1. Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC
Clinical Focus: Current Approaches to the Treatment of Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer
This program is supported by an educational grant from
Image: National Cancer Institute/Copyright©2012 Photo Researchers, Inc. All Rights Reserved

2. Endocrine Therapies for Breast Cancer
Year
Agent
Mechanism
1977
SERMs
Tamoxifen
Toremifene
Antagonizes estrogen receptor in breast tissue
1990s
AIs
Anastrozole
Exemestane
Letrozole
Inhibit estrogen production in postmenopausal women
2000s
ERD
Fulvestrant
Impairs ER dimerization, increases ER degradation, and disrupts nuclear localization of ER
AI, aromatase inhibitor; ER, estrogen receptor; ERD, estrogen receptor downregulator; SERM, selective estrogen receptor modulator.
1. Lim E, et al. Oncology (Williston Park). 2012;26: Croxtall JD, et al. Drugs. 2011;71:

3. Initial Treatment of HR-Positive Advanced Breast Cancer
AIs are the current standard of care for initial treatment of postmenopausal women with HR-positive advanced breast cancer
AIs have demonstrated improved efficacy compared with tamoxifen
TTP, anastrozole vs tamoxifen: 10.7 vs 6.4 mos[6]
TTP, letrozole vs tamoxifen: 9.4 vs 6.0 mos[5]
PFS, exemestane vs tamoxifen: 9.9 vs 5.8 mos[7]
Fulvestrant has demonstrated improved efficacy compared with anastrozole
TTP, fulvestrant vs anastrozole: 23.4 vs 13.1 mos[8]
Fulvestrant has demonstrated similar efficacy compared with tamoxifen[9]
Combination fulvestrant and anastrozole was not more efficacious than anastrozole alone[10]
AI, aromatase inhibitor; HR, hormone receptor; PFS, progression-free survival; TTP, time to progression.
6. Bonneterre J, et al. Cancer. 2001;92: Mouridsen H, et al. J Clin Oncol. 2003;21: Paridaens RJ, et al. J Clin Oncol. 2008;26: Robertson FJ, et al. Breast Cancer Res Treat. 2012;136: Howell A, et al. J Clin Oncol. 2004;22: Mehta RS, et al. N Engl J Med 2012;367:

4. Resistance to Endocrine Therapy
Complex interconnecting signaling pathways regulate cellular response to estrogen[13,14]
May contribute to various mechanisms of resistance
Resistance may be described as[15]
Intrinsic or de novo: tumor does not respond to a drug from the onset of therapy
Acquired: tumor that initially responded to therapy resumes growing
Interconnectivity of pathways offers opportunities and challenges for combining therapies
13. Chang J, et al. Anticancer Agents Med Chem. 2012;[Epub ahead of print]. 14. Roop RP, et al. Future Oncol. 2012;8: Hurvitz SA, et al. Cancer. 2008;113:

5. Progression on Endocrine Therapy in HR-Positive Advanced Breast Cancer
50% of patients with HR-positive advanced breast cancer will respond to initial endocrine treatment but will eventually relapse
Multiple mechanisms allow for development of resistance to antiestrogen therapy
Delaying systemic chemotherapy is the preferred therapeutic strategy
Adding a second antiestrogen to inhibit the estrogen receptor pathway does not improve outcome
Inhibition of both estrogen receptor and progrowth/antiapoptotic cell signaling pathways (eg, PI3K/AKT/mTOR) may improve therapeutic outcomes
ER, estrogen receptor; HR, hormone receptor; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin.
16. Di Leo A, et al. J Clin Oncol. 2010;28: Chia, S, et al. J Clin Oncol. 2008;26: Johnston SR, et al. European Breast Cancer Conference Abstract LBA2.

6. Crosstalk Between ER and PI3K/AKT/mTOR Signaling: Rationale for Dual Inhibition
PTEN
mTOR
RAS
RAF
MEK
MAPK
ER target gene transcription P
EGFR HER2 E ER
mTOR activates ER in a ligand-independent manner
Estradiol suppresses apoptosis induced by mTOR blockade
Hyperactivation of the mTOR pathway is observed in endocrine therapy–resistant breast cancer cells
AKT, protein kinase B; E, estrogen; EGFR, epidermal growth factor receptor; ER, endocrine receptor; HER2, human epidermal growth factor receptor-2; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin. 6

7. BOLERO-2: Exemestane ± Everolimus in Nonsteroidal AI–Refractory ABC
Postmenopausal women with HR-positive, HER2-negative advanced breast cancer refractory to letrozole or anastrozole
(N = 724)
Everolimus 10 mg/day +
Exemestane 25 mg/day
(n = 485)
Placebo +
Exemestane 25 mg/day
(n = 239)
Refractory to therapy:
Recurrence during or within mos of end of adjuvant treatment
Progression during or within 1 mo after end of treatment for advanced disease
Stratification:
Sensitivity to previous hormonal therapy
Presence of visceral disease
No crossover allowed
Primary endpoint: PFS
Secondary endpoints: OS, ORR, CBR, safety, QoL, bone markers
ABC, advanced breast cancer; AI, aromatase inhibitor; CBR, clinical benefit rate; OS, overall survival; ORR; overall response rate; PFS, progression-free survival; QoL, quality of life.
25. Baselga J, et al. N Engl J Med. 2012;366:

8. BOLERO-2: Baseline Characteristics
Everolimus + Exemestane
(n = 485)
Placebo + Exemestane
(n = 239)
Metastatic site Liver Lung Bone
Number of metastatic sites 1 2
≥ 3 32 31 36 29 34 37
Visceral disease 56
Measurable disease* 70 68
*All other patients had ≥ 1 lytic bone lesion
26. Baselga J, et al. N Engl J Med. 2012;366:

9. BOLERO-2: PFS at 18-Mo Follow-up
100
Median PFS, Mos EVE + EXE: 7.82
PBO + EXE: 3.19
Hazard ratio: 0.45 (95% CI: ; log-rank P < .0001)
Censoring times
EVE + EXE (n/N = 310/485)
PBO + EXE (n/N = 200/239) 80 60
Probability of Event (%) 40 20
CI, confidence interval; EVE, everolimus; EXE, exemestane; PBO, placebo. 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
102
108
114
120 Wk
Patients at Risk, n
EVE + EXE
485
436
366
304
257
221
185
158
124 91 66 50 35 24 22 13 10 8 2 1
PBO + EXE
239
190
132 96 67 50 39 30 21 15 10 8 5 3 1 1 1
28. Piccart-Gebhart M, et al. ASCO Abstract 559.

10. BOLERO-2: Adverse Events at 18-Mo Follow-up
Everolimus + Exemestane (n = 482)
Placebo + Exemestane
(n = 238)
Grade
All 3 4
Total
100 44 9 91 23 5
Stomatitis 59 8 12
< 1
Rash 39 1 7
Fatigue 37 27
Diarrhea 34 2 19
Nausea 31 29
Appetite decreased 13
Noninfectious pneumonitis 16
Hyperglycemia 14
29. Piccart-Gebhart M, et al. ASCO Abstract 559.

11. Everolimus: Adverse Effects
Noninfectious pneumonitis
Reported in 11% to 14% of patients treated with everolimus[1]
Onset typically occurs within 2-6 mos of initiating therapy
Infections
Immunosuppressive properties
Opportunistic infection: pneumonia and other bacterial and fungal infections
Reported in up to 37% of the patients studied in everolimus clinical trials
Patients should avoid live vaccines and close contact with those who have received live vaccines
Potential for viral reactivation: hepatitis B, others
30. Everolimus [package insert].

12. Current Guidelines for Endocrine Therapy in Advanced Breast Cancer
Previous Endocrine Therapy Within 1 Yr
Premenopausal
Ovarian ablation + ET
Postmenopausal
Second-line ET
Visceral metastasis
Consider initial chemotherapy
No Endocrine Therapy Within 1 Yr
Ovarian ablation + ET or antiestrogen
AI or antiestrogen
Second-line endocrine therapy for all subsequent treatment
Patients with bone disease should be treated with bone-targeted therapy
Consider the addition of everolimus to exemestane in postmenopausal women who are resistant to nonsteroidal AIs
AI, aromatase inhibitor; ET, endocrine therapy.
31. NCCN. Clinical practice guidelines in oncology: breast cancer. v 12

13. Factors That Guide Selection of Subsequent Lines of Therapy
Disease burden
Response to previous therapy
Patient disease symptoms
Visceral crisis
Age

14. Available Classes of Therapy for ER+, HER2-Negative Postmenopausal Women
Endocrine therapy
Selective nonsteroidal AIs
Steroidal AIs
Pure antiandrogens
Progestin
High-dose estrogen therapy
Selective estrogen receptor modulators
Chemotherapy
Taxanes
Antimetabolites
Anthracyclines
Other microtubule inhibitors
Targeted therapy
AI, aromatase inhibitor; ER, estrogen receptor.

15. Combining Targeted and Antiestrogen Therapies in HR-Positive Breast Cancer
EGFR HER2 E
Aromatase Inhibitor
Nonsteroidal AIs
Anastrozole
Letrozole
Steroidal AIs
Exemestane
TKI E
RAS
PI3K
PTEN
ER Downregulator
Fulvestrant
RAF ER E
mTOR Inhibitors
Everolimus
Sirolimus
Temsirolimus
AKT
AI, aromatase inhibitor; E, estrogen; ER, estrogen receptor; HR, hormone receptor; mTOR, mammalian target of rapamycin; TKI, tyrosine kinase inhibitor.
MEK
MAPK
mTOR
Selective Estrogen Receptor Modulators
Tamoxifen
Toremifene
CDK 4/6 Inhibitor PD
Cell
Cycle
ER target gene transcription ER E ER E
HDAC Inhibitor
Entinostat
Transcription
Silencing

16. Cyclin-Dependent Kinase 4/6 Inhibition as a Therapy in HR-Positive Breast Cancer
CDK4/6 regulates passage of cells through the cell cycle[35]
PD is an orally active CDK4/6 inhibitor that induces G0/G1 arrest
Factors associated with PD sensitivity: luminal ER expression, elevated expression of cyclin D1 and Rb protein, and reduced p16 expression
Synergistic with tamoxifen in vitro
Phase I results of PD plus letrozole (N = 12)[36]
Determination of recommended phase II dosing in combination with letrozole
PD mg/day for 3 wks of a 4-wk cycle
Letrozole 2.5 mg/day
Most common adverse events included neutropenia, leukopenia, and fatigue
AI, aromatase inhibitor; ER, estrogen receptor; HR, hormone receptor.
35. Finn RS, et al. Breast Cancer Res. 2009;11:R Slamon DJ, et al. J Clin Oncol. 2010;28: Finn RS, et al. Cancer Res. 2012;72:S1-S6.

17. TRIO-18: Phase II, PD0332991 + Letrozole
Part 1: ER-positive, HER2-negative breast cancer (N = 66)
Exploratory biomarkers for p16 loss, cyclin D1 gene amplification did not improve over ER positivity alone as a selection marker
Part 2: ER-positive, HER2-negative breast cancer with cyclin D1 gene amplification and/or p16 loss (N = 99)
Median PFS: letrozole + PD vs letrozole: 26.1 vs 7.5 mos (hazard ratio: 0.37; 95% CI: ; P < .001)
Best Overall Response (ITT)
PD Letrozole (n = 84)
Letrozole (n = 81)
All randomized patients, n
ORR, % 34 26
CR, % 1
PR, % 25
SD ≥ 24 wks, % 36 18
Clinical benefit rate, % 59
CI, confidence interval; CR, complete response; ER, estrogen receptor; ITT, intent to treat; ORR, overall response rate; PFS, progression-free survival; PR, partial response.
39. Finn RS, et al. Cancer Res. 2012;72:S1-S6.

18. HDAC Inhibitors Mechanism of Action
HDAC inhibitors relax the structure of DNA making it more accessible to RNA polymerases
Closed chromatin = genes off
Histone acetyltransferases (HATs)
Histone deacetylases (HDACs)
Open chromatin = genes on
HDAC inhibitors AC
HAT, histone acetyl transferase; HDAC, histone deacetylase
40. Pathiraja TN, et al. J Mam Gland Biol Neoplasia. 2010;15:35-47.

19. Epigenetic Therapy With Entinostat
Oral, isoform-selective HDAC inhibitor
Long half-life ( hrs) allows for weekly and biweekly dosing
Targets cancer-relevant class 1 HDACs
Well-characterized safety profile
No evidence of cardiac toxicity
ENCORE 301 trial randomized 130 postmenopausal women with ER- positive advanced breast cancer who progressed on previous nonsteroidal AI therapy
Exemestane 25 mg/day + entinostat 5 mg/wk (n = 64)
Exemestane 25 mg/day + placebo (n = 66)
AML, acute myeloid leukemia; ER, estrogen receptor; HDAC, histone deacetylase.
42. Knipstein J, et al. Expert Opin Investig Drugs. 2011;20:

20. ENCORE 301: PFS, ORR, CBR[45]
1.00
PFS, Mos
ORR, %
CBR, %
Placebo
2.27
4.6
25.8
Entinostat
4.28
4.7
26.6
Hazard ratio: 0.73 (95% CI: ; 1-sided P = .06)
0.75
Progression Probability
0.50
0.25 2 4 6 8 10 12 14 16 18
CBR, clinical benefit rate; CI, confidence interval; HDAC, histone deacetylase; ORR, overall response rate; PFS, progression-free survival.
Mos
Placebo Entinostat
31/66 15/64
13/33 14/45
4/20 11/29
4/15 3/16
1/7 3/10
3/6 0/3
0/2 0/1
0/1 0/1
1/1 1/1
Analyses of patient samples, demonstrated an association of HDAC inhibitor–induced lysine hyperacetylation in circulating B, T, and monocyte cells with improved clinical outcome and may be useful biomarker for HDAC inhibitor action[46]
45. Klein P, et al. ASCO 2012 Breast Cancer Symposium. Abstract Ordentlich P. Mol Cancer Ther. 2011;10:Abstract PR-6.

21. Summary
AIs have become the standard of care for initial treatment of postmenopausal women with HR-positive advanced breast cancer
However, many patients with advanced breast cancer fail to respond initially and all patients eventually progress
Patients progressing or recurring after initial endocrine therapy demonstrate low ORR and limited survival benefit due to endocrine resistance
New treatments may overcome endocrine resistance and delay need for chemotherapy
Combined targeting of both ER and growth factor receptor or intracellular signaling pathways may be promising treatment approach
ER, estrogen receptor; HR, hormone receptor; ORR, overall response rate.