3333 2020 1111 1111 66 33 33 11 00 00


BOLEROBOLERO--2: Most Common G3/4 AEs2: Most Common G3/4 AEs

Everolimus + Everolimus + Exemestane Exemestane

(N = 482), %(N = 482), %Placebo + Exemestane Placebo + Exemestane

(N = 238), %(N = 238), %

All All GradesGrades

Grade Grade 33

Grade Grade 44

All All GradesGrades Grade 3Grade 3 Grade 4Grade 4

StomatitisStomatitis 5656 88 00 1111 11 00

FatigueFatigue 3333 33 <1<1 2626 11 00FatigueFatigue 3333 33 <1<1 2626 11 00

DyspneaDyspnea 1818 44 00 99 11 <1<1

AnemiaAnemia 1616 55 <1<1 44 <1<1 <1<1

HyperglycemiaHyperglycemia 1313 44 <1<1 22 <1<1 00

ASTAST 1313 33 <1<1 66 11 00

PneumonitisPneumonitis 1212 33 00 00 00 00


BOLEROBOLERO--2 PFS in Subgroups2 PFS in Subgroups

<65 (449)<65 (449)≥65 (275)≥65 (275)

YES (610)YES (610)NO (114)NO (114)

YES (406)YES (406)NO (318)NO (318)

0 (435)0 (435)

All (724)All (724)AgeAge

Hormonal sensitivityHormonal sensitivity

Visceral metastasisVisceral metastasis

Baseline ECOG PSBaseline ECOG PS

Subgroups (N)Subgroups (N)

Favors Placebo + Favors Placebo + ExemestaneExemestane

Favors Everolimus Favors Everolimus + Exemestane+ Exemestane

0 (435)0 (435)1, 2 (274)1, 2 (274)

YES (493)YES (493)NO (231)NO (231)

1 (118)1 (118)2 (217)2 (217)≥3 (389)≥3 (389)

YES (398)YES (398)NO (326)NO (326)

YES (523)YES (523)NO (184)NO (184)

0.00.0 0.20.2 0.40.4 0.60.6 0.80.8 1.01.0 1.21.2

Hazard RatioHazard Ratio

Prior chemotherapyPrior chemotherapy

No. of prior therapiesNo. of prior therapies

NonNon--NSAI hormonal therapyNSAI hormonal therapy

PgR status positivePgR status positive


BOLEROBOLERO--2: Response & Clinical Benefit2: Response & Clinical Benefit

50,5%50,5%

4040

5050

6060 Everolimus + ExemestaneEverolimus + Exemestane

Placebo + ExemestanePlacebo + Exemestane

P < 0.0001


12,0%12,0%

1,3%1,3%

25,5%25,5%

00

1010

2020

3030

ResponseResponse Clinical BenefitClinical Benefit

BOLEROBOLERO--2: Bone Markers2: Bone Markers% C

han

ge F

rom B

aselin

e% C

han

ge F

rom B

aselin

e

20.920.9

35.535.529.529.5

18.118.1

40.740.7 40.340.3

3030

4040

5050BSAPBSAP P1NPP1NP CTXCTX BSAPBSAP P1NPP1NP CTXCTX

6 weeks6 weeks 12 weeks12 weeks

% C

han

ge F

rom B

aselin

e% C

han

ge F

rom B

aselin

e

--5.65.6

--20.320.3

--6.36.3 --3.63.6

--26.726.7

--0.40.4

20.920.9 18.118.1

--4040

--3030

--2020

--1010

00

1010

2020

EVE + EXEEVE + EXEPBO + EXEPBO + EXE

ΔΔ27%27% ΔΔ56%56% ΔΔ36%36% ΔΔ22%22% ΔΔ67%67% ΔΔ41%41%

Hortobagyi et al. SABCS 2011

PI3K pathway: markers vs. targetsPI3K pathway: markers vs. targets

INPP4BLKB1

Modified from McAuliffe P et al. Clin P et al. Clin Breast Cancer 2010

LKB1

RegistrationRegistration

PIK3CA/PTENPIK3CA/PTENanalysisanalysis

Arm A Arm A -- GDCGDC--0941 (Daily)0941 (Daily)

RandomizationRandomizationStratificationStratification

PIK3CA/PTEN PIK3CA/PTEN ResultsResults

Fulvestrant in ER positive breast cancer Fulvestrant in ER positive breast cancer with GDCwith GDC--0941 and GDC0941 and GDC--0980 0980 InhibitorsInhibitors

C2D1C2D1C1D1C1D1 C1D15C1D15DD--2828

RegistrationRegistration

“run“run--in”in”screeningscreening

FulvestrantFulvestrant500mg500mg

FulvestrantFulvestrant500mg500mg

Arm B Arm B -- GDCGDC--0980 (Daily)0980 (Daily)

C3D1C3D1

Arm C Arm C –– Placebo (Daily)Placebo (Daily)

FulvestrantFulvestrant500mg/Q4w500mg/Q4w

FulvestrantFulvestrant500mg/Q4w500mg/Q4w

D1D1--D28 D28 D1D1--D28 D28

NodeNode--positive HRpositive HR--positive and HER2positive and HER2--negative breast cancernegative breast cancer

Patients consent to studyPatients consent to study--sponsored RSsponsored RStesting if not already donetesting if not already done

RECURRENCE RECURRENCE

Number of positive nodes ?Number of positive nodes ?

11--3 positive3 positive4+ positive4+ positive

RS > 25RS > 2511--3 positive nodes and 3 positive nodes and

Phase III Randomized, placeboPhase III Randomized, placebo--controlled clinical trial evaluating the use of controlled clinical trial evaluating the use of adjuvant endocrine therapy +/adjuvant endocrine therapy +/-- everolimuseverolimus in patients with highin patients with high--risk, noderisk, node--

positive, hormone receptorpositive, hormone receptor--positive and HER2positive and HER2--neu normal breast cancer neu normal breast cancer

RECURRENCE RECURRENCE SCORE evaluatedSCORE evaluated

Chemotherapy; Chemotherapy; endocrine therapyendocrine therapy

No Chemotherapy; No Chemotherapy; endocrine therapyendocrine therapy

RANDOMIZATIONRANDOMIZATION

Chemotherapy vs.Chemotherapy vs.No ChemotherapyNo Chemotherapy

Adjuvant or Adjuvant or neoadjuvant neoadjuvant

chemotherapychemotherapy

RANDOMIZATIONRANDOMIZATIONPostPost--chemotherapychemotherapy

(stratification by number of (stratification by number of lymph nodes and timing of lymph nodes and timing of

chemotherapy)chemotherapy)

Everolimus vs. Everolimus vs. PlaceboPlacebo

RS ≤ 25RS ≤ 25

Everolimus +Everolimus +Endocrine TherapyEndocrine Therapy

Placebo + Placebo + Endocrine TherapyEndocrine Therapy

Current Current RxPONDERRxPONDER trialtrial New adjuvant trialNew adjuvant trial

Low riskLow risk11--3 positive nodes3 positive nodes

and RS ≤ 25and RS ≤ 25

11--3 positive nodes and 3 positive nodes and RS > 25 or 4+ positive RS > 25 or 4+ positive

nodesnodes

A phase II A phase II neoadjuvantneoadjuvant trial of BEZtrial of BEZ--235 in 235 in combination with endocrine therapy in postcombination with endocrine therapy in post--menopausal patients with operable hormone menopausal patients with operable hormone

receptorreceptor--positive breast cancerpositive breast cancer

PostmenpausalPostmenpausalBreast CancerBreast CancerT1T1--3/N03/N0--11

Arm 1:Arm 1:LetrozoleLetrozoleBEZ235BEZ235

2 weeks2 weeks

Biops

yBiops

y

Sur

gery

Sur

gery

22 weeks22 weeks

LetrozoleLetrozoleBEZ235BEZ235

T1T1--3/N03/N0--11ER or PR+/HER2ER or PR+/HER2––PostPost--menopausalmenopausal

PI3K pathway aberrationPI3K pathway aberration(core biopsy)(core biopsy)

KiKi--6767TUNELTUNEL

PP--AktAkt, etc., etc.microarraysmicroarrays

RPPARPPAFDGFDG--PETPET

KiKi--6767TUNELTUNEL

PP--Akt, etcAkt, etcmicroarraysmicroarrays

RPPARPPAFDGFDG--PETPET

Arm 2:Arm 2:LetrozoleLetrozolePlaceboPlacebo

Biops

yBiops

y

Sur

gery

Sur

gery

Path CRPath CRClinClin ResponseResponse(US, (US, MammoMammo))

Breast Cons SurgeryBreast Cons SurgeryKiKi--6767TUNELTUNEL

PP--Akt, etcAkt, etcmicroarraysmicroarrays

RPPARPPA

2:1 randomization2:1 randomization

LetrozoleLetrozolePlaceboPlacebo

ConclusionsConclusions•• The PI3K pathway is one of the most important active signaling pathways in The PI3K pathway is one of the most important active signaling pathways in

cancer growth through various mechanismscancer growth through various mechanisms

•• Modulation of signal transduction pathway may modulate activity of Modulation of signal transduction pathway may modulate activity of endocrine therapy and influence outcome… Assuming of course that the endocrine therapy and influence outcome… Assuming of course that the tumor is “addicted” to the intended target!!tumor is “addicted” to the intended target!!

•• PI3K PI3K pathway activation is an important component in all subtypes of breast pathway activation is an important component in all subtypes of breast cancer, both in cancer growth and in therapy resistancecancer, both in cancer growth and in therapy resistancecancer, both in cancer growth and in therapy resistancecancer, both in cancer growth and in therapy resistance

•• The PI3K pathway is a common The PI3K pathway is a common mechanism of mechanism of endocrine therapy resistanceendocrine therapy resistance. . Benefit Benefit is is impressive.impressive.

Will Will be studied in the adjuvant be studied in the adjuvant settingsetting

Toxicities?Toxicities?

Patient Patient selection (awaiting correlativesselection (awaiting correlatives))

•• Clinical Clinical trials to evaluate the role PI3K pathway inhibitors at different trials to evaluate the role PI3K pathway inhibitors at different levels of the pathway are ongoing and should have extensive correlative levels of the pathway are ongoing and should have extensive correlative components to be able to decipher the best use of these drugs according to components to be able to decipher the best use of these drugs according to the molecular aberrations of the the molecular aberrations of the tumorstumors

AcknowledgementsAcknowledgementsMentorshipMentorship

•• G.N. HortobagyiG.N. Hortobagyi•• G.B. MillsG.B. Mills•• F. MericF. Meric--BernstamBernstam

GonzalezGonzalez--Angulo’s LabAngulo’s Lab•• S. LiuS. Liu•• X. MengX. Meng•• C. PhanC. Phan•• H. H. ChenChen•• E. E. TarcoTarco

MericMeric--Berstam’s LabBerstam’s Lab•• A. AkcakanatA. Akcakanat

Collaborators MDACCCollaborators MDACC

Systems BiologySystems Biology•• KK. . HaleHale•• J. J. MendelsohnMendelsohnTranscriptional ProfilingTranscriptional Profiling•• L. PusztaiL. Pusztai•• W.F. Symmans W.F. Symmans Tumor BankTumor Bank•• A. SahinA. SahinBMOBMO•• L. HsuL. Hsu

Surgical OncologySurgical Oncology•• E. MittendorfE. Mittendorf

BioinformaticsBioinformatics•• K. Coombes K. Coombes •• Y. JiY. Ji•• Z. JuZ. Ju•• W. LiuW. LiuBiostatisticsBiostatistics•• D. BerryD. Berry•• K. DoK. Do•• X. LeiX. Lei

T and H&NT and H&N•• G. BlumenscheinG. BlumenscheinPhase IPhase I

Collaborators Outside MDACollaborators Outside MDA

•• C. Perou, L. CareyC. Perou, L. Carey•• I. KropI. Krop•• R. Bernards, H. HorlingsR. Bernards, H. Horlings•• A. Lluch, J. FerrerA. Lluch, J. Ferrer•• C. C. ArteagaArteaga•• J. BaselgaJ. Baselga•• J. J. TaberneroTabernero, , J. RodonJ. Rodon•• J. GrayJ. Gray•• M. EllisM. Ellis•• C. Hudis, N. RosenC. Hudis, N. Rosen•• C. C. SotiriouSotiriou•• P. P. LorussoLorusso•• AL. BorresenAL. Borresen--DaleDale•• A. AkcakanatA. Akcakanat

•• G. SinghG. Singh•• E. MittendorfE. Mittendorf Phase IPhase I

•• Razelle KurzrockRazelle Kurzrock

•• AL. BorresenAL. Borresen--DaleDale•• F. F. AndreAndre•• M. PollakM. Pollak

Funding ByFunding By•• NIHNIH•• MDACC PhysicianMDACC Physician--Scientist Start up FundsScientist Start up Funds•• Komen for the CureKomen for the Cure•• BCRFBCRF•• Texas Fed of Business and Professional WomenTexas Fed of Business and Professional Women•• Commonwealth Foundation for Cancer ResearchCommonwealth Foundation for Cancer Research•• AACR SU2C Dream TeamAACR SU2C Dream Team•• ACSACS•• Clayton Foundation Clayton Foundation

•• PI of Investigator Initiative Trials with Novartis, BMS, GSK, PI of Investigator Initiative Trials with Novartis, BMS, GSK, Abraxis, Roche Dx, Genomic Health Inc, Merck.Abraxis, Roche Dx, Genomic Health Inc, Merck.•• Lab MTAs with NIH, Merck, Exelixis, Novartis, Xcovery, Lab MTAs with NIH, Merck, Exelixis, Novartis, Xcovery, EMD Serono, Genentech, BayerEMD Serono, Genentech, Bayer

Thank you !!!!Thank you !!!!

[email protected]@mdanderson.org

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