Enhancing Endocrine Therapy for Hormone Receptor Positive Advanced Breast Cancer

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1 Enhancing Endocrine Therapy for Hormone Receptor Positive Advanced Breast Cancer Sung-Bae Kim, MD, PhD Professor, Dept of Oncology, Asan Medical Center University of Ulsan College of Medicine Seoul, Korea

2 Outline Overview AI or Fulvestrant Endocrine resistance - ESR1 mtor inhibitor/cdk4/6 inhibitors Cotargeting signaling pathways Immuno-oncology drug in ER+

3 Conclusions: Treatment of ER+ MBC First Line Rx: Can achieve PFS of ~14-16 months with single agent AI or fulvestrant Likely ceiling for endocrine alone approach, but still an important option for many Combination approaches with CDK 4/6 inhibitors can achieve 1 st PFS of 24+ months: Do all patients need a combination approach 1 st Line? What therapy do we use after progression on CDK 4/6 inhibitors? Second Line Rx: Combination approaches standard of care with additional 2 nd PFS of 7 9 months Wide range of targets still under investigation (ie. PI3K, mtor/ AKT) Sequencing and Patient Selection: Always consider tumor biology, clinical features, and patient factors when selecting most appropriate therapy

4 Evolution of Chemo/Endocrine Treatment in Advanced Breast Cancer Chemotherapy Anthracyclines 1 Doxorubicin Epirubicin 1980s Taxanes 1 Paclitaxel Docetaxel 1990s Others 1 Capecitabine Gemcitabine Ixabepilone Eribulin Nab paclitaxel 2000s Endocrine Therapy s Oophorectomy 2,3 SERMS 4 Tamoxifen Toremifene AIs 4 Anastrozole Letrozole Exemestane ERDs 5 Fulvestrant ERDs 5 High dose Fulvestrant * Targeting mechanisms of endocrine resistance: everolimus Palbociclib Ribociclib Abbreviations: AI, aromatase inhibitor; ERDs, estrogen receptor downregulator; HR + ; hormone receptor positive; SERMS, selective estrogen receptor modulators. * Marginal improvement over lower dose fulvestrant Beatson CT. Lancet. 1896;2: ; 3. Beatson CT. Lancet. 1896;2: ; 4. Cohen MH, et al. Oncologist. 2001;6:4 11; 5. Faslodex [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP;

5 Management of post-menopausal ER+ MBC Determine sites and extent of disease & symptoms; ER status; HER2 status; disease free & treatment-free intervals; performance status No life-threatening disease Hormone-responsive Hormone-unresponsive, or life-threatening disease 1 st -line hormonal therapy 1 st -line chemotherapy Response Median PFS 9 13 mo Progression 2nd-line hormonal therapy Response Median PFS 3 4 mo No Response No Response Progression 2nd-line chemotherapy Progression 3rd-line chemotherapy Progression 3rd-line hormonal therapy No Response Supportive care NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V3.2012

6 Criteria Criteria to support 1 st line choices in ER+ HER2- advanced disease In favor of chemotherapy Uncertain (grey area) DFI < 1year 1-2 years > 2years Visceral metastases High burden, impending organ dysfunction (visceral crisis) Moderate burden In favor of endocrine therapy Minimal burden or absent Symptoms Prominent Moderate Minimal or asymptomatic Hart CD, et al. Nat Rev Clin Oncol 2015

7 Definition of endocrine resistance

8 PFS / TTP of AIs as 1 st -line endocrine therapy trials in HR+ MBC Trial Date AI (months) Tamoxifen (months) AI + fulvestrant 250mg (m onths) HR Nabholtz et al Anastrozole vs tamoxifen Bonneterre et al Anastrozole vs tamoxifen Mouridsen et al Letrozole vs tamoxifen Chernozemsky et al Exemestane vs tamoxifen Paridaens et al Exemestane vs tamoxifen Mehta et al (SWOG0226) Anastrozole vs anastrozole + fulvestrant 250mg Bergh et al (FACT) Anastrozole vs anastrozole + fulvestrant 250mg Range Plenary Lecture 1. San Antonio Breast Cancer Symposium, Dec 6-10, 2016

9 FALCON: Phase III 1 st line study of Fulvestrant 500 vs AI in Endocrine Therapy Naïve MBC / LABC N=450 ER +ve, HER2 negative Locally advanced (not suitable for surgery) or metastatic disease Up to 1 line of chemotherapy At least 1 lesion that can be assessed Fulvestrant 500mg i.m. Anastrozole 1mg OD Note no prior endocrine therapy allowed Primary endpoint: PFS Secondary endpoint: OS Other secondary endpoints include ORR, CBR, duration of response, duration of clinical benefit, time to deterioration of HRQoL, Safety Ellis et al, LBA14 ESMO 2016 Plenary Lecture 1. San Antonio Breast Cancer Symposium, Dec 6-10, 2016

10 FALCON: Phase III 1 st line study of Fulvestrant 500 vs AI in Endocrine Therapy Naïve MBC / LABC Proportion of patients alive and progression free HR (95% CI 0.637, 0.999) p= Primary endpoint: PFS Median PFS Fulvestrant: 16.6 months Anastrozole: 13.8 months Fulvestrant (n=230) Anastrozole (n=232) 0.0 Number of patients at risk: Time (months) Fulvestrant Anastrozole Proportion of patients alive and progression-free Proportion of patients alive and progression-free HR 0.59 (95% CI 0.42, 0.84) PFS without visceral disease Fulvestrant (n=95) Anastrozole (n=113) Median PFS Fulvestrant: 22.3 months Anastrozole: 13.8 months HR 0.99 (95% CI 0.74, 1.33) Median PFS Fulvestrant: 13.8 months Anastrozole: 15.9 months Plenary Lecture 1. San Antonio Breast Cancer Symposium, Dec 6-10, 2016 Time (months) PFS with visceral disease Time (months) Fulvestrant (n=135) Anastrozole (n=119) Ellis et al, LBA14 ESMO 2016

11 Rationale for the Combination of Fulvestrant plus Aromatase Inhibitors Brodie A et al, Cancer Res 65: , 2005 Macedo et al, Cancer Res 68, , 2008

12 SCHEMA for FACT and SWOG 0226 Trials Anastrozole Eligibility Postmenopausal ER+ 1 st line therapy for MBC >1 yr since adjuvant AI 1 mg PO QD 1:1 randomization 1 Endpoint TTP / PFS Anastrozole plus Fulvestrant 500 mg d1, 250 mg d14, 28 and every 28 days thereafter

13 Fulvestrant AI as 1 st -line Rx for ER+ MBC FACT: PFS SWOG 0226: PFS Bergh J et al. JCO 2012;30: Mehta RS et al. N Engl J Med 2012;367:

14 SWOG 0226: PFS according to subgroups Mehta RS et al. N Engl J Med 2012;367:

15 SoFEA Trial Design: Fulvestrant + Anastrozole vs Fulvestrant + Placebo vs Exemestane ER + and/or PgR + postmenopausal patients with locally advanced/ metastatic BC following progression on NSAI RANDOMIZE Fulvestrant 250 mg + Anastrozole n = 250 AI blinded Fulvestrant 250 mg + placebo n = 250 Exemestane n = 250 Abbreviation: AE, adverse event; AI, aromatase inhibitor; BC, breast cancer; ER +, estrogen-receptor positive; NSAI, nonsteroidal aromatase inhibitor; PgR +, progesterone-receptor positive. Johnston SRD, et al. Lancet Oncol

16 SoFEA Results: Fulvestrant + Anastrozole vs Fulvestrant + Placebo vs Exemestane FUL + ANA FUL alone EXE alone Median PFS 4.4 months 4.8 months 3.4 months Median OS 20.2 months 19.4 months 21.6 months ORR 7.4% 6.9% 3.6% AE profiles were similar across treatment arms except for rates of dyspnea in the FUL alone arm 12 deaths not related to BC (4 in each arm) were reported Abbreviation: AE, adverse event; ANA, anastrozole; BC, breast cancer; EXE, exemestane; FUL, fulvestrant; ORR, objective response rate; OS, overall survival; PFS, pr ogression-free survival. Johnston SRD, et al. Lancet Oncol

17 Effects of ER Mutational Status 50 Disease Progression and LBD Mutation Frequency Patients With LBD Mutations, % Primary Early Metastatic Disease Late Metastatic Disease LiToy, W. et al. Nat Gen 2013 Robinson, D.R. et al. Nat Gen 2013 Jeselsohn, R. et al. Clin Cancer Res 2014

18 Acquired ESR1 mutation in metastatic ER+ breast cancer ESR1 mutation confers constitutive ER activation without ligand binding. ER antagonists partially inhibit mutant ER transcription activity whereas higher concentration of fulvestrant fully inhibits growth of ER mutant cell lines. Toy W, et al. Nature Genetics 2013;45:1439

19 ESR1 mutations activate the estrogen receptor LBD ESR1 mutations Ligand independent signaling Constitutive agonist conformation through the formation of hydrogen bonds between S537 or G538 and N351 in helix 12 Toy et al. J Nat Gen 2013

20 ESR1 mutated ESR1 wild type ESR1 wild type Fribbens C, et al. J Clin Onc. 2016;34(25):2961-8

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22 The Cell Cycle Regulators CDK1 Cyclin B Cyclin D1/ D2/D3 CDK4/6 M G1 G2 S Cyclin E CDK2 CDK1 Cyclin A Cyclin A CDK2 Go:resting phase; G1:prepare for DNA synthesis/ checkpoint S:DNA synthesis; G2:pre-division/mitosis, checkpoint, M:mitosis/cell division 22

23 Regulation of the G1/S Checkpoint NF-κB Pl3K/Akt (ER/PR/AR) Wnt/β-catenin STATs MAPKs Active tumor supp ressor Cyclin D CDK4/6 M G0 E2F RB p16 G2 S G1 E2F Gene transcription P P P P RB Inactive 23

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25 Defects in the RB/CDK4/Cyclin D/p16 Pathway are common CDK4 Amplification/Mutation: Sarcomas (18%) Gliomas (18%) Melanoma (5%) Rb E2F/DP1 Cdk4 Cyclin D P P p16 Rb P P Cyclin D1- Amplification: Head and Neck (43%) Esophageal (34%) Breast (13%) Over-Expression: MCL t(11;14) translocation Myeloma (34%) Rb - Inactivation: Retinoblastoma (100%) SCLC (90%) NSCLC (30%) Gliomas (14%) inactive E2F/DP1 active G1 S phase G2 M P16 Deletion/Mutation/ Methylation Glioblastoma (70%) Mesothelioma (55%) Pancreatic (50%) Dickson MA, Schwartz GK. Curr Oncol 2009;16:36 43 Shapiro GI. J Clin Oncol 2006;24:

26 Timeline of CDKs Early 1970s: Lee Hartwell identifies a number of genes involved in cell division CDCs (cell division cycle) Using yeast mutation model identified genes involved in the cell cycle Developed the concept of checkpoints Late 1970s/early 1980s: Paul Nurse, again using yeast models, identifies other cdc2 and demonstrates its role in controlling the cell cycle Demonstrates the function of CDKs and their conservation Early 1980s: Tim Hunt, using sea urchins, identifies proteins that increase before cell division, then abruptly drop off (a cyclical pattern) Cyclins and their degradation as a control mechanism in the cell cycle 2001: Hartwell, Nurse, and Hunt win the Noble Prize in Medicine and Physiology

27 Objectives of the meeting in Yr 2004

28 Palbociclib - A Sleeping Beauty

29 Preferential inhibition of Luminal ER+ and HER2+ breast cancer cell lines by palbociclib Finn RS, et al. BCR 2009;11(5):R77. Luminal HER2 amplified Immortalized Non-luminal/post EMT Non-luminal This presentation is the intellectual property of the author/presenter. Contact for permission to reprint and/or distribute

30 Palbociclib Acts Synergistically with Tamoxifen in ER+ Breast Cancer Cell Lines MCF7 Inhibition (%) Palbociclib alone Tamoxifen alone Palbociclib/Tamoxifen combination EFM19 CI m = 0.37±0.04 Inhibition (%) 100 CI m = 0.45± Tamoxifen Palbociclib Concentration nm 0 Tamoxifen Palbociclib Concentration nm T47D Inhibition (%) CI m = 0.1± Tamoxifen Palbociclib Concentration nm Mean combination index (CI m ) <1 indicates synergy for the combinations Finn RS, et al. Breast Cancer Res. 2009;11(5):R77 30

31 Selective CDK 4/6 inhibitors Abemaciclib Palbociclib Ribociclib O Leary B, et al. Nat Rev Clin Oncol. 2016;13(7):

32 Clinical data for CDK 4/6 inhibitors in HR+/HER2 MBC Palbociclib: NCT , NCT , NCT Abemaciclib: NCT Ribociclib: NCT PALOMA-1 PALOMA-3 PALOMA-2 1L ER+, HER2 mbc Palbociclib + AI (letrozole) 2014 Recurrent HR+, HER2 mbc Palbociclib + ful vestrant 1L ER+, HER2 mbc Palbociclib + AI (letrozole) Other trials ongoing Data read-out dates MONARCH-1 MONALEESA-2 Recurrent ER+, HER2 mbc Abemaciclib 1L ER+, HER2 ABC Ribociclib + letr ozole

33 PALOMA-2 & MOLALEESA-2: Design of Phase III Studies PALOMA-2 MOLALEESA-2 Postmenopausal ER + HER2 advanced breast cancer with no prior treatment fo r advanced disease. AI-resistant patients excluded N=666 R A N D O M I S E (2:1) Palbociclib (125 mg QD, 3/1 schedule) + letrozol e (2.5 mg QD) Placebo + letrozole (2.5 mg QD) Postmenopausal women with HR+/ HER2 advanced breast cancer with no prior therapy for advanced disease N=668 R A N D O M I S E (1:1) Ribociclib (600 mg QD, 3/1 schedule) + letrozole (2.5 mg QD) Placebo + letrozole (2.5 mg QD) Stratified by the presence/absence o f liver and/or lung metastases Primary endpoint: PFS Secondary endpoints: Response, OS, safety, biomarkers, PROs Primary endpoint: PFS Secondary endpoints: OS (key), ORR, CBR, safety

34 Populations in recent Phase III 1 st -line ER+ MBC trials PALOMA-2 1 (n=666) MONALEESA-2 2 (n=668) SWOG (n=707) FALCON 4 (n=462) Disease Free Interval De novo MBC < 12 mo > 12 mo 37% 22% 40% 34% 2% 64% 39% nil 61% (> 10 yr) 28% MBC 87 % LABC 18 % Prior Treatment Adjuvant Endocrine Rx Adjuvant Chemotherapy Chemotherapy for MBC 56% 40% nil 52% 43% nil 40 % 33 % nil nil 19 % 17 % Site of Disease Visceral Bone only 48% 23% 59% 21% 54 % 22 % 55 % 10 % Median PFS for AI control (95 % CI) 14.5 mo ( ) 14.7 mo ( ) 13.5 mo ( ) 13.8 mo (NR) 1. Finn R, et al. NEJM. 2016;375(20): ; 2. Hortobagyi G, et al. NEJM. 2016;375(18): ; 3. Mehta RS et al. N Engl J Med 2012;367:435-44; 4. Ellis et al, LBA14 ESMO 2016

35 PALOMA-2 & MONALEESA-2: PFS PALOMA-2 MONALEESA-2 mpfs (months) Palbociclib letrozole: 24.8 Placebo letrozole: 14.5 mpfs (months) Ribociclib letrozole: ribociclib letrozole: NR Placebo letrozole: placebo letrozole: Finn R, et al. NEJM. 2016;375(20): Hortobagyi G, et al. NEJM. 2016;375(18):

36 PALOMA-2 & MONALEESA-2: Secondary endpoints PALOMA-2 Measurable disease Palbociclib + letrozole Placebo + letrozole OR (95% CI): 2.23 ( ) p< MONALEESA-2 Measurable disease Ribociclib + letrozole Placebo + letrozole p=0.02 Rate (%) OR (95% CI): 1.55 ( ) p= Rate (%) p= Objective response rate Clinical benefit rate 0 Objective response rate Clinical benefit rate Finn R, et al. NEJM. 2016;375(20): Finn R, et al. Abstract 507, ASCO 2016 Hortobagyi G, et al. NEJM. 2016;375(18): Hortobagyi G, et al. LBA01, ESMO 2016

37 PALOMA-2 & MONALEESA-2: Toxicity PALOMA-2 MONALEESA-2 Finn R, et al. NEJM. 2016;375(20): Hortobagyi G, et al. NEJM. 2016;375(18):

38 BOLERO-2 & PALOMA-3: Design of Phase III studies BOLERO-2 PALOMA-3 Postmenopausal wo men with estrogen re ceptor positive locally advanced or metastat ic breast cancer who are refractory to letro zole or anastrozole R A N D O M I S E (2:1) Everolimus 10 mg daily + exe mestane 25 mg daily (n=485) Placebo + exem estane 25 mg daily (n=239) HR+, HER2- ABC Pre/peri or postmenopausal Progressed on prior ET on o r within 12 months of adjuva nt therapy and/or on therapy for advanced breast cancer 1 or more prior chemothera py regimen for advanced ca ncer R A N D O M I S E (2:1) Palbociclib (125 mg QD; 3 weeks on, 1 week off) + fulvestrant (500 mg IM Q4W) (n=347) Placebo (3 weeks on, 1 we ek off) + fulvestra nt (500 mg IM Q4 W) (n=174) Primary endpoint: PFS Secondary endpoints: OS, ORR, Safety, QoL, CBR Primary endpoint: PFS Secondary endpoints: OS, OR, CBR, Safety, QoL

39 BOLERO-2 & PALOMA-3: PFS BOLERO-2 PALOMA-3 Baselga J, et al. N Engl J Med 2012;366:520-9 Turner N, et al. N Engl J Med 2015;373:209-19

40 BOLERO-2 & PALOMA-3: Safety BOLERO-2 PALOMA-3 Baselga J, et al. N Engl J Med 2012;366:520-9 Turner N, et al. N Engl J Med 2015;373:209-19

41 Biomarkers to Predict for Response to Palbociclib Examination in MBC enrolled on Phase 2 trial assessing the efficacy of palbociclib in patients with Rb positive metastatic cancer (UPCC 03909) To predict for response to palbociclib Rb, p16 or Ki-67 protein expression or CCND1 amplification Biomarkers and PFS Clark AS 2013 SABCG PFS analysis with all biomarkers was not significant

42 PALOMA2: PFS by Biomarker Qualitative Analysis n HR (95% CI) All patients ( ) Quantitative Analysis Percentile n HR (95% CI) All patients ( ) ER+ ER Rb+ Rb ( ) 0.41 ( ) 0.53 ( ) 0.68 ( ) ER status 25 th >25 th to <75 th 75 th ( ) 0.53 ( ) 0.65 ( ) Cyclin D1+ Cyclin D ( ) 1.0 ( ) Rb status 25 th >25 th to <75 th 75 th ( ) 0.46 ( ) 0.63 ( ) p16+ p16 Ki-67 20% Ki-67 >20% HR (95% CI) Favors PAL+LET Favors PCB+LET 0.52 ( ) 0.73 ( ) 0.53 ( ) 0.57 ( ) HR=hazard ratio; LET=letrozole; PAL=palbociclib; PCB=placebo; PFS=progression-free survival. Cyclin D1 status p16 status 25 th >25 th to <75 th 75 th 25 th >25 th to <75 th 75 th Favors PAL+LET HR (95% CI) 0.41 ( ) 0.69 ( ) 0.52 ( ) Favors PCB+LET 0.74 ( ) 0.62 ( ) 0.33 ( )

43 Biomarkers for Response to Endocrine Combinations Biology of the Primary Tumour: ER & PgR expression Molecular Profiling (ie. PAM-50 intrinsic subtype) Genetics Alterations in key signaling pathways PIK3CA / PTEN FGFR 1/2 Cell Cycle (CCND1) Real Time Biology in Metastatic Disease: ctdna analysis of acquired mutations (ESR1 and PIK3CA)

44 The PI3K/AKT/mTOR Pathway in Breast Cancer: Common Molecular Alterations ~40% of HR + breast cancer have PIK3CA mutations Frequency of PI3K and PTEN mutations in 547 human breast cancer samples Baselga J. Oncologist 2011; 16: Suppl 1: 12 Polivka Jr et al. Pharm Thera 2014; 142: 164

45 PIK3CA mutation status & response to CDK4/6 inhibitors in PALOMA-3 PIK3CA mutant PIK3CA WT PIK3CA mutations do not predict response to CDK4 inhibitors Cristofanilli M, et al. Lancet Oncol. 2016;17(4):

46 Combining Targeted and Antiestrogen Therapies in HR-Positive Breast Cancer PI3K inhibitors BMK120 BYL790 GDC0980 mtor Inhibitors Everolimus Sirolimus Temsirolimus CDK 4/6 Inhibitor Palbociclib HDAC Inhibitor Entinostat P EGFR HER2 RAS RAF Cell Cycle MEK P PI3K MAPK Transcription Silencing AKT TKI mtor PTEN E E ER ER E E Aromatase Inhibitor Nonsteroidal AIs Anastrozole Letrozole Steroidal AIs Exemestane ER Downregulator E Fulvestrant ER Selective Estrogen Receptor Modulators Tamoxifen Toremifene ER target gene transcription

47 I3K / TORC / AKT inhibitors in clinical development 2016 Alpelisib Taselisib Buparlisib Pictilisib Probability of Progression-free Survival, % BELLE-3 Buparlisib + fulvestrant (n/n=349/576) Placebo + fulvestrant (n/n=435/571) Time (months) Vistusertib Baselga J et al, SABCS 2015 Oral Abstract S6-0 1 FERGI Krop IE. Lancet Oncol Jun;17(6):

48 Early adaptive resistance to CDK inhibitors Resistance develop rapidly, within 72 hrs Herrera-Abreu MT, et al. Cancer Res 2016;1-13

49 Combined targeting: CDK4/6 and PI3K Herrera-Abreu MT, et al. Cancer Res 2016;1-13

50 Optimal sequencing of endocrine therapy in ER+ MBC 1 st line 2 nd line Delay Start of Chemotherapy OS A. Conventional ET AI alone 8 14 months Exemestane 3 4 months AI + everolimus 7 9 months A B C Fulvestrant+ CDK4/6 i 7 9 months B. Optimally selected ET Fulvestrant months (ie. endo Rx naïve, non-visceral mets, biomarker) AI + CDK4/6 i 7 9 months? AI + everolimus 7 9 months? 2 nd line post Fulvestrant: responsive to 2 nd line combinations? C. Combination ET AI + CDK4/6 i 24 months Fulvestrant months? AI + everolimus 7 9 months? 2 nd Line post CDK 4/6 inhibitors: still endocrine responsive and to what therapy? Cumulative Median PFS in months Plenary Lecture 1. San Antonio Breast Cancer Symposium, Dec 6-10, 2016

51 Key Pathways of endocrine resistance Rugo HS, et al. ASCO education book 2016

52 ENCORE 301: Ph II RCT of Exemestane+/-Entinostat in ER+ MBC progessing after NSAI 1. Klein P, et al. ASCO 2012 Breast Cancer Symposium. Abstract Ordentlich P. Mol Cancer Ther. 2011;10:Abstract PR 6.

53 KEYNOTE-028 Breast Cancer Cohort: Study Design Phase Ib multicohort study Pts with locally advanced or metastatic PD-L1+, ER +/HER2- breast cancer; failed or ineligible for stan dard therapy; ECOG PS 0-1; 1 measurable lesion; (N = 25) Pembrolizumab 10 mg/kg IV Q2W CR, PR, or SD PD or unacceptable toxicity Tx to 24 mos or PD or toxicity Discontinue Primary endpoint: ORR Secondary endpoints: PFS, OS, DoR Rugo HS, et al. SABCS Abstract S5-07.

54 KEYNOTE-028 Breast Cancer Cohort: Antitumor Activity Characteristic, % (95% CI) Pembrolizumab (N = 25) ORR 12 ( ) CR 0 (0-13.7) PR* 12 ( ) SD 16 ( ) Clinical benefit rate (CR + PR + SD for 24 wks) 20 ( ) PD 60 ( ) No assessment 12 ( ) Pembrolizumab showed ORR of 12% and CBR of 20% ORR 14%, CBR 23% in 22 evaluable pts *All had received 3 lines of prior therapy in metastatic setting. Includes pts who discontinued therapy before first post-bl scan. Rugo HS, et al. SABCS Abstract S5-07.

55 Conclusions Treatment strategies for MBC largely based on disease pattern, symptoms and pretreatment. New insights in tumor biology can help predict endocrine responsiveness and optimal sequencing. Acquired mutation in ER alpha (ESR1) in response to endocrine deprivation Cross talk between ER and growth factor receptor signaling such as HER family members, FGFR pathways, PI3/Akt/mTOR Tumor microenvironment and host immune response Understanding and inhibiting these pathways are being developed to improve efficacy of hormone therapy.