ABC1 - B. Kaufman - Endocrine resistance mechanisms and solutions
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![[object Object],[object Object],[object Object],[object Object],[object Object]](https://image.slidesharecdn.com/erresistanceversion12-111117035410-phpapp01/85/abc1-b-kaufman-endocrine-resistance-mechanisms-and-solutions-1-320.jpg)
![Estrogen Receptor positive Breast Cancer ,[object Object],[object Object],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](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
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ABC1 - B. Kaufman - Endocrine resistance mechanisms and solutions
- 3. Tumor Microenvironment ER Action and Signaling d a b c F T AI F AI T +
- 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 +
- 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)
- 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%
- 11. ER Crosstalk with Growth Factor Receptor Pathways - a Working Model of Endocrine Resistance. Massarweh S , Schiff R, Clin Cancer Res, 2007.
- 12. ER Crosstalk with Growth Factor Receptor Pathways – The Targets
- 13. Prospective Randomized Trials Testing Combination of RTKs and ET
- 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
- 17. Study EGF 3008 : Kaplan-Meier Estimate of Investigator-Evaluated PFS Johnston S, et al. J Clin Oncol. 2009;27:5538-5546.
- 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
- 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. 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
Editor's Notes
- 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