1. 18th Annual Perspectives in Breast Cancer
Growth Factor Pathways in Hormone Resistant Breast Cancer
Christy A Russell, MD
Fight On!

2. Tumors Classified as ER+ Have Varied Receptor Expression Profiles
ASCO/CAP recommends that a tumor specimen be considered ER+ if >1% of tumor cells test positive for ER.
Breast cancer classified as ER+ is a heterogeneous disease, based on varying
ER expression level
PR status
HER2 status
BC with strong ER expression are biologically distinct from those with weak ER expression

3. Hormone Receptor Positive Determination
Any endocrine therapy (n = 777)
Allred Score* for Estrogen Receptor
Score
Component of Score
Straining
Proportion of malignant cells straining for ER
None 1
<0.01 2 3 4 5
>0.67
Intensity
Average intensity of positively stained cells
Weak
Intermediate
Strong
Allred Score of > 3 are generally considered hormone-sensitive
Harvey et al. J Clin Oncol 1999;17:

4. Stable disease on hormone therapy provides similar benefit as CR or PR
Compare Survival with Stable Disease (Clinical Benefit) to Survival with CR or PR with Anastrozole Use in ABC
Clinical Benefit = CR + PR + Stable  24 wks
100 80
At 2-Year Risk Deaths Estimate
CR or PR %
Stable  24wk %
Other % 60
Survival (%) 40 20 1 2 3 4
Years From Randomization
Stable disease on hormone therapy provides similar benefit as CR or PR
ABC = advanced breast cancer, Clinical benefit = no prognosis for > 24wks
Robertson JF, et al. Breast Cancer Res Treat. 1999;58:

5. Patients with Disease Progression on One Hormone Therapy May Respond to Another Hormone TherapyC
40%
30%
25%
15%
1st
Line
2nd
Line
3rd
Line
4th
Line
An optimal sequence of hormone therapies has not been defined
Bavior C, et al. Ann Oncol Epub Feb 8; Osborne Ck, Schiff R. Ann Res Med 2011;62:

6. NCCN Guidelines Recommend Serial Endocrine Therapy for Hormone Receptor Positive, HER2- Advanced Breast Cancer, Not in Visceral Crisis
NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, version ; Osborne CK, et al. Ann Rev Med 2011;62:

7. Hormone Receptor Positive, Advanced Breast Cancer Unmet Need
With initial hormone therapy of advanced breast cancer:
About 30% will have clinical response (PR, CR)
About 50% will have clinical benefit (no progression for 24 weeks)
However, almost all will develop resistance and ultimately have disease progression

8. Endocrine Agents for Postmenopausal Breast Cancer
SERMs
Tamoxifen
Toremifene
Raloxifene
Estrogens
Estradiol
DES, EE2
ER-Down Regulator
Fulvestrant
Aromatase Inhibitors
Anastrozole
Letrozole
Exemestane
Progestins
Megestrol Acetate
MPA
Androgens
Fluoxymesterone

9. Review of Trials of Hormone Therapy in First-Line Advanced Breast Cancer

10. Selected Trials of HT in First-Line ABC
Trial or Lead Author N
Nabholtlz Anastrozole vs tamoxifen
1021
Mouridsen Letrozole vs tamoxifen
916
Paridaens Exemestane vs tamoxifen
371
Howell Fulvestrant (250) vs tamoxifen
587
S Fulvestrant (250, loading) + anastrozole vs anastrozole
694
FACT Fulvestrant (250, loading) + anastrozole vs anastrozole
514
FIRST Fulvestrant (500) vs anastrozole
205
Mehta SABCS 2011, Abst S1-1; Bergh J Clin Oncol 2012 [Epub ahead of print]; Nabholtz Eur J Cancer 2003;39: ; Mouridsen 2003;21: ; Paridaens 2008;26: ; Howell J Clin Oncol 2004;22:

11. First-Line Phase III Studies: AIs and/or Fulvestrant (250) vs Tamoxifen
AIs have improved efficacy compared with tamoxifen2-4
TTP (mo): anastrozole (10.7) vs tamoxifen (6.4)2
TTP (mo): letrozole (9.4) vs tamoxifen (6.0)3
PFS (mo): exemestane (9.9) vs tamoxifen (5.8)4
Fulvestrant (250) has similar efficacy compared with tamoxifen5
TTP (mo): fulvestrant (8.2) vs tamoxifen (8.3)

12. First-Line Phase III Studies Fulvestrant (250, loading )
First-Line Phase III Studies Fulvestrant (250, loading )* + Anastrozole vs Anastrozole
In SWOG S0226 (n = 694), fulvestrant addition improved:
PFS (mo); fulvestrant + anastrozole (15.0) vs anastrozole (13.3), P = 0.007
OS (mo): fulvestrant + anastrozole (47.7) vs anastrozole (41.3), P = 0.049
In FACT (n=514), fulvestrant addition had: no effect on PFS or OS seen:
OS (mo): fulvestrant + anastrozole (37.8) vs anastrozole (38.2), P = 1.00
Mixed results for fulvestrant 250, loading
Mehta, et al. SABCS 2011, Abst S Bergh, et al. J Clin Oncol 2012;30(16):
*Fulvestrant 500 mg d 1 IM, 250 mg d 14 and 28, 250 mg every 28 days thereafter.

13. FIRST: Fulvestrant (500) vs Anastrozole (Phase II)
FULVESTRANT 500 mg IM days 1, 14, 28 and q28days thereafter
Primary
CBR defined as CR, PR, and SD for > 24 wks
Secondary
ORR, TTP, DoR
N = 205
PMW with previously untreated HR+ advanced breast cancer
ANASTROZOLE 1 mg QD orally
FUL (500) n = 102
ANAS n = 103 HR
P-value
TTP (mo)
23.4
13.1
0.66
0.01
ORR (%)
36.0
35.5
1.02
0.947
CBR (%)
72.5
67.0
1.30
0.386
Robertson JRF, et al. SABCS Abstract S1-3, Robertson et al. J Clin Oncol 2009;27: 13

14. FIRST: TTP, Fulvestrant (500) vs Anastrozole (Phase II)
1.0
Fulvestrant 500 mg
0.8
Anastrozole 1 mg
0.6
Proportion of patients alive and progression-free
0.4
HR = 0.66
0.2
95% CI (0.47, 0.92)
p=0.01
0.0 6 12 18 24 30 36 42 48
Time (months)
Fulvestrant 500 mg
n = 102 (%)
Anastrozole 1 mg
n = 103 (%)
Percent with progression (%)
63 (61.8)
79 (76.7)
Median (months)
23.4
13.1
Robertson SABCS 2010, Abst S1-3 14

15. Review of Trials of Hormone Therapy in Advanced Breast Cancer After Progression on Prior Non-Steroidal Aromatase Inhibitor

16. Selected Trials of Fulvestrant Use After Progression on Prior NSAI*
EFECT Fulvestrant vs exemestane
693
SoFEA Fulvestrant + anastrozole vs fulvestrant vs exemestane
750
CONFIRM Fulvestrant high vs fulvestrant low
736
Fulvestrant 250, loading
Fulvestrant 500
*Non-steroidal aromatase inhibitor.

17. EFECT: Fulvestrant (250, loading) vs Exemestane
PMW with advanced HR+ BC after failure of NSAI therapy
FULVESTRANT 500 mg IM day 1, 250 mg day 14, 28, monthly
Primary
TTP
Secondary
ORR, CBR, DOR, TTR, OS, tolerability
EXEMESTANE 25 mg QD
FUL n = 351
EXE n = 342
P-value
TTP (mo)
3.7
0.653
ORR (%)
7.4
6.7
0.736
Fulvestrant (250 loading) similar to exemestane
Chia S, et al. J Clin Oncol 2008;26(10): 17

18. SoFEA: Fulvestrant (250, loading) With or Without Anastrozole vs Exemestane
FULVESTRANT 500 mg loading dose on day 1, then 250 mg monthly +
ANASTROZOLE 1 mg/daily
N = 723
Post menopausal women with advanced HR+ BC following progression on NSAI
Primary
PFS
Secondary
ORR, CBR, OS, tolerability
FULVESTRANT 500 mg loading dose on day 1, then 250 mg monthly +
Placebo daily
EXEMESTANE 25 mg/daily
No significant differences were observed in PFS, ORR, CBR, or OS
FUL n = 231
FUL + ANA n = 243
EXE
PFS (mo)
4.8
4.4
3.4
Johnston S et al. EBCC 18

19. CONFIRM: Fulvestrant 250 vs 500 mg
FULVESTRANT 500 mg IM on day 1, 14, 28, monthly
N = 736
PMW with advanced HR+ BC after failure of prior endocrine therapy
Primary
PFS
Secondary ORR, CBR, DoCB, OS, Qol
FULVESTRANT 250 mg IM monthly
FUL n = 362
FUL n = 374
P-value
PFS (mo)
6.5
5.5
0.004
ORR (%)
9.1
10.2
0.795
CBR (%)
45.6
39.6
0.100
Bachelot T, et al. J Clin Oncol Epub 1-7; DiLeo et al. J Clin Oncol 2010;28: 19

20. Mechanisms of ER Action in Breast Cancer

21. ER Target Gene Transcription
Mechanisms of Endocrine Resistance
MoAb
IGF1R
Increased upstream
signaling through
EGFR and/or IGF-IR
and or VEGFR
TKI AB
EGFR/HER2
VEGFR
MoAb P P P P P
TKI P
SOS
PI3-K
TKI
RAS
RAF
Increased signaling
through PI3-K pathway
CCI
RAD
Akt
MEK
p90RSK
MAPK
SERD AI T ER E2 P
p160
Basal
Transcription
Machinery
CBP ER
Cytoplasm
ERE
ER Target Gene Transcription
Cell
Growth
Nucleus
Plasma
Membrane
Mechanisms of intrinsic and acquired resistance likely similar
From Johnston CCR 2005

22. Endocrine Resistance and the PI3K/AKT/mTOR Pathway
Evidence suggests that the PI3K/AKT/mTOR pathway becomes activated in hormone resistant breast cancer
This pathway allows cells to survive despite concurrent endocrine therapy
Targeting the PI3K/AKT/mTOR pathway could provide benefit in metastatic breast cancer that is becoming resistant to the current endocrine therapy
Johnston, S. Role of the mTOR Pathway in Endocrine Resistant Breast Cancer — Opportunities for Novel Combination Strategies

23. PI3K/AKT/mTOR Pathway

24. Everolimus as mTOR Kinase Inhibitor
Mechanisms of Action (MOA): everolimus inhibits mTOR through allosteric binding to the mTORC1 complex
Reduces tumor angiogenesis by inhibiting VEGF and HIF-1 expression
Targets pathway known to be involved in endocrine resistance
Available as oral agent
Villarreal-Garza, et al. Ann Oncol 2012 May 2 Epub ahead of print
Barnett, et al. Pharmacotherapy 2012;32:383-96

25. Selected Trials of Hormonal Therapy Including Everolimus After Progression on Prior AI*
EFECT Fulvestrant (250) vs exemestane
693
CONFIRM Fulvestrant (500) vs fulvestrant (250)
736
SoFEA Fulvestrant + anastrozole vs fulvestrant (250) vs exemestane
750
TAMRAD Tamoxifen + everolimus
110
BOLERO Exemestane + everolimus
725
Fulvestrant 250
Everolimus Combinations
Fulvestrant 500
*Non-steroidal aromatase inhibitor.

26. TAMRAD: Tamoxifen + Everolimus (Phase II)
Phase 2 study; N= PMW with advanced HR+ HER2- BC Previously treated with non-steroidal aromatase inhibitor therapy in adjuvant or metastatic setting
Tamoxifen 20 mg/day + Everolimus 10 mg/day
Primary CBR at 6 months
Secondary Safety, TTP, OS, ORR
Tamoxifen 20 mg/d + Placebo
TAM+EVE n = 54
TAM n = 57
P-value
CBR (6 mo)
61%
42%
0.045
TTP (mo)
8.6
4.5
0.002
Bachelot T, et al. J Clin Oncol Epub 1-7. 26

27. TAMRAD: Time to Progression
Hazard Ratio (HR) = 0.53; 95% CI ( )
Exploratory log-rank: P =
TAM: 4.5 mo.
TAM + EVE: 8.6 mo.
Month
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Probability of Survival
TAM
TAM + EVE
Patients at risk
TAM + RAD: n =
TAM : n = 54 57 45 44 39 30 34 25 13 19 11 7 1 9
Everolimus plus tamoxifen reduced time to progression by 47%
Bachelot T, et al. J Clin Oncol 2012.Epub 1-7 27

28. TAMRAD: Overall Survival
Everolimus plus tamoxifen increased overall survival by 55% 28

29. Tamoxifen With or Without Everolimus: TAMRAD: Safety
The addition of everolimus resulted in an increase in the expected toxicities, including fatigue, stomatitis, rash, diarrhea, and pneumonitis (predominantly grade 1-2)
Select Grade 3-4 Adverse Events
Tamoxifen + Everolimus (n = 54)
Tamoxife n (n = 57)
Stomatitis
6 (11%)
Rash
3 (6%)
1 (2%)
Anorexia
5 (9%)
2 (3.5%)
Dose reductions due to AEs
15 (28%)
Treatment discontinuation due to AEs
4 (7%)
Bachelot et al. J CLin Oncol Epub 1-7.

30. BOLERO-2: Everolimus in Postmenopausal, Hormone Receptor Positive ABC
Postmenopausal ER+ HER2- breast cancer pts refractory to letrozole or anastrozole
Everolimus 10 mg/day +
Exemestane 25 mg/day
(N = 485)
Primary
PFS
Secondary OS
ORR Bone Markers Safety PK
Placebo +
Exemestane 25 mg/day
(N = 239)
Stratification:
Sensitivity to prior hormonal therapy
Presence of visceral disease
No cross-over
Baselga J, et al. N Engl J Med 2012;366(6):520-9. 30

31. BOLERO-2: Baseline Characteristics
Everolimus + Exemestane
(N = 485), %
Placebo + Exemestane
(N = 239), %
Median age (range), years
62 (34, 93)
61 (28, 90)
Race
Caucasian 74 78
Asian 20 19
Performance status 0 60 59
Liver involvement 33 30
Lung involvement 29
Measurable disease* 70 68
*All other patients had ≥ 1 bone lesion.
Baselga J, et al. N Engl J Med 2012;366(6):520-9. 31

32. BOLERO-2: Prior Therapy
Everolimus + Exemestane
(N = 485), %
Placebo + Exemestane
(N = 239), %
Sensitivity to prior hormonal therapy 84
Last treatment: LET/ ANA 74 75
Last treatment
Adjuvant 21 16
Metastatic 79
Prior tamoxifen 47 49
Prior fulvestrant 17
Prior chemotherapy for metastatic BC 26 24
Number of prior therapies: ≥ 3 54 53
Baselga J, et al. N Engl J Med 2012;366(6):520-9. 32

33. BOLERO-2 Primary Endpoint: PFS Central Assessment12 6 18 24 30 36 48 60 42 54 72 66 78 80 40 20
100
Probability of Event (%)
Everolimus + Exemestane (E/N=114 / 485)
Placebo + Exemestane (E/N=104 / 239)
HR = 0.36 (95% CI: )
Log rank P value = 3.3 x
EVE + EXE: 10.6 Months
PBO + EXE: 4.1 Months
Time (weeks)
Everolimus plus exemestane increased progression-free survival by 64%
Baselga J, et al. N Engl J Med 2012;366(6):520-9. 33

34. BOLERO-2: Overall Response Rate and Clinical Benefit Rate by Local Assessment
Baselga J, et al. N Engl J Med 2012;366(6):520-9. 34

35. BOLERO-2: Most Common G3/4 AEs
Everolimus + Exemestane (N = 482), %
Placebo + Exemestane (N = 238), %
All Grades
Grade 3
Grade 4
Stomatitis 56 8 11 1
Fatigue 33 3
<1 26
Dyspnea 18 4 9
Anemia 16 5
Hyperglycemia 13 2
AST 6
Pneumonitis 12
Baselga J, et al. N Engl J Med 2012;366(6):520-9. 35

36. BOLERO-2: Overall Survival
As of PFS interim analysis: 83 deaths
10.6% in everolimus arm
13.0% in placebo arm
OS interim analysis after 173 events
OS final analysis at 392 events
80% power to detect 26% reduction in hazard ratio (0.74)
Baselga J, et al. N Engl J Med 2012;366(6):520-9. 36

37. BOLERO-2: Clinical Implications
The PFS of HR+ MBC patients who took everolimus + exemestane had a significantly higher PFS than those who took exemestane alone
Everolimus may slow progression of MBC in patients who initially became resistant to endocrine therapy alone

38. Other Mechanisms of Resistance PI3K Compensatory Pathways

39. PI3K Compensatory Pathways Rapalogs Activate Akt
IGFR-1
Phase I Everolimus Study
Tumor pAkt
IRS
PI3K
pre-therapy
PIP3
PTEN
Akt
PDK1
Tuberin
on-therapy
Rheb
10mg/day
50mg/week
TORC1
S6K
4EBP1 S6
Tabernero A, et al. J Clin Oncol. 2008;26(10):

40. PI3K Compensatory Pathways PI3K Inhibitors Activate ERK Pathway via Enhanced RTK Signaling
IGFR1
HER2
EGFR P P P P P P P P P P P P
PI3K
Ras
PTEN
PIP3
Raf
Akt
PDK1
MEK
Tuberin
Erk
Rheb
Rsk
TORC1

41. [TITLE]

42. Conclusions
The effectiveness of ET is limited by high rates of de novo and acquired endocrine resistance.
Resistance to ET is a step-wise progression of BC cells that renders them estrogen-independent
Bidirectional crosstalk between the ER and growth factor receptor signaling pathways, such as the PI3K/AKT/mTOR pathway, is implicated in resistance to ET
Under the pressure of ET, dynamic interplay between ER and growth factor receptor expression exists that can alter BC cell phenotype
Overcoming endocrine resistance remains critical to enhancing further the benefit of existing endocrine therapies.