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Rachel Schiff Breast Center Baylor College of Medicine

Estrogen Receptor and EGFR/HER2 Pathways Cross Talk in Breast Cancer Endocrine Resistance. Rachel Schiff Breast Center Baylor College of Medicine. 2/2003. Endocrine Therapies. Lower E level in tumor. Selective ER modulators; antagonist vs. agonist activity.

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Rachel Schiff Breast Center Baylor College of Medicine

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  1. Estrogen Receptor and EGFR/HER2 Pathways Cross Talk in Breast Cancer Endocrine Resistance Rachel Schiff Breast Center Baylor College of Medicine 2/2003

  2. Endocrine Therapies • Lower E level in tumor. • Selective ER modulators; antagonist vs. agonist activity. • ER modulators with pure antagonist activity. • High dose estrogens, progestins, androgens.

  3. Tamoxifen (SERM) • Agonist activity: bone, endometrium, liver, brain (cognitive function), clotting. • Antagonist activity: breast, vagina, brain (hot flashes). • Breast cancer – treatment benefit: • Adjuvant therapy: 50% reduction in recurrence. • Metastatic disease: disease control. • prevention: 50% reduction.

  4. Major Problem • RESISTANCE • De novo • Acquired

  5. ER Function – 2002/3 Classical E Coregulators Activators Repressors ER ER E E Tumor Growth ER ER mRNA ERE TARGET GENE

  6. ER Fos Jun mRNA ER Function – 2002/3 (con’t) Non Classical ER ERK 1,2 PI3K AP-1 GROWTH

  7. ER Function – 2002/3 (con’t) Growth Factor Crosstalk P P ERSignaling ER - CoA = ERK 1,2 Proliferation AKT Survival JNK, p38 MAPK Stress, Cytokines

  8. Breast Tumor Growth E ER- CoA Growth GF Stress

  9. Activation of the EGFR/HER2 Signaling Pathway Leads to Tamoxifen Resistance • Clinical studies • HER2 overexpression predicts a poor response to tamoxifen therapy • Preclinical studies • Overexpression of HER2 or its stimulation by HRG leads to tamoxifen resistance de novo • Acquired tamoxifen resistance in MCF-7 cells is associated with EGFR overexpression

  10. De novo Tam-R Tam-S Tam-R MCF7 MCF7/HER2 In vivo Model of Endocrine Resistance Ovx Athymic Mice Tumor volume (mm3) 1200 E2 1000 800 600 Tam 400 200 0 0 21 49 77 105 Days (Benz, et al., Breast Cancer Res Treat, 1992)

  11. Agonist activity GF ER-GF Cross-Talk and CoAs in and the Agonist/ Antagonist Activity of Tamoxifen CoR Antagonist activity P E2 ER CoA

  12. Agonist activity ER-GF Cross-Talk and CoAsin the Agonist/ Antagonist Activity of Tamoxifen CoR Antagonist activity P Tam ER CoA

  13. P P HER-2 Genomic Non-genomic ER-GF Cross-Talk and CoAsin the Agonist/ Antagonist Activity of Tamoxifen CoR Antagonist activity P Tam ER CoA Agonist activity

  14. Breast Tumor Endocrine Resistance Tam ER- CoA EGFR/HER2

  15. Tam ER- CoA Breast Tumor Endocrine Resistance + EGFR/HER2

  16. Tam Hormonal Resistance ER- CoA Tumor Growth Breast Tumor Endocrine Resistance + EGFR/HER2

  17. Hypothesis (1) Coactivators Corepressors ER Agonist Antagonist Tamoxifen GF Signaling Tumors with high levels of HER2andcoactivators should be relatively resistant to tamoxifen

  18. AIB1 / SRC-3 • CoA in SRC family. • Binds ER; augments ER signaling. • Overexpressed in 65% breast cancer. • Amplified in 5-10%. • Phosphorylated (activated) by ERK1/2, JNK, p38. •  tam agonist activity.

  19. AIB1 and Tamoxifen Benefit in the Adjuvant Setting • 316 patients, primary breast ca, N+ • -119 no adjuvant systemic therapy • -187 adjuvant tamoxifen • -median follow-up 8 years • Western blot analyses for AIB1 • Correlated with patient and tumor variables HER-2 • Effect on DFS

  20. AIB1 and DFS No Adjuvant Therapy Tamoxifen Adjuvant Therapy 1.00 1.00 0.75 0.75 Low High n=141 n = 29 Proportion DFS 0.50 0.50 High n=46 0.25 0.25 Low n = 90 0.00 0.00 0 20 40 60 80 100 120 0 20 40 60 80 100 120 Time in months Time in months p-value=0.018 p-value=0.22 Osborne et al. ASCO 2002

  21. AIB1 / HER-2 and DFS Tamoxifen Adjuvant Therapy 1.00 0.75 All others Proportion DFS 0.50 n = 162 0.25 AIB1 high / HER2 high n = 25 p-value=0.0024 0.00 0 20 40 60 80 100 120 Time in months

  22. Summary • AIB1 with HER-2, is a strong predictive marker of tam resistance. • Blocking GF pathways and/or AIB1 may reverse tam resistance.

  23. Tam Hormonal Resistance ER- CoA Tumor Growth Breast Tumor Endocrine Resistance + EGFR/HER2

  24. Iressa (ZD1839, Gefitinib) • Selective EGFR tyrosine kinase inhibitor • Blocks EGFR and HER2 signaling Hypothesis (2): Iressa can block tamoxifen- stimulated growth of HER2 overexpressing tumors by eliminating the cross-talk that causes tamoxifen’s agonist activity

  25. De novo Tam-R Tam-S Tam-R MCF7 MCF7/HER2 In vivo model of endocrine resistance Tumor volume (mm3) 1200 1000 800 600 Tam 400 200 0 0 21 49 77 105 Days (Benz, et al., Breast Cancer Res Treat, 1992)

  26. MCF-7/HER2

  27. Experimental design (Endocrine sensitivity of HER2+ tumors) E2 Randomize E2 _E2 TAM MCF-7 HER2

  28. Endocrine sensitivity of HER2 tumors 1400 1200 E2 1000 800 Tumor volume 600 400 200 0 1 30 60 90 120 Days

  29. Endocrine sensitivity of HER2 tumors 1400 1200 E2 1000 800 Tumor volume 600 400 -E2 200 0 1 30 60 90 120 Days

  30. Endocrine sensitivity of HER2+ tumors 1400 1200 TAM E2 1000 800 Tumor volume 600 400 -E2 200 0 1 30 60 90 120 Days

  31. Response to letrozole and tamoxifen in the neoadjuvant setting EGFR/HER2EGFR/HER2 _+ Letrozole 54% 88% Tamoxifen 42% 21% Ellis et al., J Clin Oncol. (2001) 19 3808-16

  32. Experimental design (Iressa effect on endocrine treatment of HER2+ tumors) Iressa + E2 - Randomize E2 + _E2 - + TAM - MCF-7 HER2

  33. Iressa effect on endocrine treatment of HER2 tumors 1400 1200 E2 1000 E2+Iressa 800 Tumor volume 600 400 200 0 1 30 60 90 120 Days

  34. Iressa effect on endocrine treatment of HER2 tumors 1400 1200 TAM E2 1000 E2+Iressa 800 Tumor volume 600 400 TAM+Iressa 200 0 1 30 60 90 120 Days

  35. Iressa effect on endocrine treatment of HER2 tumors 1400 1200 TAM E2 1000 E2+Iressa 800 Tumor volume 600 400 TAM+Iressa 200 0 1 30 60 90 120 Days

  36. Iressa effect on endocrine treatment of HER2 tumors 1400 1200 E2 1000 E2+Iressa 800 Tumor volume 600 - E2 400 -E2+Iressa 200 0 1 30 60 90 120 Days

  37. Hypothesis (3): Targeting the EGFR/HER2 pathway will delay the development of acquired resistance to tamoxifen in tumors with normal levels of EGFR/HER2. Tam-S Tumor volume (mm3) Tam-R 1200 1000 800 Tam 600 400 200 0 0 21 49 77 105 Days

  38. - - - Experimental Design (Iressa and endocrine treatment of MCF-7 tumors) Iressa E2 + Randomize E2 + _E2 TAM + MCF-7

  39. Iressa Effect on E2-StimulatedMCF-7 Xenografts 1400 1200 E2+ Iressa E2 1000 800 Tumor volume 600 400 200 0 0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210 Days

  40. ZD1839 Effect on Tamoxifen Therapy in MCF-7 Xenografts 1400 1200 E2+ Iressa TAM E2 1000 800 Tumor volume TAM+Iressa 600 400 200 0 0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210 Days

  41. Iressa Effect on Tamoxifen Therapy in MCF-7 Xenografts 1400 1200 E2+ Iressa TAM E2 1000 800 Tumor volume TAM+Iressa 600 400 200 0 0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210 Days

  42. Iressa Effect on Estrogen Deprivation 1400 -E2 1200 E2+ Iressa E2 1000 800 Tumor volume - E2+ Iressa 600 400 200 0 0 14 28 42 56 70 98 84 126 154 112 140 Days

  43. Conclusions • Molecular cross-talk increases tamoxifen agonist activity in tumors with high HER-2 (de novo resistance). • Cross-talk also contributes to tamoxifen agonist activity acquired during treatment • (low HER-2). • Receptor TKIs can block this cross-talk, improve tamoxifen performance, and overcome or delay resistance.

  44. Conclusions HER2+ breast tumors • Tamoxifen stimulates growth as a mechanism of de novo resistance • Estrogen deprivation inhibits tumor growth Iressa • Modestly affects as a monotherapy • Inhibits tamoxifen-stimulated growth • Delays resistance to estrogen deprivation

  45. Conclusions Breast tumors with normal low HER2 • Tamoxifen is an effective antiestrogen, but tumors will acquire resistance Iressa • No effect as a monotherapy • Delays acquired resistance to tamoxifen • No significant benefit when combined with estrogen deprivation

  46. Conclusion • ER-targeted therapy combined with EGFR/HER2 inhibitors like Iressa should be tested in clinical trials to delay de novo and acquired resistance. ? Agonist Breast/ Uterus “Optimal SERM” SERM + TKI Agonist Bone/LM

  47. Collaborators • Baylor Breast Center • Shou Jiang • Suleiman Massarweh • Margaret DiPietro • Kent Osborne • Powel Brown • Syed Mohsin/Craig Allred • Sue Hilsenbeck • AstraZeneca • Alan Wakeling

  48. P-ER, HER2, MAPK, AIB1 Iressa Proliferation ER-dependent transcription Effect of Iressa on ER and GF Pathways MCF7 (Tam sensitive) MCF7/HER2 (Tam resistant)

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