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Angelo Raffaele Bianco

MECHANISMS OF ENDOCRINE RESISTANCE AND NEW TARGETS FOR HORMONE THERAPY OF BREAST CANCER. Angelo Raffaele Bianco. Department of Molecular and Clinical Oncology and Endocrinology, University “Federico II” School of Medicine, Naples Italy.

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Angelo Raffaele Bianco

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  1. MECHANISMS OF ENDOCRINE RESISTANCE AND NEW TARGETS FOR HORMONE THERAPY OF BREAST CANCER Angelo Raffaele Bianco Department of Molecular and Clinical Oncology and Endocrinology, University “Federico II” School of Medicine, Naples Italy Estrogen Receptor/HER Tyrosine Kinase receptor family interaction: molecular mechanisms and clinical implications for Endocrine Therapy Resistance

  2. Factors influencing evolution and development of mammary gland and breast cancer (BC) Estrogen receptor: ERa and ERb Nuclear (ER66) and cytoplasmic (plasma membrane) ER (ER46) Growth factor receptor (GFR) signaling EGFR (HER, c-erbB family), IGFR Crosstalk ER/GFR: BC cell survival and progression

  3. Endocrine therapy of Breast Cancer (First targeted therapy of cancer) • Antiestrogens • SERMS (Tamoxifen, TAM; Raloxifene) • SERDS (steroidal pure antiestrogens: Fulvestrant) • Estrogen deprivation • Premenopausal: oophorectomy, LHRH • Postmenopausal: aromatase inhibitors (AIs): • anastrozole, letrozole (nonsteroidal), • exemestane (steroidal)

  4. Inhibitors of GFR signaling Small molecules TKIs Gefitinib, Erlotinib, Lapatinib Monoclonal antibodies Trastuzumab, Pertuzumab

  5. Resistance to Endocrine Therapy De novo (upfront, intrinsic) Acquired

  6. Evidence that TAM is less effective in HER2+ tumors Clinical Preclinical

  7. Genomic action of ER (NISS: nuclear initiated steroid signaling)

  8. Genomic action of ER (1) Binding of E2 and estrogen antagonists E2 (ligand): conformational change of ER release from chaperon (heat shock) inhibitory proteins dimerization activation of AF1 and AF2 binding of nuclear co-regulatory proteins (P160): co-activators NCoA1 (SRC-1), NCoA2 (SRC-2), NCoA3 (SRC-3 or AIB1) aggregation in large complexes binding to ERE in the promoter region of the target gene Estrogen antagonists, SERMS: distintive ER change activation of AF1only binding of nuclear co-repressors, NCoR1 and 2 shutting off gene transcription Estrogen antagonists, SERDS: degradation of ER

  9. Genomic action of ER (2) Consequences of E2 binding to ER Expression of genes favoring BC cell survival and proliferation (IGF1R, Cyclin D1, Bcl-2, VEGF) Expression of ligands of HER family (TGFa, amphiregulin) Inhibition of transcriptional repressors, antiproliferative and proapoptotic genes

  10. Non Genomic action of ER (MISS: membrane initiated steroid signaling) Truncated (ER46) protein variant localizated at or near plasma membrane

  11. GFR regulated ER action Signaling from GFR dependent downstream kinases Phosphorylation of factors in the ER pathway (ER, AF1) Regulation of genomic ER activity

  12. ER regulated GFR action Activated GFR kinases and downstream signaling by ER binding to E2 or TAM (MISS) phosphorylation of nuclear ER and coregulatory nuclear proteins activated GFR signaling by genomic action of ER (NISS)

  13. The GFR family in the development of endocrine resistance Preclinical models

  14. HER/ER crosstalk: molecular determinants ER phosporylation (serine 106, 107, 118, 165, 305; threonine 311) mainly at AF1 domain by several kinases of GFR signaling network (p42/44 MAPK, PI3K/Akt, PKA, p38 MAPK activated by cytokines and GFS). Ligand independent/TAM mediated ER activation Phosphorylation of coregulators: - coactivators (AIB1): enhanced genomic activity even in absence E2 or in presence of antiestrogen - corepressors: export from nucleus Membrane function of ER: ER and GFR levels, ligand levels This mode of ER signaling prevalent in BC cells expressing high levels of TK receptors, SERMS as agonists

  15. De novo resistance models • MCF7/HER2-18 overexpressing HER2 and AIB1 model: • in low estrogen environment TAM behaves as a potent • agonist of tumor growth • BT474 ER/HER2 overexpressing BC model: c-erbB signaling • Induce resistance to TAM by blocking the apoptotic effect of • the drug.

  16. HER overexpression and Tam-Stimulated Growth 800 E2 Tam 600 Tumor Volumes (mm3) 400 200 0 1 50 100 150 200 1 21 42 63 84 105 126 147 168 189 209 Days MCF7/HER2 Tumors

  17. Gefitinib Effect on Endocrine Treatment of HER2+ Tumors 1400 1200 TAM E2 1000 E2+gefitinib 800 Tumor volume 600 400 TAM+gefitinib 200 0 1 30 60 90 120 Days Shou J, JNCI 2004

  18. Acquired resistance models BC cells with acquired resistance to TAM have enhanced GFR signaling (overexpression of EGR, HER2, increased phosphorylation of p42/44 MAPK, Akt, nuclear ER). They are growth inhibited by gefitinib and trastuzumab. Enhanced GFR signaling, which upregulates both genomic and non-genomic ER functions, is a key contributor also to the mechanism of acquired resistance to estrogen deprivation (AI exposure) and fulvestrant.

  19. The GFR family in the development of endocrine resistance Clinical evidence

  20. De novo resistance (I) Patients with HER2/EGFR overexpressing tumors treated with TAM have poor outcome. In metastatic BC results of published studies have produced inconsistent results. A recently published meta-analysis shows that HER2+ BC is less responsive to endocrine treatment. EGFR generates similar downstream signals as HER2. In a recent study (Arpino G, Clin Can Res 2004) tumors with high EGFR less likely respond to TAM and with shorter TTF.

  21. De Laurentiis, M. et al. Clin Cancer Res 2005;11:4741-4748

  22. De Laurentiis, M. et al. Clin Cancer Res 2005;11:4741-4748

  23. De Laurentiis, M. et al. Clin Cancer Res 2005;11:4741-4748

  24. De novo resistance (II) In patients with early BC several studies suggest that tumors overexpressing HER2 may derive less benefit from adjuvant TAM than HER2s negative. NATO/Cancer Research Compaign BC adjuvant trials (TAMX 2 years vs nil): RR of recurrence for TAM and EGFR/HER2 negative tumors = 0,54 For EGFR+/HER+, RR = 1,17

  25. The GUN Trial (1970) GUN = Gruppo Università di Napoli GUN-1 TAM Premenopausal N-Postmenopausal N-/N+ n=308 TAM yes (n=206) Nil GUN-2 CMF+TAM TAM no (n=227) Premenopausal N+n=125 CMF = Random

  26. The GUN Trial

  27. c-erbB2 - c-erbB2 + 1,00 | | | 1,00 | | | | | | | | | | | | | | | | | | | | | | | 0,75 | | | 0,75 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0,50 | | | | | | | | | 0,50 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0,25 Control Control 0,25 Tamoxifen Tamoxifen 0,00 0,00 0 5 10 15 20 0 5 10 15 20 Years Years ErbB2 and TamoxifenThe GUN Trial

  28. The GUN Trial HR (95%CI) TAM worse   TAM better PreN- 0.72 (0.29-1.77) PreN+ 0.77 (0.47-1.29) PostN- 0.74 (0.38-1.42) PostN+ 0.61 (0.38-0.96) ER/PgR- 0.80 (0.48-1.35) ER/PgR+ 0.73 (0.46-1.17) ER/PgR++ 0.65 (0.38-1.13) Overall 0.68 (0.51-0.91)

  29. Adjuvant SettingThe GUN Trial  TAM better TAM worse  HR (95% CI) c-erbB2- 0.59 (0.4-0.87) c-erbB2+ 1.09 (0.63-1.87) PrlR- 0.73 (0.48-1.12) PrlR 0.73 (0.41-1.3) MVC low 0.76 (0.49-1.2) MVC high 0.75 (0.49-1.17) EGFR- 0.75 (0.51-1.1) EGFR+ 0.76 (0.46-1.27) SPF low 0.67 (0.33-1.33) SPF high 0.66 (0.45-0.98) Diploid 0.78 (0.43-1.41) non Diploid 0.63 (0.44-0.89)

  30. HER status and outcome in AIs adjuvant trials • Breast International Study Group BIG1-98: HER2 + • significantly higher relapse rate, regardless of treatment • (letrozole or TAM for 5 years). • ATAC: see section on PgR negativity.

  31. HER status and outcome from neoadjuvant trials with AIs Study 1 Ellis Study 2 Zhu Study 3 Smith TAM LETR TAM ANASTR TAM LETR EGFR/HER2 Negative 54% 42% 35% - 41% 43% Positive 88% 21% 75% - 58% 22%

  32. Notes to neoadiuvant trials • Zhu: relevance of HER decrease after treatment with letrozole: • RR = 73% with decrease of HER2/EGFR expression; 38% with no • decrease. • Smith (IMPACT): anastrozole vs TAM vs combination for 3 months, • 330 pts. Ki67 suppression at 2 and 12 weeks greater for anastrozole • as compared to TAM or combination (see ATAC). 34 pts were • HER2/EGFR positive: ORR A vs TAM vs Comb = 58 vs 22 vs 31. • in HER2 negative response rate = 41 vs 43 vs 52 .

  33. PgR negativity, HER signaling and endocrine resistance PgR positivity: downstream effect of ER activation PgR activation = ER activation signaling (genomic and non genomic) PgR negativity in ER+ BC: markers of hyperactive GFR signaling rather than non functioning ER pathway. PgR- tumors have more aggressive features such as size, nodal metastasis, ploidy, prolifaration rate; overexpression of HER2/EGFR 30% in PgR neg , 10% in PgR pos (Arpino 2005).

  34. PgR transcriptional hyperactivity and increased PgR turnover Phosphorylation of PgR and its accessory proteins by HER downstream kinases (p42/44 MAPK, Cyclin-dependent Kinase 2) Increased PgR turnover PgR low/negative tumors

  35. PgR predictive of outcome of endocrine therapy • Metastatic BC • Adjuvant: no definitive role of PgR • Oxford overview 2005: 41% RR reduction of recurrence for • TAM x 5 years in ER+ PgR- and 40% ER+ PgR- • Large nonrandomized: benefit from TAM< in ER+PgR- • Many clinical studies, adjuvant and metastatic • ATAC trial: ER+PgR+ recurrence rate = 7,6%; ER+PgR- = 14,8% • (5 years); reduced efficacy of TAM in ER+PgR- • BIG1-98: PgR- worse clinical outcome. No effect of PgR status • on outcome of treatment (letrozole vs TAM for 5 years)

  36. Dowsett, M. et al. J Clin Oncol; 23:7512-7517 2005

  37. PgR predictive of outcome of endocrine therapy Trans ATAC: failure to confirm selective benefit of anastrazole vs TAM in PgR- tumors. Worse outcome in patients with PgR- tumors regardless of treatment

  38. Dowsett, M. et al. J Clin Oncol; 26:1059-1065 2008

  39. Dowsett, M. et al. J Clin Oncol; 26:1059-1065 2008

  40. Dowsett, M. et al. J Clin Oncol; 26:1059-1065 2008

  41. HER2/ER crosstalk in acquired resistance • Acquired resistance to TAM = increased HER2 • Strong positive correlation between ER, PgR, Bcl2, inverse HER2/ER correlation prior to TAM • Strong correlation between ER and phosphorilated p38MAPK and p42/44MAPK. ER loss in 17% of tumors, HER2 positivity in 11% of HER2- at TAM resistance (Gutierez 2005) • In metastatic BC acquired HER2 overexpression during endocrine therapy (adaptative mechanism for cell survival)

  42. Preclinical Studies • GFR inhibitors: no effect in hormone sensitive BC • Strategies combining endocrine and STIs against GFR signaling= Farnesyl transferase inhibitors (RAS signaling), mTOR inhibitors • In vitro combination of TAM and gefitinib: complete inhibition of downstream signaling molecules, suppression of Bcl-2, GO-G1 arrest, delay of TAM resistance

  43. Combining Strategies in “de novo” resistant cells MCF7/HER2-18 and BT474 ER+ HER2+ xenografts: combination of several STIs with TAM and/or E2 deprivation

  44. 1 21 42 63 84 105 126 147 168 189 209 Effect of HER Family Inhibitors on Tam-Stimulated Growth 800 Complete Regression Tam+P 5/18 Tam+P+T 12/18 Tam+P+T+G 19/20 E2 Tam 600 Tumor Volumes (mm3) 400 Tam+P Stop Rx Tam+P+T 200 Tam+P+T+G 0 1 50 100 150 200 Days MCF7/HER2 Tumors

  45. Effect of HER Family InhibitorsonBT474 Tumor Growthin Mice Treated with Tamoxifen, Estrogen Supplementation, or Estrogen Withdrawal Complete Regression Tam+P 2/9 E2+P+T+G 11/11 Tam+P+T+G 10/10 -E2+P+T+G 12/12 800 -E2 E2 Tam 600 Tumor Volumes (mm3) Tam+P 400 E2+P+T+G 200 Tam+P+T+G -E2+P+T+G 0 1 21 42 63 84 105 126 147 168 189 1 50 100 150 200 Days

  46. Summary • In MCF7/HER2 tumors, ER and HER signaling are the dominant pathways driving tumor growth and survival. • Blocking HER signaling blocks ER cross-talk and restores tamoxifen’s antagonist activity. • Trastuzumab, pertuzumab and gefitinib inhibit distinct components of the HER signaling pathway. • Complete blockade of the ER and HER signaling pathways is needed for optimal therapy.

  47. Clinical Studies • Trastuzumab in HER2+ BC • Farnesyl transferase inhibitors and mTOR antagonists • Phase II trials with lapatinib and erlotinib in metastatic BC • Neoadjuvant study with gefitinib+anastrozole greater reduction of Ki67 • Lapatinib • Phase II-III clinical trials with TKIs and monoclonals in combination with TAM, fulvestrant, AIs

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