1. Clinical Focus: Current Approaches to the Treatment of Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer
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3. Faculty
Denise A. Yardley, MD Senior Investigator Breast Cancer Research Program The Sarah Cannon Research Institute and Tennessee Oncology Nashville, Tennessee
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5. Disclosures
Denise A. Yardley, MD, has no relevant disclosures. The following PIM clinical content reviewers, Linda Graham, RN, BSN, BA, Jan Hixon, RN, BSN, MA, Trace Hutchison, PharmD, Julia Kirkwood, RN, BSN and Jan Schultz, RN, MSN, CCMEP hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.
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7. Goal The goal of this activity is to provide participants with therapeutic strategies that integrate emerging clinical trial data to improve outcomes for patients with hormone receptor–positive, HER2-negative metastatic breast cancer.
Target Audience This program is intended for physicians and other healthcare professionals who provide care for patients with metastatic breast cancer.
Learning Objectives
At the conclusion of this activity, participants will be able to:
Plan treatment strategies based on important data from clinical trials investigating combination approaches targeting multiple pathways for HR-positive, HER2-negative metastatic breast cancer
Discuss relevant ongoing clinical trials and potential participation with appropriate patients
This slide summarizes the target audience, goal, and learning objectives for this CME activity.

8. Physician Continuing Medical Education
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This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine and Clinical Care Options, LLC. Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.
Credit Designation
Postgraduate Institute for Medicine designates this educational activity for a maximum of X.X AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
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9. 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.
Until this year, there had been a paucity of new agents to manage patients with hormone receptor (HR)–positive, HER2-negative breast cancer. In fact, fulvestrant was the last new endocrine agent approved, approximately 10 years ago, for the management of these patients.[1,2] As a result, it has been a struggle to identify new treatment opportunities for patients with HR-positive advanced breast cancer. The development of HER2-targeted agents is a great help for that population, as are new chemotherapy agents, but very little has been developed for the treatment of tumors whose growth is driven by hormone receptor activation.
1. Lim E, et al. Oncology (Williston Park). 2012;26: Croxtall JD, et al. Drugs. 2011;71:

10. 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.
For the initial treatment of HR-positive advanced breast cancer, aromatase inhibitors (AIs) are the current standard of care for postmenopausal patients.[3-5] In clinical trials, AIs provided longer time to progression compared with tamoxifen.[6,7] Fulvestrant was hoped to be the next big advancement in the treatment of HR-positive advanced breast cancer and, in fact, demonstrated improved time to progression when compared with anastrozole, although overall survival was similar between groups.[8] Fulvestrant had similar efficacy when compared with tamoxifen,[9] and the combination of fulvestrant and anastrozole turned out to have a similar efficacy as anastrozole alone.[10] Of note, the recent CONFIRM study of fulvestrant in estrogen receptor (ER)–positive advanced breast cancer demonstrated significantly increased overall survival with a dose of 500 mg instead of the approved dose of 250 mg (median time to death: 26.4 vs 22.3 months, respectively).[11]
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:

11. 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
In our patient's case, 4 years after responding to endocrine therapy, she relapsed with progression. This suggests the development of resistance to letrozole. Hormonal therapy resistance represents a very complex interplay of connected cell-signaling pathways that results in metastasis, proliferation, and growth, even in the presence of antagonistic therapies.[13-15] Unraveling these pathways and developing actionable targets in them is the current focus in development of novel endocrine therapies. Tumors that may be more susceptible to these treatments have demonstrated a previous response to endocrine therapies and then developed subsequent resistance.
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:

12. 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.
Unfortunately, patients with demonstrated benefit from endocrine therapy will eventually develop progression. The treatment goal is to delay the eventual transition to chemotherapy (in circumstances outside of visceral crises).[16-18] In this particular patient, options include endocrine therapy with fulvestrant or exemestane, or chemotherapy. In addition, results from the BOLERO-2 trial were recently published, demonstrating benefit from the combination of exemestane and the mammalian target of rapamycin (mTOR) inhibitor everolimus.[19] This trial was designed with knowledge that the PI3K/AKT/mTOR pathway can drive therapy resistance.[20,21]
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.

13. 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.
The PI3/AKT/mTOR pathway is key to normal cellular functions, including metabolism, growth, cell proliferation and survival.[22,23] With the development of the mTOR inhibitor everolimus, tumors can be resensitized to exemestane endocrine therapy, as seen in BOLERO-2.[24] Everolimus has been used in multiple other tumor types and now is being evaluated in breast cancer in the HR-positive, HER2-negative, and HER2-positive populations.
25. Baselga J, et al. N Engl J Med. 2012;366:

14. 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
In BOLERO-2, the nonsteroidal AI did not have to be the most recent therapy,[26] and 40% of the patients received it as second-line therapy. The example case patient was treated with letrozole in the first-line metastatic setting. The median age of the patients in BOLERO-2 was approximately 62 years, about 30% had had bone-only disease at their diagnosis, and approximately 50% had evidence of visceral disease. Many patients had more significant disease, where one third had at least 3 organs involved, and approximately one quarter came straight from adjuvant therapy without any therapy for metastatic disease; their nonsteroidal AI was prescribed as part of adjuvant therapy but failed to prevent progression.
*All other patients had ≥ 1 lytic bone lesion
26. Baselga J, et al. N Engl J Med. 2012;366:

15. 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.
Results from BOLERO-2 clearly showed that adding everolimus to exemestane therapy improved PFS in postmenopausal patients.[27] Importantly, the curves split very early.[28] The divergence was evident at the first tumor check, at 6 weeks, demonstrating an early benefit.
Of note, the advantage was independent of age, sensitivity to the primary hormonal therapy, presence of visceral disease, performance score, or whether they had bone-only disease. There was no subgroup that did not benefit. The addition of everolimus to exemestane improved median PFS by approximately 2-fold. In my opinion, this is a substantial increase in the durability of the response to endocrine therapy for patients that previously demonstrated resistance to a nonsteroidal AI. 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.

16. 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
The adverse events of the combination of everolimus plus exemestane are manageable with dose reductions and interruptions. Nearly one half of the patients experienced some dose interruptions or reductions during the course of their therapy that easily addressed the adverse effects.[29]
29. Piccart-Gebhart M, et al. ASCO Abstract 559.

17. 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
One of the adverse events associated with everolimus that patients and physicians need to be aware of is pneumonitis.[30] This is also an uncommon adverse effect for endocrine therapies. Patients may have some shortness of breath or a mild cough. These may be patients that have pulmonary involvement with their cancer or who received radiation therapy to their lung and might be experiencing a simple pneumonia. However, as pneumonitis is a class effect with the mTOR inhibitors, it is important to pay attention when patients come in with these complaints. In addition, patients should be educated on these adverse effects.
30. Everolimus [package insert].

18. 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.
The NCCN guidelines now recommend considering the combination of everolimus and exemestane for HR-positive, HER2-negative postmenopausal patients failing second-line treatment.[31] One of the primary benefits of this combination is that it maintains patients on endocrine therapy for a longer time period before their disease again develops resistance and evidence of progression.
31. NCCN. Clinical practice guidelines in oncology: breast cancer. v 18

19. Factors That Guide Selection of Subsequent Lines of Therapy
Disease burden
Response to previous therapy
Patient disease symptoms
Visceral crisis
Age
When considering whether to use chemotherapy or endocrine therapy in a patient who has bone and visceral involvement, we must take into account the patient’s disease and disease burden. The previous patient has isolated lung involvement, suggesting asymptomatic visceral disease.

20. 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.
Since the case patient is postmenopausal, endocrine therapy is an option, as recommended in the most recent NCCN guidelines.[32] But this patient could also receive chemotherapy. To reach the optimal balance of benefits and adverse effects requires incorporating resistance as part of this patient’s endocrine profile. Her relapse less than 1 year from completing her hormonal therapy suggests that manipulation of the PI3K/AKT/mTOR pathway may result in a more durable response.

21. 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
MEK
AI, aromatase inhibitor; E, estrogen; ER, estrogen receptor; HR, hormone receptor; mTOR, mammalian target of rapamycin; TKI, tyrosine kinase inhibitor.
The complex interactions between endocrine therapies and cell-signaling pathways involve cross-talk between surface signals on the outside of the cell and internal cell signaling that ultimately leads to proliferation, growth, and resistance.[33]
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

22. 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.
Inhibition of cell-cycle progression has demonstrated potential to improve outcomes in other tumor models.[34,35] Studies have suggested that agents that inhibit CDK4/6 would work antagonistically with at least some cytotoxic agents, such as anthracyclines,[36,37] whereas attempts at identifying prognostic biomarkers have pointed to luminal ER expression as marker of sensitivity to CDK4/6 inhibitors, such as PD [38]
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.

23. 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.
The TRIO-18 study explored the combination of PD with letrozole vs single agent letrozole in post-menopausal women with ER-positive, HER2-negative tumors who had not received treatment for metastatic or advanced disease.[39] The study demonstrated improved PFS for the combination vs letrozole alone, (26.1 vs 7.5 months, respectively), and superior clinical benefit rate. Although these results did not indicate an improved overall response rate with the additions of PD , they are encouraging and have warranted moving this agent into phase III trials.
39. Finn RS, et al. Cancer Res. 2012;72:S1-S6.

24. 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
Epigenetic modulation has arisen as another potential treatment avenue for HR-positive patients, based on data from studies of histone deacetylase (HDAC) inhibitors.[40] Resistance to endocrine therapy may involve methylation and silencing of multiple genes, which could be reversed with an HDAC inhibitor. HDAC inhibitors alter the balance between the histone acetyl transferase and the HDAC activities that open and close the DNA to being read by RNA polymerases in the nucleus.[41] As a result, these agents promote the transcription of genes that the cancer cell suppresses.
40. Pathiraja TN, et al. J Mam Gland Biol Neoplasia. 2010;15:35-47.

25. 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.
Entinostat is one such promising agent being evaluated in breast cancer.[42] Entinostat has been looked at in patients with breast cancer who are developing endocrine resistance. The ENCORE 301 trial was a blinded, randomized, placebo-controlled study of the addition of entinostat to exemestane in patients failing a nonsteroidal AI.[43] These patients may have had previous chemotherapy, but their last treatment was a nonsteroidal AI.
42. Knipstein J, et al. Expert Opin Investig Drugs. 2011;20:

26. 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
Mos
CBR, clinical benefit rate; CI, confidence interval; HDAC, histone deacetylase; ORR, overall response rate; PFS, progression-free survival.
These results from the ENCORE 301 trial add to the growing body of data that suggest we may be able to manipulate hormonal resistance mechanisms in postmenopausal patients with HR-positive breast cancer with HDAC inhibitors.[44] This population can have some resistance to exemestane, but adding entinostat improves PFS.[45] In this study, median PFS was 2.3 months for exemestane alone vs 4.3 months for the combination of entinostat and exemestane. Overall response rate and clinical benefit rate did not significantly differ between arms. An analysis 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] Additional trials of patients with HR-positive breast cancer will compare various agents in combination with entinostat, and some studies will include exploratory biomarker analyses,[47] hopefully pointing to ways to monitor the effectiveness of this new agent and identify appropriate patients.
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.

27. 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.
In summary, endocrine therapy in postmenopausal, HR-positive patients provides good tumor control and remains the preferred treatment option for patients outside of a visceral crisis. Endocrine therapy is the mainstay of the NCCN guidelines for first- and second-line therapies.[48]
Unfortunately, patients will relapse on endocrine therapy, with constitutive activation of the PI3/AKT/mTOR pathway, which leads to resistance, cell growth, and proliferation. The use of everolimus to inhibit the mTOR pathway in combination with endocrine therapies, such as exemestane and tamoxifen, continues to show benefit.
Looking forward, new treatments are being developed that will, hopefully, overcome resistance to endocrine therapy and further delay the eventual transition to chemotherapy.

28. Go Online for More CCO Coverage of Breast Cancer!
Capsule Summaries of all the key data, plus Expert Analysis panel discussions exploring the clinical implications of the recent San Antonio meeting Breast Cancer Quiz: Challenge yourself to see how many questions you can answer correctly and compare yourself to your colleagues Expert Recap (slides and audio) plus downloadable PowerPoint slides
clinicaloptions.com/oncology