hormone-dependent breast cancer: mechanisms of resistance and treatment aternatives

Hormone-Dependent Breast Cancer: Mechanisms of Resistance and

Treatment Aternatives

VIII Simposio Internacional GEICAM - A Coruña, 2011

Carlos H. Barrios, MD

PUCRS School of Medicine

Porto Alegre, RS, Brazil

Endocrine Receptors and Breast Cancer

• Estrogen receptors (ER) are expressed in 60-70% of breast cancer cases (incidence increases with age).

• Tamoxifen (5y adjuvant Rx in ER+)– Reduces:

• Recurrence by 38%

• BC death by 30%

• Contralateral BC by 40%

• 50-60% ER (+) tumors respond to first-line ET.• But…up to 50% of ER+ tumors are inherently refractory

or acquire resistance during endocrine treatment.

VIII Simposio Internacional GEICAM – A Coruña 2011

Tamoxifen inER+ Disease

Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

Absolute benefit in 14%

of patients

Absolute benefit in 14%

of patients

Recurrence in 33% of

patients in spite Rx

Recurrence in 33% of

patients in spite Rx

47% of patients do

not need Rx !!

47% of patients do

not need Rx !!

Primary or Acquired

Resistance

Primary or Acquired

Resistance

Some Proposed Mechanisms of Resistance Development

Adapted from Johnston S. Clin Cancer Res. 2005;11:889S

SOSSOSRASRAS

RAFRAF

BasalBasaltranscriptiontranscription

machinerymachineryp160p160

EREERE ER target gene transcriptionER target gene transcription

ERER CBPCBPERER

PPp90p90RSKRSK

AktAkt PP

MAPKMAPKPP

CellCellsurvivalsurvival

CytoplasmCytoplasm

NucleusNucleus

ERER

PI3-KPI3-KPP

PP

PPPPPP

PP

CellCellgrowthgrowth

MEKMEKPP

EGFR / HER2EGFR / HER2

IGFRIGFRGrowth factorGrowth factorEstrogenEstrogen

PPPP PP

PP

INCREASED SIGNALING THROUGH THE PI3K PATHWAY

INCREASED SIGNALING THROUGH THE PI3K PATHWAY

CHANGE IN CO-ACTIVATORSCHANGE IN CO-ACTIVATORS

AromataseAromataseInhibitorsInhibitorsTamoxifenTamoxifen

INCREASED EXPRESSION/SIGNALING THROUGH GF RECEPTORS

(IGFR, HER2, etc.)

INCREASED EXPRESSION/SIGNALING THROUGH GF RECEPTORS

(IGFR, HER2, etc.)

Pathways associated with ET resistance in vitro

Hoskins JM, et al. Nat Rev Cancer 9: 631-43, 2009

Konecny et al. J Natl Cancer Inst. 95:142, 2003.

Inverse Relationship: ER/PgR and HER2 in Primary Breast Cancers

02000 4000 6000 8000 10,000 12,000 0 2000 4000 6000 8000 10,000 12,000

100

200

300

400

500

600

700

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

900

400

100

00

100

400

900

0 400 1600 3600 6400 10,000 0 400 1600 3600 6400 10,000

HER2/neu protein (fmol/mg) HER2/neu protein (fmol/mg)

ER

(fm

ol/

mg

)

Pg

R (

fmo

l/m

g)

HER2/neu protein (fmol/mg)

ER

(fm

ol/m

g)

HER2/neu protein (fmol/mg)

Pg

R (

fmo

l/mg

)

0

Cross-Talk Between GF Signal Transduction and Endocrine Pathways


SOSSOSRASRAS

RAFRAF



EREERE ER target gene transcriptionER target gene transcription

ERER CBPCBPERER

p90p90RSKRSK

AktAkt PP

MAPKMAPKPP


CytoplasmCytoplasm

NucleusNucleus

ERER

PI3-KPI3-KPP

PP

PP


MEKMEKPP


Growth factorGrowth factorEstrogenEstrogen

PPPP PP

PP

P P

PHOSPHORYLATION OF ERHER2-normal MCF-7 cells

Activation of HER2 receptor with heregulinresults in phosphorylation of ER tyrosine residues, enhances nuclear binding of ER, and E2-independent growthPietras et al, Oncogene 10:2435, 1995

PHOSPHORYLATION OF ERHER2-normal MCF-7 cells

Activation of HER2 receptor with heregulinresults in phosphorylation of ER tyrosine residues, enhances nuclear binding of ER, and E2-independent growthPietras et al, Oncogene 10:2435, 1995

TAnDEM: Anastrozole ± Trastuzumab in ER+/HER2+ MBC

Post-menopausalHER2+ (IHC 3+or FISH+) ER+

and/or PgR+ MBC

RANDOMISE

Anastrozole 1 mg daily + Trastuzumab 4 mg/kg loading

dose, then 2 mg/kg qw (n=103)

Anastrozole 1 mg daily (n=104)

Crossover to receive trastuzumab offered to all patients who developed tumour progression on anastrozole alone (70% crossed over)

Primary end point: PFS

Mackey et al. Breast Cancer Res Treat. 2006;100(suppl 1):S5. Abstract 3.

Kaufman B, et al. J Clin Oncol 27: 5529-5537, 2009

Kaufman B, et al. J Clin Oncol 27: 5529-5537, 2009

TAnDEM: Efficacy

Letrozol + Lapatinib in: ER+/HER2+ MBC

1286 post-menopausal women with HR+ MBC*

RANDOMISE

Letrozol 2.5mg/d + Lapatinib 1500mg/d

(n=642) (HER2+=111)

Lapatinib 1500mg/d (n=644) (HER2+=108)

*No prior therapy for metastatic disease; neo-adjuvant/adjuvant ET allowed: AI/or trastuzumab completed > 1 yr; ECOG 0-1; normal organ function

Primary end point: PFS

Johnston S, et al. J Clin Oncol. 27:5538, 2009.

Lapatinib + Letrozole in the ITT Population


Lapatinib + Letrozole enhances PFS and CBR in pts with HER2+, HR+ MBC


No benefit for Lapatinib + Letrozole in HR+/HER2-/ET sensitive MBC. Possible benefit in ET resistant MBC.

HER2-/ET sensitive population HER2-/ET resistant population

• A combined targeted strategy with AIs (Letrozole or Anastrozole) and anti-HER2 therapy (Trastuzumab or Lapatinib) enhances PFS and CBR in pts with MBC that co-expresses HR and HER2.

• HER2 over-expression is associated with endocrine resistance and poor DFS. These studies clearly demonstrate that these tumors are relative insensitive to hormonal therapy (AIs)– ORR of 6.8-28%

– TTP of 2.4-3.0 months

• The possibility of chemotherapy plus anti-HER2 therapy being a better alternative needs to be considered. Additional strategies are urgently needed for these patients.

The PI3K pathway and Breast Cancer

• Constitutive activation of the PI3K pathway is frequent.

• PI3K pathway activation conveys malignant transformation, cell growth and invasion, tumor neo-angiogensis and resistance towards anti-cancer treatments.

• Known mechanisms of PI3K pathway activation include activating mutations of RTKs, gain-of-function mutation of the PIK3CA gene, and loss-of-function mutations of PTEN.

Ras

4EBP14EBP1

Raf

ErkErk

RskRsk

PI3K

TORC1TORC1

S6KS6K

Rheb Rheb

S6S6

PIP3PIP3

Tuberin

PTEN

TORC2TORC2MEKMEK

Akt PDK1PDK1

HER2/HER3

The PI3K/Akt/mTOR pathway is frequently deregulated in human cancer

Gymnopoulos M,et al. Proc. Natl. Acad. Sci. USA 104, 5569-74, 2007

Map and frequency distribution of PI3K mutations

Stemke-Hale, K. et al. Cancer Res 68:6084-91, 2008

Frequency of mutations in PIK3CA and PTEN (n=547 breast cancer cases)

PI3K/Akt/mTOR pathway inhibitorsPI3K/Akt/mTOR pathway inhibitors

McAuliffe P. et al. Clin Breast Cancer

SOSRAS

RAF

Basaltranscription

machineryp160

ERE ER target gene transcription

ER CBPPP P P

ER

P

P

MAPKP

Cytoplasm

Nucleus

PP

PPP

P

MEKP

Plasmamembrane

HER2-1

IGFR-1

Estrogen

mTOR

Addressing Resistance inHR+ Breast Cancer

TAMRAD: Phase II trial of Everolimus + Tamoxifen

MBCHR positive

HER2 negativePrevious AI exposure

MBCHR positive

HER2 negativePrevious AI exposure

RR

Tamoxifen 20 mg dailydaily + Everolimus 10 mg daily

(n=54)

Tamoxifen 20 mg dailydaily + Everolimus 10 mg daily

(n=54)

Tamoxifen 20 mg daily (n=57)Tamoxifen 20 mg daily (n=57)

Hypothesis: Previous exposure to AIs may “enrich” the population of patients driven by activation of the PI3K/Akt/mTOR pathway.

Stratification: primary or secondary endocrine resistance

Primary end point: CBR (CR+PR+SDx6m)

Bachelot T, et al. Ca Res 70 (24 Suppl):S1-6. SABCS 2010.

TAMRAD: Phase II Trial of Everolimus + Tamoxifen

Bachelot T, et al. Ca Res 70 (24 Suppl):S1-6. SABCS 2010.

• Primary Resistance: • Relapse during adjuvant treatment or progression within first 6 months of AI for MBC

• TTP: TAM 3.9 vs. TAM+RAD 5.0 months, HR 0.74

• Secondary Resistance:• TTP: TAM 5.0 vs. TAM+RAD 17.4 months, HR 0.38

(*) Primary Objective

Phase II trial of BEZ235 in patients with HR+, HER2-, MBC with and without activation of the PI3K pathway

BEZ235: Dual PI3K and mTOR inhibitor

MBCHR positive

HER2 negative1 prior ET and 2-3 prior CT

Explore PI3K mutation status *

MBCHR positive

HER2 negative1 prior ET and 2-3 prior CT

Explore PI3K mutation status *

www.clinicaltrials.gov, NCT01288092

BEZ235 1600mg/day PO(until disease progression)BEZ235 1600mg/day PO

(until disease progression)

(*) Group 1: PI3K activation (mutation) + with or without PTEN alterations Group 2: PI3K activation (wild type) + with PTEN alterations (mutation or PTEN-) Group 3: No activation of the PI3K pathway (wild type)

Primary objective: 16 weeks PFSR

Proliferation/SurvivalProliferation/Survival

PI3KPI3KPTEPTENN

AKTAKT

TSC 1/2TSC 1/2

mTORmTOR

S6KS6K

X

X

SOSRAS

RAF

Basaltranscription

machineryp160

ERE ER target gene transcription

ER CBPPP P P

ER

P

P

MAPKP

Cytoplasm

Nucleus

PP

PPP

P

MEKP

Plasmamembrane

HER2-1

IGFR-1

Estrogen

mTOR

Addressing Resistance inHR+ Breast Cancer

A Two-Arm Randomized Open Label Phase 2 Study Of CP-751,871 In Combination With Exemestane Versus Exemestane Alone As First Line

Treatment For Postmenopausal Patients With Hormone Receptor Positive Advanced Breast Cancer

MBCHR positive

No previous RxN=260

MBCHR positive

No previous RxN=260

RR

CP-751,871 20 mg/kg IV q21 day Exemestane 25 mg/day

CP-751,871 20 mg/kg IV q21 day Exemestane 25 mg/day

Examestane 25 mg/dayExamestane 25 mg/day Primary end point: PFS

www.clinicaltrials.gov, NCT00372996

Treatment until progression or toxicitySecond line therapy with Faslodex

http://www.clinicaltrials.gov/

Conclusions

• The molecular/genetic complexity of Breast Cancer is increasingly recognized.

• Targeting the HER2 pathway or the use of endocrine manipulations have a positive impact in the natural history of breast cancer.

• Therapeutic strategies simultaneously targeting multiple pathways have the potential of greater clinical impact.

• Further understanding of the molecular interaction among different pathways will:

• give us further insights into the heterogeneity of breast cancer• allow for better patient selection • provide us with a more rational therapeutic approach

Potential Conflict of Interests• Research Support

• Honoraria

• Financial Disclosure


Saphner et al. J Clin Oncol. 1996;14:2738.

0

0.1

0.2

0.3

0 1 2 3 4 5 6 7 8 9 10 11 12

Re

cu

rren

ce

ha

zard

ra

te

Years

ER– (n=1305)

ER+ (n=2257)

Long-Term Risk of Breast Cancer Recurrence ER+ and ER- Patients

Patients received CT, ET, or both (10 ECOG trials)

Annual hazard of recurrence by estrogen receptor status

Conclusions

• Understanding breast cancer as a molecular disease is leading to novel therapies

• Clinical trials will continue to evaluate the efficacy and safety of biologic therapy in combination or following standard chemotherapy and endocrine therapy

• Patient selection will be increasingly important for the integration of novel agents in the treatment of breast cancer

• This is an exiting time, but we have to be smart to avoid waste of time and resources

• A combined targeted strategy with AIs (Letrozole or Anastrozole) and anti-HER2 therapy (Trastuzumab or Lapatinib) enhances PFS and CBR in pts with MBC that co-expresses HR and HER2.

• HER2 over-expression is associated with endocrine resistance and poor DFS. These studies clearly demonstrate that these tumors are relative insensitive to hormonal therapy (AIs)– ORR of 6.8-28%– TTP of 2.4-3 months

• Additional strategies are needed for these patients

Osborne CK, et al. Ann Rev Med 62:14.1-15, 2010

Estrogen Signaling PathwayPHOSPHORYLATION OF ERHER2-normal (HER2–) MCF-7 cells

Activation of HER2 receptor with heregulinresulted in phosphorylation of ER tyrosine residues, enhanced nuclear binding of ER, and E2-independent growthPietras et al, Oncogene 10:2435, 1995

PHOSPHORYLATION OF ERHER2-normal (HER2–) MCF-7 cells

Activation of HER2 receptor with heregulinresulted in phosphorylation of ER tyrosine residues, enhanced nuclear binding of ER, and E2-independent growthPietras et al, Oncogene 10:2435, 1995

INCREASED EXPRESSION OF GFINCREASED EXPRESSION OF GF

Cross-Talk Between Signal Transduction and Endocrine Pathways


SOSSOSRASRAS

RAFRAF



EREERE ER target gene ER target gene transcriptiontranscription

ERER CBPCBPERER

PPp90p90RSKRSK

AktAkt PP

MAPKMAPKPP


CytoplasmCytoplasm

NucleusNucleus

ERER

PI3-KPI3-KPP

PP

PPPPPP

PP


MEKMEKPP


IGFRIGFRGrowth factorGrowth factorEstrogenEstrogen

PPPP PP

PP

AromatasAromatasee

InhibitorInhibitor

AntibodiesAntibodiesand TKIsand TKIs

TamoxifenTamoxifen

Long-term estrogen deprivation (LTED)

• ER (+) BC cells after LTED become hypersensitive to low-dose estrogen.

• LTED is NOT due to up-regulation of ER.• LTED is likely due to activation

of MAPK, PI3K, EGFR, or non-

genomic effect of estrogen.

Masamura S, et al. J Clin Endocrinol Metab 2918-25, 1995

Pathways associated with ET resistance

in vitro

Nat. Rev. Cancer 9: 631-43

Mechanisms of SERM resistanceMechanisms of SERM resistance

TAnDEM trial

• First randomized phase III to combine ET and trastuzumab for HER2/HR + MBC

208 postmenopausal women with HR/HER2 +

MBC*

208 postmenopausal women with HR/HER2 +

MBC*

anastrozolen=104

(n=73 HR +)

anastrozolen=104

(n=73 HR +)

anastrozole + trastuzumab

n=103(n=77 HR +)

anastrozole + trastuzumab

n=103(n=77 HR +)

Randomized

*previous ET or anastrozole < 4 months, adequate organ

functions, ECOG 0-1

(2001-2004)

187 withdrawals due to PD73/104 pts received trastuzumab-containing regimen

187 withdrawals due to PD73/104 pts received trastuzumab-containing regimen

anastrozole 1 mg qdTrastuzumab 4 mg/kg IV day 1, followed by 2mg/kg, qwk

double-blinded

Primary EP: PFS2nd EP: CBR, ORR, TTP, OS, 2-yr SR

J Clin Oncol 27: 5529-5537

TAnDEM: Efficacy Summary

• Trastuzumab added to anastrozole (A + T) vs anastrozole alone (A) significantly improved efficacy

– PFS

– Secondary end points: TTP, ORR, CB

Update of Mackey et al. Breast Cancer Res Treat. 2006;100(suppl 1):S5. Abstract 3.

End PointA + T

(n=103)A

(n=104) P Value

PFS, mo 4.8 2.4 0.0016

TTP, mo 4.8 2.4 0.0007

ORR, % 20.3 6.8 0.018

CB, % 42.7 27.9 0.026

TAnDEM trial

• Trastuzumab plus anastrozole improves PFS and TTP, but not OS for pts with HER2/HR + MBC compared with anastrozole alone.

• Poor response on both arms is likely due to aggressive nature of the cancer.

Breast Cancer Subtype

Mutation

PIK3CA catalytic domain*

PIK3CA other PIK3CA total PTEN

All breast tumors

73/547 (13.3%) 44/547 (8.0%)117/547 (21.4%)

2/88 (2.3%)

HR+ 48/232 (20.7%) 32/232 (13.8%) 80/232 (34.5%) 2/58 (3.4%)

ER+PR+ 39/186 (21%) 22/186 (11.8%) 61/186 (32.8%) 1/48 (2.1%)

ER+PR– 9/41 (22%) 10/41 (24.4%) 19/41 (46.3%) 1/8 (12.5%)

ER–PR+ 0/5 (0%) 0/5 (0%) 0/5 (0%) 0/2 (0%)

HER2+ 13/75 (17.3%) 4/75 (5.3%) 17/75 (22.7%) 0/10 (0%)

Triple Negative 12/240 (5.0%) 8/240 (3.3%) 20/240 (8.3%) 0/20 (0%)

Stemke-Hale, K. et al. Cancer Res 68:6084-91, 2008

Frequency of mutations in PIK3CA and PTEN (n=547 breast cancer cases)

PI3K/AKT pathway activationPI3K/AKT pathway activation

ERER

Breast Breast cancer cell cancer cell growthgrowth

AKT ->AKT ->PI3K ->PI3K -> mTORmTORSrc->Src->

How do we take it to the clinic?How do we take it to the clinic?Y

XX

XX

MK-0646MK-0646

DasatinibDasatinib

FulvestrantFulvestrant

TrastuzumabTrastuzumab

PertuzumabPertuzumab

LapatinibLapatinib

DasatinibDasatinibAZD 0530AZD 0530

LY 294002LY 294002SF 1126SF 1126PX 166PX 166BEZ 235BEZ 235

PerifosinePerifosineA797A797A838450A838450LY2101831LY2101831GSK690693GSK690693BBKP86328KP86328

CCI 779CCI 779RAD 001RAD 001AP23573 AP23573

MK 0646MK 0646AMG 479 AMG 479 AMC A12AMC A12AVE 1642AVE 1642

IGFR1IGFR1

TamoxifenTamoxifenAnastrazolAnastrazoleeLetrozoleLetrozoleExemestanExemestaneeFulvestranFulvestrantt

HER2HER2

A phase I-II, randomized clinical trial for A phase I-II, randomized clinical trial for metastatic HR-positive HER2-negative metastatic HR-positive HER2-negative

breast cancer breast cancer

HR- HR- positive positive

and and HER2-HER2-

negativenegative

Day 14Day 14

PET-CTPET-CTBiopsyBiopsy

AR= Adaptive RandomizationAR= Adaptive Randomization

Fulvestrant + Fulvestrant + MK-0646MK-0646

Fulvestrant + Fulvestrant + MK-0646 + MK-0646 + DasatinibDasatinib

Fulvestrant + Fulvestrant + DasatinibDasatinib

FulvestrantFulvestrant

PIK3CA PIK3CA mutationsmutations

Pre-RxPre-Rx

StaginStagingg

Week 12Week 12

PI3K/PTEN/AKTmutationsPI3K/PTEN/AKTmutations

PI3K/PTEN/AKT-activationPI3K/PTEN/AKT-activation

Src -activationSrc -activation

ER levelsER levels

PET-CTPET-CTBiopsyBiopsy BiopsyBiopsy

ARAR

www.clinicaltrials.gov

(PI: Gonzalez-Angulo & Meric-(PI: Gonzalez-Angulo & Meric-Bernstam)Bernstam)

Breast CancerBreast CancerT1-3/N0-1T1-3/N0-1

ER or PR+/HER2–ER or PR+/HER2–Post-menopausalPost-menopausalPI3K aberrationsPI3K aberrations

(core biopsy)(core biopsy)

Ki-67Ki-67TUNELTUNEL

P-Akt, etc.P-Akt, etc.microarraysmicroarrays

RPPARPPAFDG-PETFDG-PET

Ki-67Ki-67TUNELTUNEL

P-Akt, etcP-Akt, etcmicroarraysmicroarrays

RPPARPPAFDG-PETFDG-PET

Arm 1:Arm 1:LetrozoleLetrozoleBEZ235BEZ235

Arm 2:Arm 2:LetrozoleLetrozolePlaceboPlacebo

2 weeks2 weeks

Bio

psy

Bio

psy

Su

rgery

Su

rgery

22 weeks22 weeks

Path CRPath CRClin ResponseClin Response(US, Mammo)(US, Mammo)

Br Cons SurgeryBr Cons SurgeryKi-67Ki-67

TUNELTUNELP-Akt, etcP-Akt, etc

microarraysmicroarraysRPPARPPA

1:1 1:1 randomizationrandomization

A phase II neoadjuvant trial of BEZ235 in A phase II neoadjuvant trial of BEZ235 in combination with endocrine therapy in post-combination with endocrine therapy in post-

menopausal patients with operable HR-positive menopausal patients with operable HR-positive breast cancer breast cancer

LetrozoleLetrozoleBEZ235BEZ235

LetrozoleLetrozolePlaceboPlacebo

1286 postmenopausal women with HR+ MBC*1286 postmenopausal

women with HR+ MBC*

Letrozole + lapatinibn=642

(111 HER2 +)

Letrozole + lapatinibn=642

(111 HER2 +)

Letrozole + PlaceboN=644

(108 HER2 +)

Letrozole + PlaceboN=644

(108 HER2 +)

Randomized

*No prior therapy for metastatic disease allowed; but

neoadjuvant/adjuvant ET allowed; AI/or trastuzumab completed > 1 yr; ECOG 0-1;

normal organ function

(2003-2006)

Median follow-up 1.8 yrsMedian follow-up 1.8 yrs

Letrozole 2.5 mg qdLapatinib 1500 mg qd double-blinded

Primary EP: PFS2nd EP: ORR, CBR,

OS, safety

UK/USA 1950-2006: BC mortality (ages 35-69)

Berry D et al. N Engl J Med 2005;353:1784-1792

Estimated and Actual Rates of Death from Breast Cancer among Women 30 to 79 Years of Age from 1975 to 2000 (Panel A) and under Hypothetical Assumptions about the Use of Screening Mammography and Adjuvant Treatment (Panel B)

Breast Cancer Mortality - US

Screening: 50%

Adjuvant Therapy: 50%

Berry D et al. N Engl J Med 2005;353:1784-1792

Rates of Death from Breast Cancer among Women 30 to 79 Years of Age from 1975 to 2000 under Hypothetical Assumptions about the Use of Screening Mammography and Adjuvant Treatment

Breast Cancer Mortality - US

Screening: 50%

Adjuvant Therapy: 50%

Outline

• Endocrine Receptors and Breast Cancer

• Potential Mechanisms of Resistance to Endocrine Manipulation

• Clinical Trials

• Future Developments• Ongoing Trials


Tamoxifen improves 15-y outcomes in ER+/unknown

ControlTamoxifen

33.2

34.8

Bre

ast c

anc

er

mo

rta

lity

(%)

0 10

20

0

30

40

60

50

10

5 15

Years

11.9

25.7

8.3

17.8

25.6

Re

cu

rren

ce

(%

)

0 10

20

0

30

40

60

50

10

5 15

Years

45.0

38.3

24.7

26.5

15.1


10 386 women: 20% ER-unknown, 30% node-positive.

~5 years Tamoxifen vs not, split by ER status only: RECURRENCE

ER+ disease


ER+ER poor

~5 years Tamoxifen vs not, ER+ split by PgR status: RECURRENCE


ER+ / PR poor ER+ / PR+

Distant Mets Comprise the Majority of Early Recurrences During Tam Therapy

Updates of Doughty JC, et al. Breast Cancer Res Treat. 2007;106(suppl 1):S145. Abstract 3057; Mansell J, et al. Breast Cancer Res Treat. 2006;100(suppl 1):S111. Abstract 2091. Poster presented at: 29th Annual San Antonio Breast Cancer Symposium. December 14-17, 2006; San Antonio, Texas. Poster 2091.

4,245 postmenopausal women with ER+ operable breast cancer, all treated with TAM

Cumulative recurrence rate, (% of overall) Cumulative recurrence rate, (% of overall)

2.5 years2.5 years 5 years5 yearsOverallOverall 6.26.2 13.913.9

DistantDistant 4.54.5 (73 %)(73 %) 9.89.8 (71%)(71%)

Locoregional Locoregional 1.01.0 (16)(16) 2.72.7 (19)(19)

Contralateral Contralateral 0.50.5 (8)(8) 1.31.3 (9)(9)

0

0.01

0.02

0.03

0.04

0.05

0 1 2 3 4 5

OverallLocoregionalDistantContralateral

An

nu

al r

ecu

rren

ce r

ate

Years from diagnosis

53

2010 EBCTCG OVERVIEWTAMOXIFEN

10 yrs vs 5 yrs of adjuvant TAMOXIFEN inER+/? Disease• Absolute reduction in recurrence by 1% (2p=0.03)• Reduces contralateral BC by 1.3% (2p=0.03) • Increases endometrial cancer by 0.7% (2p=0.00004)• Reduces BC mortality by 3% (2p=0.55) • Increases death without recurrence by 1.5% (2p=0.59)

THE 2010 OVERVIEW

Experience with locally defined predictive biomarkers used to identify patients who do not benefit

Endocrine therapy Chemotherapy

ER+ tumor not benefiting from endocrine therapy ?

ER+ tumor benefiting from AI rather than TAM ?

PgR does not help!

Subgroup without benefit ?

No apparent interaction of ER, PgR or grade with CT benefit!

The current paradox

First generation multigene signatures

Current message Right or wrong ?

Too few patients studied could lead to wrong conclusions…!

« Among ER positive BC

there is no CT benefit

for the low proliferative

tumors »

« There is no group

identified without

a benefit! »

The 2010 Overview Many patients studied with poor reproducibility in biomarkers measurement could lead to wrong conclusions…

ER: 15% error ? Grade : 40% error ?


Molecular Targets Agent Company Clinical Trials

PI3K Selective I nhibitors XL- 147 Exelixis Phase I / I I GDC0941 Genentech Phase Ib/ I I BKM120 Novartis Phase Ib/ I I PX866 Oncothyreon Phase I

PIK3Cd CAL- 101 Calistoga Phase I / I I

PI3Ka BYL719 Novartis Phase I

Dual PI3K/mTOR I nhibitors GSK1059615 GlaxoSmithKline Phase I XL- 765 Exelixis Phase I / I I BEZ235 Novartis Phase I / I I BGT226 Novartis Phase I / I I

Multimodal I nhibitor (PI3K, mTOR, DNA- PK, HIF- 1α)

SF1126 Semafore Phase I

AKT Inhibitors GSK690693 (AKT 1,2,3) GlaxoSmithKline Phase I / I I MK2206 (AKT 1,2,>3) Merck Phase I / I I Perifosine Keryx Phase I I

mTOR kinase inhibitors AZD8055 AstraZeneca Phase I OSI027 OSI Oncology Phase I INK128 Intellikine Phase I

Rapalogs Sirolimus Wyeth/Pfizer Phase I I Temsirolimus (CCI779) Wyeth/Pfizer Phase I I I Everolimus (RAD001) Novartis Phase I I

Ridaforolimus (AP23573) ARIAD/Merck Phase I I

McAuliffe P. et al. Clin Breast Cancer (In Press)


Molecular Targets Agent Company Clinical Trials

PI3K Selective I nhibitors XL- 147 Exelixis Phase I / I I GDC0941 Genentech Phase Ib/ I I BKM120 Novartis Phase Ib/ I I PX866 Oncothyreon Phase I

PIK3Cd CAL- 101 Calistoga Phase I / I I

PI3Ka BYL719 Novartis Phase I

Dual PI3K/mTOR I nhibitors GSK1059615 GlaxoSmithKline Phase I XL- 765 Exelixis Phase I / I I BEZ235 Novartis Phase I / I I BGT226 Novartis Phase I / I I

Multimodal I nhibitor (PI3K, mTOR, DNA- PK, HIF- 1α)

SF1126 Semafore Phase I

AKT Inhibitors GSK690693 (AKT 1,2,3) GlaxoSmithKline Phase I / I I MK2206 (AKT 1,2,>3) Merck Phase I / I I Perifosine Keryx Phase I I

mTOR kinase inhibitors AZD8055 AstraZeneca Phase I OSI027 OSI Oncology Phase I INK128 Intellikine Phase I

Rapalogs Sirolimus Wyeth/Pfizer Phase I I Temsirolimus (CCI779) Wyeth/Pfizer Phase I I I Everolimus (RAD001) Novartis Phase I I

Ridaforolimus (AP23573) ARIAD/Merck Phase I I

2010 EBCTCG OVERVIEWTAMOXIFEN

5y in ER+ disease• Reduces:

– Recurrence by 38% – BC death by 30%– All deaths by 22%

• Contralateral BC by 40% • Benefits all women with ER+ disease• Unclear benefits in ER-PgR+ disease • Benefits women with ER very rich tumors more • Increases endometrial cancer by 2.3 fold

Cancer Cell Signaling: Complexity

ER and HER-2 (+) Tumors

• Endocrine therapy with AIs has a significantly greater impact than tamoxifen on response biomarkers such as Ki67, indicating greater ER inhibition and anti-proliferative effects.

• Tumors that express HER2 in conjunction with ER were considerably more responsive to an AI than to tamoxifen.

• Studies are beginning to investigate the impact of HER2 positivity on anti-proliferative effects of AIs, focusing on Ki67 as a key biomarker.

Eiermann et al. Ann Oncol. 2001;12:1527. Ellis et al. J Clin Oncol. 2001;19:3808.

Ellis et al. J Clin Oncol. 2006;24:3019-3025.Smith et al. J Clin Oncol. 2005;23:5108.

Smith and Dowsett. Breast Cancer Res Treat. 2003;82(suppl 1):S6. Abstract 1.Young et al. Breast Cancer Res Treat. 2004;88(suppl 1):S38. Abstract 411.

Conclusions

• HER2 overexpression is associated with tamoxifen resistanceand poor DFS

• AIs have a significantly greater impact on response biomarkers than tamoxifen, indicating greater ER inhibition and antiproliferative effects

• Letrozole is equally effective in HER2+ and HER2– patients in the neoadjuvant and adjuvant settings– Letrozole demonstrated a significantly better response than tamoxifen in

patients with ER+, HER2+ disease in the neoadjuvant setting (88% vs 21%, respectively; P=0.0004)

– The benefit of anastrozole over tamoxifen was seen in HER2+ patients

• HER2 overexpression is a negative predictor of efficacy for both tamoxifen and AIs– Additional agents may be required for optimal management

hormone-dependent breast cancer: mechanisms of resistance and treatment aternatives

Documents

clin cancer

j clin oncol

et resistance

hr her2et sensitive

j natl cancer

lapatinib letrozole

er tumors

er tumors