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
Adapted from Johnston S. Clin Cancer Res. 2005;11:889S
SOSSOSRASRAS
RAFRAF
BasalBasaltranscriptiontranscription
machinerymachineryp160p160
EREERE ER target gene transcriptionER target gene transcription
ERER CBPCBPERER
p90p90RSKRSK
AktAkt PP
MAPKMAPKPP
CellCellsurvivalsurvival
CytoplasmCytoplasm
NucleusNucleus
ERER
PI3-KPI3-KPP
PP
PP
CellCellgrowthgrowth
MEKMEKPP
EGFR / HER2EGFR / HER2
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
Johnston S, et al. J Clin Oncol. 27:5538, 2009.
Lapatinib + Letrozole enhances PFS and CBR in pts with HER2+, HR+ MBC
Johnston S, et al. J Clin Oncol. 27:5538, 2009.
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
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
VIII Simposio Internacional GEICAM – A Coruña 2011
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
Adapted from Johnston S. Clin Cancer Res. 2005;11:889S
SOSSOSRASRAS
RAFRAF
BasalBasaltranscriptiontranscription
machinerymachineryp160p160
EREERE ER target gene ER target gene transcriptiontranscription
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
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
VIII Simposio Internacional GEICAM – A Coruña 2011
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
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
10 386 women: 20% ER-unknown, 30% node-positive.
~5 years Tamoxifen vs not, split by ER status only: RECURRENCE
ER+ disease
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
ER+ER poor
~5 years Tamoxifen vs not, ER+ split by PgR status: RECURRENCE
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
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 ?
PI3K/Akt/mTOR pathway inhibitorsPI3K/Akt/mTOR pathway inhibitors
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)
PI3K/Akt/mTOR pathway inhibitorsPI3K/Akt/mTOR pathway inhibitors
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