<ul><li>Endocrine Resistance Mechanisms and Solutions </li></ul><ul><li>Bella Kaufman  MD.  </li></ul><ul><li>Sheba Medica...
Estrogen Receptor positive Breast Cancer <ul><li>Estrogen receptor (ER) is expressed in ~70% of  </li></ul><ul><li>breast ...
Tumor Microenvironment ER  Action and Signaling d a b c F T AI F AI T +
<ul><li>30-40%  of ER +  tumors do not  respond to first-line ET ( de novo  resistance). </li></ul><ul><li>Significant per...
Tumor Microenvironment Mechanism of Endocrine Resistance d ER expression and activity loss Transcriptional machinery of ER...
<ul><li>ER expression  –  most important biomarker to predict response to ET. </li></ul><ul><li>ER loss over time occurs i...
HDAC Inhibitors (HDACi, e.g Entinostat) Histone acetyltransferases  (HATs) Histone deacetylases  (HDACs) Closed chromatin ...
Hypothesis: Entinostat re-sensitizes tumors to aromatase inhibitors (AI) Randomized,  double-blind , placebo-controlled En...
Exemestane+Entinostat (EE):  median PFS 4.28 months Exemestane+Placebo (EP):  median  PFS 2.27 months Hazard ratio 0.73 (9...
Crosstalk with RTKs and their downstream pathways. <ul><li>RTKs can stimulate cancer growth with ER signaling or by bypass...
ER Crosstalk with Growth Factor Receptor Pathways - a Working Model of Endocrine Resistance. Massarweh S , Schiff R, Clin ...
ER Crosstalk with Growth Factor Receptor Pathways – The Targets
Prospective Randomized Trials Testing Combination of RTKs and ET
<ul><li>Crossover to receive trastuzumab was actively offered to  all patients who progressed on anastrozole alone </li></...
103 48 31 17 14 13 11 9 4 1 1 0 0 A + H No. at risk 104 36 22 9 5 4 2 1 0 0 0 0 0 A Kaufman et al, J Clin Oncol 2009 27; 5...
EGF30008 - Phase III, Randomized, Double-blind Controlled Trial: Study Design <ul><li>Patient Population </li></ul><ul><li...
Study EGF 3008   : Kaplan-Meier Estimate of Investigator-Evaluated PFS Johnston S, et al. J Clin Oncol. 2009;27:5538-5546.
PFS in HER2- Patients as a Function of Prior TAM Treatment ( N=952 ),  EGF30008  <ul><li><6 mo Since D/C  of Tamoxifen </l...
Anastrozole 1 mg / day + Gefitinib  250 mg / day  Anastrozole 1 mg / day  + Placebo  1:1 randomization Randomised Phase II...
Events Median PFS (months) 22 14.5 32 8.2 Anastrozole + Gefitinib   (n = 43) Anastrozole + Placebo  (n = 50) HR (95% CI) =...
Crosstalk Between ER and mTOR Signaling <ul><li>mTORC1 activates ER in a ligand-independent fashion 1 </li></ul><ul><li>Es...
<ul><li>Randomized, phase II trial </li></ul><ul><li>Metastatic patients with prior exposure to an aromatase inhibitor </l...
Hazard ratio = 0.53; 95% CI 0.35-0.81 Exploratory log-rank:  P= .0026 TAM: 4.5 mo TAM + RAD: 8.6 mo  Bachelot T, et al.  B...
Overall Survival  (as of October 2010) Hazard ratio = 0.32; 95% CI 0.15-0.68 Exploratory log-rank:  P =.0019 Bachelot T, e...
Time to Progression as a Function of Intrinsic Hormone Resistance <ul><li>Primary hormone resistance (n=54) </li></ul><ul>...
<ul><li>ER signaling pathway is a complex network. </li></ul><ul><li>Mechanisms of ET resistance are primary or acquired. ...
Future Direction for Improving Endocrine Therapy <ul><li>To expand our understanding of endocrine resistance mechanisms. <...
<ul><li>Thank you  </li></ul>
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ABC1 - B. Kaufman - Endocrine resistance mechanisms and solutions

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  • I use ER to indicate Era. ER is predominantly a nuclear protein functioning as hormone- activated transcription factor which regulates the expression of various genes that promote BC proliferation and survival. This classical nuclear genomic pathway is the most characterized ER signaling pathway Estrogen also modulates gene expression by a second mechanism where ER does not directly bind DNA but is tethered to other transcription factor which interact with gene promoter. ER can also transduce rapid signaling via various non nuclear non genomic pathways .in response to estrogen binding, ER can directly or indirectly interact or activate several growth factor tyrosine kinases (RTKs) such as HER2, EGFR, IGF1R, This interaction activates RTK signaling and its downstream kinases. ER can also trigger a signaling cascade that involves c-Src and coactivators. Stress induced kinases and signaling also can influence ER signaling by phosphorylation of ER and coactivators.
  • Coregulators P160 (SRC1/3) NCoR/SMART Fox/FOXO
  • Any variation in ER at the gene or protein level contributes to endocrine resistance and to develop of more aggressive phenotype. DOWN REGULATION OR COMPLETE LOSS of ER may occur at multiple levels and by several machanisms. ER mutations occurs in less than 1%.
  • Restaging performed every 2 cycles
  • These pathways can also directly negate or overcome the inhibitory effect of ET by modulating ER activity
  • ER crosstalk with growth factor receptor pathways in breast cancer—a working model of endocrine resistance. In most ER-positive tumors, genomic ER activity in which ER acts as a transcription factor in the nucleus (also known as NISS) predominates, although some nongenomic ER activity, mediated by ER in the plasma membrane or the cytoplasm interacting with various growth factor receptor and cellular kinase signaling molecules (also known as MISS) also occurs. In tumors with overexpression or hyperactivation of EGFR/HER2, however, ER MISS activity may be especially enhanced. Both genomic/NISS and nongenomic/MISS ER activities are augmented in these tumors via molecular crosstalk between the coexpressed pathways. SERMs like tamoxifen usually inhibit NISS but have no effect or may even promote nongenomic/MISS ER activity. In contrast, estrogen deprivation (−E2) using aromatase inhibitors, or pure antiestrogens such as fulvestrant, can block both NISS and MISS ER activities and, thus, halt the crosstalk with growth factor receptor pathways. Targeting the growth factor receptor pathway at different nodal points of signaling using tyrosine kinase inhibitors (TKI), antibodies (Ab), or other signal transduction inhibitors (STI, e.g., mTOR and Raf inhibitors), can eliminate the molecular crosstalk and overcome endocrine resistance.
  • Review Experience in Evaluating Predictive Biomarkers November 17, 2011 Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV
  • Resistance to hormonal therapy, either de novo or acquired, is currently a major limitation in the therapy of patients with HR+ breast cancer An emerging mechanism of endocrine resistance is aberrant signaling via the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) intracellular signaling pathway. mTOR is a key central regulator of cell growth and proliferation in response to nutrient availability as well as to stimulatory signals from growth factors via the Ras and PI3K pathways growing evidence supporting a close interaction of the mTOR pathway with ER signaling. mTOR forms two different protein complexes, mTORC1 and mTORC2 A substrate of mTORC1, S6K1, directly phosphorylates the activation domain AF-1 of the ER, responsible for ligand-independent receptor activation
  • ABC1 - B. Kaufman - Endocrine resistance mechanisms and solutions

    1. 1. <ul><li>Endocrine Resistance Mechanisms and Solutions </li></ul><ul><li>Bella Kaufman MD. </li></ul><ul><li>Sheba Medical Center </li></ul><ul><li>Tel Aviv University </li></ul><ul><li>Israel </li></ul>
    2. 2. Estrogen Receptor positive Breast Cancer <ul><li>Estrogen receptor (ER) is expressed in ~70% of </li></ul><ul><li>breast cancer. </li></ul>Luminal A Luminal B High expression of ER and ER-related genes Lower proliferation rates Less aggressive behavior High responsiveness to ET Relatively lower expression of ER and ER-related genes Higher proliferation rates More aggressiveness Lower endocrine sensitivity
    3. 3. Tumor Microenvironment ER Action and Signaling d a b c F T AI F AI T +
    4. 4. <ul><li>30-40% of ER + tumors do not respond to first-line ET ( de novo resistance). </li></ul><ul><li>Significant percentage of initial responders relapse despite initial response (acquired resistance). </li></ul>Endocrine Resistance
    5. 5. Tumor Microenvironment Mechanism of Endocrine Resistance d ER expression and activity loss Transcriptional machinery of ER Cross-talk between ER and RTKs Cell cycle regulators b c a F T AI F AI T +
    6. 6. <ul><li>ER expression – most important biomarker to predict response to ET. </li></ul><ul><li>ER loss over time occurs in ~20% of patients treated with ET. </li></ul><ul><li>ER expression is controlled mostly by epigenetic and post transcriptional mechanisms and rarely at the genomic level. </li></ul><ul><li>One mechanism of regulating ER expression is by histone deacetylation (HDAC). </li></ul>ER Expression in Breast Cancer
    7. 7. HDAC Inhibitors (HDACi, e.g Entinostat) Histone acetyltransferases (HATs) Histone deacetylases (HDACs) Closed chromatin = Genes off Open chromatin = Genes on HDACi ‘open up’ the structure of DNA, enable the transcription of the ER. HDAC Inhibitors Mechanism of Action Ricky W. Johnstone, Nature Reviews, 2002 (modified)
    8. 8. Hypothesis: Entinostat re-sensitizes tumors to aromatase inhibitors (AI) Randomized, double-blind , placebo-controlled Endpoints include: 1⁰ PFS, 2⁰ ORR and CBR; Exploratory Endpoint - OS <ul><li>Stratification Factors: </li></ul><ul><li>AI disease progression (Adjuvant vs MBC setting) </li></ul><ul><li>Bone only disease (yes / no) </li></ul><ul><li>Geographic region (North America vs EU/Russia) </li></ul>Yardley D, et al. J Clin. Oncol. 2011 (Suppl 27) Abstr 268 ENCORE 301 Study Design Exemestane + Placebo (PLA) 5 mg po weekly N ~ 57 Exemestane + Entinostat (ENT) 5 mg po weekly N ~ 57 R A N D O M I Z E Post-menopausal women with metastatic or locally advanced ER+ breast cancer progressing on a non-steroidal AI (anastrozole or letrozole)
    9. 9. Exemestane+Entinostat (EE): median PFS 4.28 months Exemestane+Placebo (EP): median PFS 2.27 months Hazard ratio 0.73 (95% CI: 0.49, 1.09) P=0.06 by stratified log-rank test (1-sided) Yardley D, et al. J Clin. Oncol. 2011 (Suppl 27) Abstr 268 ENCORE 301 Primary Endpoint – PFS 2°Endpoints EP EE ORR 4.6% 4.7% CBR 25.8% 26.6%
    10. 10. Crosstalk with RTKs and their downstream pathways. <ul><li>RTKs can stimulate cancer growth with ER signaling or by bypassing it. </li></ul><ul><li>Increased expression of EGFR,HER2,IGF1R in cell lines causes TAM resistance. </li></ul><ul><li>A bidirectional crosstalk between ER and RTKs signaling has been demonstrated to cause endocrine resistance. </li></ul>
    11. 11. ER Crosstalk with Growth Factor Receptor Pathways - a Working Model of Endocrine Resistance. Massarweh S , Schiff R, Clin Cancer Res, 2007.
    12. 12. ER Crosstalk with Growth Factor Receptor Pathways – The Targets
    13. 13. Prospective Randomized Trials Testing Combination of RTKs and ET
    14. 14. <ul><li>Crossover to receive trastuzumab was actively offered to all patients who progressed on anastrozole alone </li></ul>HER2-positive, HR-positive MBC (n=208) R Anastrozole 1 mg daily + Trastuzumab 4 mg/kg loading dose  2 mg/kg qw until disease progression Anastrozole 1 mg daily until disease progression HR, hormone receptor; MBC, metastatic breast cancer; R, randomisation Kaufman et al, J Clin Oncol 2009 27; 5529-37 TAnDEM Study Design
    15. 15. 103 48 31 17 14 13 11 9 4 1 1 0 0 A + H No. at risk 104 36 22 9 5 4 2 1 0 0 0 0 0 A Kaufman et al, J Clin Oncol 2009 27; 5529-37 TAnDEM Progression Free Survival Probability 1.0 0.8 0.6 0.4 0.2 0 5 10 15 20 25 30 35 40 45 50 55 60 Months 95% CI 3.7, 7.0 2.0, 4.6 p value 0.0016 Median PFS 4.8 months 2.4 months Events 87 99
    16. 16. EGF30008 - Phase III, Randomized, Double-blind Controlled Trial: Study Design <ul><li>Patient Population </li></ul><ul><li>ER+ / PgR+ (HR+) </li></ul><ul><li>Postmenopausal </li></ul><ul><li>HER2+, HER2- or unknown </li></ul><ul><li>Stage IIIb / IIIc, IV </li></ul><ul><li>No prior treatment for MBC </li></ul><ul><li>Stratification </li></ul><ul><li>Disease sites </li></ul><ul><ul><li>Bone only / other sites </li></ul></ul><ul><li>Interval since prior adjuvant anti-estrogen therapy </li></ul><ul><li>< 6 mo / > 6 mo or None </li></ul>R A N D O M I Z E n = 1286 pts (including n=219 HER2+) Letrozole 2.5mg daily + Placebo Johnston S, et al. J Clin Oncol. 2009;27:5538-5546. Letrozole 2.5mg daily + Lapatinib 1500 mg daily
    17. 17. Study EGF 3008 : Kaplan-Meier Estimate of Investigator-Evaluated PFS Johnston S, et al. J Clin Oncol. 2009;27:5538-5546.
    18. 18. PFS in HER2- Patients as a Function of Prior TAM Treatment ( N=952 ), EGF30008 <ul><li><6 mo Since D/C of Tamoxifen </li></ul><ul><ul><li>Median tamoxifen duration 2.8 yr </li></ul></ul><ul><ul><li>Median time since d/c 1 mo </li></ul></ul><ul><li>≥ 6 mo Since D/C of Tamoxifen (33%) or No Tamoxifen (67%) </li></ul><ul><ul><li>Median tamoxifen duration 5 yr </li></ul></ul><ul><ul><li>Median time since d/c 3.5 yr </li></ul></ul>Johnston S, et al. J Clin Oncol. 2009;27:5538-5546. Endocrine Sensitive Endocrine Resistance LET (n = 370) LET + LAP (n = 382) Median PFS, mo 15.0 14.7 Hazard ratio (95% CI); P value 0.94 (0.79, 1.13); P =.522 LET (n = 104) LET + LAP (n = 96) Median PFS, mo 3.1 8.3 Hazard ratio (95% CI); P value 0.78 (0.57, 1.07); P =.117
    19. 19. Anastrozole 1 mg / day + Gefitinib 250 mg / day Anastrozole 1 mg / day + Placebo 1:1 randomization Randomised Phase II study of Anastrozole +/- Gefitinib in patients with ER+ve MBC Cristofanelli et al, ASCO 2008, Abstract 1012 <ul><li>Patients </li></ul><ul><li>Postmenopausal women </li></ul><ul><li>Age ≥ 18 years </li></ul><ul><li>Newly diagnosed ER and / or PgR positive metastatic breast cancer </li></ul><ul><li>No prior hormonal therapy, or development of metastatic disease during / after adjuvant tamoxifen </li></ul><ul><li>Measurable or non-measurable disease (via RECIST) </li></ul><ul><li>Primary </li></ul><ul><li>Progression-free survival </li></ul><ul><li>Secondary </li></ul><ul><li>Objective response rate </li></ul><ul><li>Clinical benefit rate </li></ul><ul><li>Overall survival </li></ul><ul><li>Safety and tolerability </li></ul>Response variables
    20. 20. Events Median PFS (months) 22 14.5 32 8.2 Anastrozole + Gefitinib (n = 43) Anastrozole + Placebo (n = 50) HR (95% CI) = 0.55 (0. 32 , 0.94) Cristofanelli et al, ASCO 2008, Abstract 1012 Randomised Phase II study of Anastrozole +/- Gefitinib in patients with ER+ve MBC 30 Probability of PFS 1.0 0.8 0.6 0.4 0.2 0.0 0 3 6 9 12 15 18 21 24 27 50 43 35 40 23 28 13 22 9 13 6 10 5 6 3 3 1 2 1 Placebo Gefitinib At risk: Months
    21. 21. Crosstalk Between ER and mTOR Signaling <ul><li>mTORC1 activates ER in a ligand-independent fashion 1 </li></ul><ul><li>Estradiol suppresses apoptosis induced by PI3K/mTOR blockade 2 </li></ul><ul><li>Hyperactivation of the PI3K/mTOR pathway is observed in endocrine-resistant breast cancer cells 3 </li></ul><ul><li>mTOR is a rational target to enhance the efficacy of hormonal therapy </li></ul><ul><li>Yamnik, RL. J Biol Chem 2009; 284(10):6361-6369. </li></ul><ul><li>Crowder, RJ. Cancer Res 2009;69:3955-62. </li></ul><ul><li>3. Miller, TW. J Clin Invest 2010; 120(7):2406-2413. </li></ul>Adapted from Di Cosimo and Baselga, Nature Clin Prac Oncol, 2009
    22. 22. <ul><li>Randomized, phase II trial </li></ul><ul><li>Metastatic patients with prior exposure to an aromatase inhibitor </li></ul><ul><li>Stratification: Primary or secondary hormone resistance </li></ul><ul><ul><li>Primary: Relapse during adjuvant aromatase inhibitor therapy; progression within 6 mo of starting aromatase inhibitor treatment in metastatic setting </li></ul></ul><ul><ul><li>Secondary: Late relapse (≥6 mo) or prior response and subsequent progression to aromatase inhibitor treatment in metastatic setting </li></ul></ul><ul><li>No crossover planned or allowed </li></ul>Bachelot T, et al. Breast Cancer Res Treat.  2010;100 suppl 1; SABCS 2010, abstract S1-6. TAMRAD Protocol B : Tamoxifen 20 mg/day + RAD001 10 mg/day (TAM + RAD) A : Tamoxifen, 20 mg/day (TAM)
    23. 23. Hazard ratio = 0.53; 95% CI 0.35-0.81 Exploratory log-rank: P= .0026 TAM: 4.5 mo TAM + RAD: 8.6 mo Bachelot T, et al. Breast Cancer Res Treat.  2010;100 suppl 1; SABCS 2010, abstract S1-6. Time to Progression Time, mo 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 % Alive Without Progression TAM TAM + RAD Patients at risk TAM + RAD: n = TAM: n = 54 57 45 44 39 30 34 24 28 22 25 13 19 11 12 6 7 1 1 0 0 0 26 16 16 7 9 2 1 0
    24. 24. Overall Survival (as of October 2010) Hazard ratio = 0.32; 95% CI 0.15-0.68 Exploratory log-rank: P =.0019 Bachelot T, et al. Breast Cancer Res Treat.  2010;100 suppl 1; SABCS 2010, abstract S1-6. Time, mo 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 6 12 18 24 30 36 Probability of Survival TAM TAM + RAD TAM + RAD: n = TAM: n = 54 57 53 55 51 53 49 50 49 44 45 38 38 30 26 22 14 9 6 4 0 0 Patients at risk 3 9 15 21 27 33
    25. 25. Time to Progression as a Function of Intrinsic Hormone Resistance <ul><li>Primary hormone resistance (n=54) </li></ul><ul><ul><li>TAM: 3.9 mo </li></ul></ul><ul><ul><li>TAM + RAD: 5.4 mo </li></ul></ul><ul><ul><li>HR=0.74; 95% CI 0.42-1.3 </li></ul></ul><ul><li>Secondary hormone resistance (n=56) </li></ul><ul><ul><li>TAM: 5.0 mo </li></ul></ul><ul><ul><li>TAM + RAD: 17.4 mo </li></ul></ul><ul><ul><li>HR= 0.38; 95% CI 0.21-0.71 </li></ul></ul>Bachelot T, et al. Breast Cancer Res Treat.  2010;100 suppl 1; SABCS 2010, abstract S1-6. TAM TAM + RAD 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 6 12 18 24 30 Probability of Survival Time, mo Probability of Survival 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time, mo 0 6 12 18 24 30
    26. 26. <ul><li>ER signaling pathway is a complex network. </li></ul><ul><li>Mechanisms of ET resistance are primary or acquired. </li></ul><ul><li>Multiple pathways can potentially cause resistance to ET thus serve as candidate targets. </li></ul><ul><li>Preclinical and clinical evidence suggests that EGFR/HER2 and mTOR signaling pathways contribute to endocrine therapy resistance in MBC : </li></ul><ul><li>* AI + HER2 Inhibitors is superior to AI alone for 1 st line HR+, HER2+ * In the TAMRAD randomized, Phase II trial, the addition of everolimus to TAM in AI-pretreated MBC pts showed promising activity </li></ul>Conclusion
    27. 27. Future Direction for Improving Endocrine Therapy <ul><li>To expand our understanding of endocrine resistance mechanisms. </li></ul><ul><li>Develop biomarkers to identify those mechanisms. </li></ul><ul><li>Develop better antagonists to overcome resistance mechanism. </li></ul>
    28. 28. <ul><li>Thank you </li></ul>

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