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Hormone-Dependent Breast Cancer: Mechanisms of Resistance and Treatment Aternatives

Hormone-Dependent Breast Cancer: Mechanisms of Resistance and Treatment Aternatives. VIII Simposio Internacional GEICAM - A Coruña, 2011. Carlos H. Barrios, MD PUCRS School of Medicine Porto Alegre, RS, Brazil. Endocrine Receptors and Breast Cancer.

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Hormone-Dependent Breast Cancer: Mechanisms of Resistance and Treatment Aternatives

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  1. Hormone-Dependent Breast Cancer: Mechanisms of Resistance and Treatment Aternatives VIII Simposio Internacional GEICAM - A Coruña, 2011 Carlos H. Barrios, MD PUCRS School of Medicine Porto Alegre, RS, Brazil

  2. Endocrine Receptors and Breast Cancer Estrogen receptors (ER) are expressed in 60-70% of breast cancer cases (incidence increases with age). Tamoxifen (5y adjuvant Rx in ER+) Reduces: Recurrence by 38% BC death by 30% Contralateral BC by 40% 50-60% ER (+) tumors respond to first-line ET. But…up to 50% of ER+ tumors are inherently refractory or acquire resistance during endocrine treatment. VIII Simposio Internacional GEICAM – A Coruña 2011

  3. 47% of patients do not need Rx !! Tamoxifen in ER+ Disease Absolute benefit in 14% of patients Recurrence in 33% of patients in spite Rx Primary or Acquired Resistance Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

  4. Some Proposed Mechanisms of Resistance Development Growth factor Estrogen SOS RAS RAF P P P P P P P P P Basal transcription machinery ER CBP MEK MAPK p160 PI3-K ER Akt ER ERE ER target gene transcription IGFR INCREASED EXPRESSION/SIGNALING THROUGH GF RECEPTORS (IGFR, HER2, etc.) EGFR / HER2 P P P P Cell survival Aromatase Inhibitors Tamoxifen INCREASED SIGNALING THROUGH THE PI3K PATHWAY p90RSK Cell growth P Cytoplasm CHANGE IN CO-ACTIVATORS Nucleus Adapted from Johnston S. Clin Cancer Res. 2005;11:889S

  5. Pathways associated with ET resistance in vitro Hoskins JM, et al. Nat Rev Cancer 9: 631-43, 2009

  6. Inverse Relationship: ER/PgR and HER2 in Primary Breast Cancers 1200 700 1100 900 900 1000 600 400 900 400 PgR (fmol/mg) ER (fmol/mg) 500 800 100 100 700 400 600 PgR (fmol/mg) ER (fmol/mg) 0 0 500 0 400 1600 3600 6400 10,000 0 400 1600 3600 6400 10,000 300 HER2/neu protein (fmol/mg) HER2/neu protein (fmol/mg) 400 200 300 200 100 100 0 0 0 2000 4000 6000 8000 10,000 12,000 0 2000 4000 6000 8000 10,000 12,000 HER2/neu protein (fmol/mg) HER2/neu protein (fmol/mg) Konecny et al. J Natl Cancer Inst. 95:142, 2003.

  7. Cross-Talk Between GF Signal Transduction and Endocrine Pathways Growth factor Estrogen SOS RAS RAF P P P P P Basal transcription machinery ER CBP MEK MAPK p160 PI3-K ER Akt ER ERE ER target gene transcription • PHOSPHORYLATION OF ER • HER2-normal MCF-7 cells • Activation of HER2 receptor with heregulin • results in phosphorylation of ER tyrosine • residues, enhances nuclear binding of • ER, and E2-independent growth • Pietras et al, Oncogene 10:2435, 1995 EGFR / HER2 Cell survival P P P P P p90RSK Cell growth P Cytoplasm Nucleus Adapted from Johnston S. Clin Cancer Res. 2005;11:889S

  8. TAnDEM: Anastrozole ± Trastuzumab in ER+/HER2+ MBC Anastrozole 1 mg daily + Trastuzumab 4 mg/kg loading dose, then 2 mg/kg qw (n=103) R A N D O M I S E Post-menopausalHER2+ (IHC 3+or FISH+) ER+ and/or PgR+ MBC Anastrozole 1 mg daily (n=104) • Crossover to receive trastuzumab offered to all patients who developed tumour progression on anastrozole alone (70% crossed over) • Primary end point: PFS Mackey et al. Breast Cancer Res Treat. 2006;100(suppl 1):S5. Abstract 3. Kaufman B, et al. J Clin Oncol 27: 5529-5537, 2009

  9. TAnDEM: Efficacy Kaufman B, et al. J Clin Oncol 27: 5529-5537, 2009

  10. Letrozol + Lapatinib in: ER+/HER2+ MBC R A N D O M I S E Letrozol 2.5mg/d + Lapatinib 1500mg/d(n=642) (HER2+=111) 1286 post-menopausal women with HR+ MBC* Lapatinib 1500mg/d (n=644) (HER2+=108) • *No prior therapy for metastatic disease; neo-adjuvant/adjuvant ET allowed: AI/or trastuzumab completed > 1 yr; ECOG 0-1; normal organ function • Primary end point: PFS Johnston S, et al. J Clin Oncol. 27:5538, 2009.

  11. Lapatinib + Letrozole in the ITT Population Johnston S, et al. J Clin Oncol. 27:5538, 2009.

  12. Lapatinib + Letrozole enhances PFS and CBR in pts with HER2+, HR+ MBC Johnston S, et al. J Clin Oncol. 27:5538, 2009.

  13. No benefit for Lapatinib + Letrozole in HR+/HER2-/ET sensitive MBC. Possible benefit in ET resistant MBC. HER2-/ET sensitive population HER2-/ET resistant population

  14. A combined targeted strategy with AIs (Letrozole or Anastrozole) and anti-HER2 therapy (Trastuzumab or Lapatinib) enhances PFS and CBR in pts with MBC that co-expresses HR and HER2. • HER2 over-expression is associated with endocrine resistance and poor DFS. These studies clearly demonstrate that these tumors are relative insensitive to hormonal therapy (AIs) • ORR of 6.8-28% • TTP of 2.4-3.0 months • The possibility of chemotherapy plus anti-HER2 therapy being a better alternative needs to be considered. Additional strategies are urgently needed for these patients.

  15. The PI3K pathway and Breast Cancer Constitutive activation of the PI3K pathway is frequent. PI3K pathway activation conveys malignant transformation, cell growth and invasion, tumor neo-angiogensis and resistance towards anti-cancer treatments. Known mechanisms of PI3K pathway activation include activating mutations of RTKs, gain-of-function mutation of the PIK3CA gene, and loss-of-function mutations of PTEN. HER2/HER3 PI3K Ras Raf PIP3 PTEN PDK1 Akt TORC2 MEK Tuberin Erk Rheb Rsk TORC1 S6K 4EBP1 S6

  16. The PI3K/Akt/mTOR pathway is frequently deregulated in human cancer

  17. Map and frequency distribution of PI3K mutations Gymnopoulos M,et al. Proc. Natl. Acad. Sci. USA 104, 5569-74, 2007

  18. Frequency of mutations in PIK3CA and PTEN (n=547 breast cancer cases) Stemke-Hale, K. et al. Cancer Res 68:6084-91, 2008

  19. PI3K/Akt/mTOR pathway inhibitors McAuliffe P. et al. Clin Breast Cancer

  20. PI3-K Akt ER ERE ER target gene transcription Addressing Resistance inHR+ Breast Cancer IGFR-1 HER2-1 Plasma membrane P P P P P SOS P RAS Estrogen RAF P MEK P MAPK mTOR P P Cytoplasm Basal transcription machinery P P P ER P CBP p160 ER Nucleus

  21. TAMRAD: Phase II trial of Everolimus + Tamoxifen Tamoxifen 20 mg daily + Everolimus 10 mg daily (n=54) MBC HR positive HER2 negative Previous AI exposure R Tamoxifen 20 mg daily (n=57) • Hypothesis: Previous exposure to AIs may “enrich” the population of patients driven by activation of the PI3K/Akt/mTOR pathway. • Stratification: primary or secondary endocrine resistance • Primary end point: CBR (CR+PR+SDx6m) Bachelot T, et al. Ca Res 70 (24 Suppl):S1-6. SABCS 2010.

  22. TAMRAD: Phase II Trial of Everolimus + Tamoxifen (*) Primary Objective • Primary Resistance: • Relapse during adjuvant treatment or progression within first 6 months of AI for MBC • TTP: TAM 3.9 vs. TAM+RAD 5.0 months, HR 0.74 • Secondary Resistance: • TTP: TAM 5.0 vs. TAM+RAD 17.4 months, HR 0.38 Bachelot T, et al. Ca Res 70 (24 Suppl):S1-6. SABCS 2010.

  23. Phase II trial of BEZ235 in patients with HR+, HER2-, MBC with and without activation of the PI3K pathway BEZ235: Dual PI3K and mTOR inhibitor MBC HR positive HER2 negative 1 prior ET and 2-3 prior CT Explore PI3K mutation status * X PI3K PTEN AKT TSC 1/2 X mTOR S6K Proliferation/Survival BEZ235 1600mg/day PO (until disease progression) Primary objective: 16 weeks PFSR (*) Group 1: PI3K activation (mutation) + with or without PTEN alterations Group 2: PI3K activation (wild type) + with PTEN alterations (mutation or PTEN-) Group 3: No activation of the PI3K pathway (wild type) www.clinicaltrials.gov, NCT01288092

  24. PI3-K Akt ER ERE ER target gene transcription Addressing Resistance inHR+ Breast Cancer IGFR-1 HER2-1 Plasma membrane P P P P P SOS P RAS Estrogen RAF P MEK P MAPK mTOR P P Cytoplasm Basal transcription machinery P P P ER P CBP p160 ER Nucleus

  25. A Two-Arm Randomized Open Label Phase 2 Study Of CP-751,871 In Combination With Exemestane Versus Exemestane Alone As First Line Treatment For Postmenopausal Patients With Hormone Receptor Positive Advanced Breast Cancer CP-751,871 20 mg/kg IV q21 day Exemestane 25 mg/day MBC HR positive No previous Rx N=260 R Examestane 25 mg/day • Primary end point: PFS Treatment until progression or toxicity Second line therapy with Faslodex www.clinicaltrials.gov, NCT00372996

  26. Conclusions • The molecular/genetic complexity of Breast Cancer is increasingly recognized. • Targeting the HER2 pathway or the use of endocrine manipulations have a positive impact in the natural history of breast cancer. • Therapeutic strategies simultaneously targeting multiple pathways have the potential of greater clinical impact. • Further understanding of the molecular interaction among different pathways will: • give us further insights into the heterogeneity of breast cancer • allow for better patient selection • provide us with a more rational therapeutic approach

  27. Potential Conflict of Interests Research Support Honoraria Financial Disclosure VIII Simposio Internacional GEICAM – A Coruña 2011

  28. Long-Term Risk of Breast Cancer Recurrence ER+ and ER- Patients Patients received CT, ET, or both (10 ECOG trials) 0.3 ER+ (n=2257) ER– (n=1305) 0.2 Recurrence hazard rate 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years Annual hazard of recurrence by estrogen receptor status Saphner et al. J Clin Oncol. 1996;14:2738.

  29. Conclusions • Understanding breast cancer as a molecular disease is leading to novel therapies • Clinical trials will continue to evaluate the efficacy and safety of biologic therapy in combination or following standard chemotherapy and endocrine therapy • Patient selection will be increasingly important for the integration of novel agents in the treatment of breast cancer • This is an exiting time, but we have to be smart to avoid waste of time and resources

  30. A combined targeted strategy with AIs (Letrozole or Anastrozole) and anti-HER2 therapy (Trastuzumab or Lapatinib) enhances PFS and CBR in pts with MBC that co-expresses HR and HER2. • HER2 over-expression is associated with endocrine resistance and poor DFS. These studies clearly demonstrate that these tumors are relative insensitive to hormonal therapy (AIs) • ORR of 6.8-28% • TTP of 2.4-3 months • Additional strategies are needed for these patients

  31. Estrogen Signaling Pathway • PHOSPHORYLATION OF ER • HER2-normal (HER2–) MCF-7 cells • Activation of HER2 receptor with heregulin • resulted in phosphorylation of ER tyrosine • residues, enhanced nuclear binding of • ER, and E2-independent growth • Pietras et al, Oncogene 10:2435, 1995 Increased Expression of GF Osborne CK, et al. Ann Rev Med 62:14.1-15, 2010

  32. Cross-Talk Between Signal Transduction and Endocrine Pathways Growth factor Estrogen Antibodies and TKIs SOS RAS RAF Aromatase Inhibitor Tamoxifen P P P P P P P P P Basal transcription machinery ER CBP MEK MAPK p160 PI3-K Akt ER ER ERE ER target gene transcription IGFR EGFR / HER2 P P P P Cell survival p90RSK Cell growth P Cytoplasm Nucleus Adapted from Johnston S. Clin Cancer Res. 2005;11:889S

  33. Long-term estrogen deprivation (LTED) • ER (+) BC cells after LTED become hypersensitive to low-dose estrogen. • LTED is NOT due to up-regulation of ER. • LTED is likely due to activation of MAPK, PI3K, EGFR, or non- genomic effect of estrogen. Masamura S, et al. J Clin Endocrinol Metab 2918-25, 1995

  34. Pathways associated with ET resistance in vitro Nat. Rev. Cancer 9: 631-43

  35. Mechanisms of SERM resistance

  36. TAnDEM trial *previous ET or anastrozole < 4 months, adequate organ functions, ECOG 0-1 208 postmenopausal women with HR/HER2 + MBC* • First randomized phase III to combine ET and trastuzumab for HER2/HR + MBC (2001-2004) Randomized anastrozole + trastuzumab n=103 (n=77 HR +) Primary EP: PFS 2nd EP: CBR, ORR, TTP, OS, 2-yr SR anastrozole n=104 (n=73 HR +) anastrozole 1 mg qd Trastuzumab 4 mg/kg IV day 1, followed by 2mg/kg, qwk double-blinded 187 withdrawals due to PD 73/104 pts received trastuzumab-containing regimen J Clin Oncol 27: 5529-5537

  37. Trastuzumab added to anastrozole (A + T) vs anastrozole alone (A) significantly improved efficacy PFS Secondary end points: TTP, ORR, CB TAnDEM: Efficacy Summary Update of Mackey et al. Breast Cancer Res Treat. 2006;100(suppl 1):S5. Abstract 3.

  38. TAnDEM trial • Trastuzumab plus anastrozole improves PFS and TTP, but not OS for pts with HER2/HR + MBC compared with anastrozole alone. • Poor response on both arms is likely due to aggressive nature of the cancer.

  39. Frequency of mutations in PIK3CA and PTEN (n=547 breast cancer cases) Stemke-Hale, K. et al. Cancer Res 68:6084-91, 2008

  40. Y Trastuzumab MK 0646 AMG 479 AMC A12 AVE 1642 How do we take it to the clinic? MK-0646 Pertuzumab IGFR1 HER2 Lapatinib PI3K/AKT pathway activation X Perifosine A797 A838450 LY2101831 GSK690693B KP86328 Src-> PI3K -> AKT -> mTOR Dasatinib LY 294002 SF 1126 PX 166 BEZ 235 CCI 779 RAD 001 AP23573 Dasatinib AZD 0530 Breast cancer cell growth X Fulvestrant Tamoxifen Anastrazole Letrozole Exemestane Fulvestrant ER

  41. A phase I-II, randomized clinical trial for metastatic HR-positive HER2-negative breast cancer PET-CT Biopsy PET-CT Biopsy Biopsy Pre-Rx Week 12 Day 14 Staging Fulvestrant HR- positive and HER2-negative PI3K/PTEN/AKTmutations PI3K/PTEN/AKT-activation Src -activation ER levels Fulvestrant + MK-0646 AR PIK3CA mutations Fulvestrant + Dasatinib Fulvestrant + MK-0646 + Dasatinib AR= Adaptive Randomization (PI: Gonzalez-Angulo & Meric-Bernstam) www.clinicaltrials.gov

  42. 2 weeks A phase II neoadjuvant trial of BEZ235 in combination with endocrine therapy in post-menopausal patients with operable HR-positive breast cancer 22 weeks Arm 1: Letrozole BEZ235 Letrozole BEZ235 Breast Cancer T1-3/N0-1 ER or PR+/HER2– Post-menopausal PI3K aberrations (core biopsy) Biopsy Surgery 1:1 randomization Arm 2: Letrozole Placebo Letrozole Placebo Path CR Clin Response (US, Mammo) Br Cons Surgery Ki-67 TUNEL P-Akt, etc microarrays RPPA Ki-67 TUNEL P-Akt, etc microarrays RPPA FDG-PET Ki-67 TUNEL P-Akt, etc. microarrays RPPA FDG-PET

  43. *No prior therapy for metastatic disease allowed; but neoadjuvant/adjuvant ET allowed; AI/or trastuzumab completed > 1 yr; ECOG 0-1; normal organ function 1286 postmenopausal women with HR+ MBC* (2003-2006) Randomized Primary EP: PFS 2nd EP: ORR, CBR, OS, safety Letrozole + lapatinib n=642 (111 HER2 +) Letrozole + Placebo N=644 (108 HER2 +) Letrozole 2.5 mg qd Lapatinib 1500 mg qd double-blinded Median follow-up 1.8 yrs

  44. UK/USA 1950-2006: BC mortality (ages 35-69)

  45. Breast Cancer Mortality - US Screening: 50% Adjuvant Therapy: 50% Estimated and Actual Rates of Death from Breast Cancer among Women 30 to 79 Years of Age from 1975 to 2000 (Panel A) and under Hypothetical Assumptions about the Use of Screening Mammography and Adjuvant Treatment (Panel B) Berry Det al. N Engl J Med 2005;353:1784-1792

  46. Breast Cancer Mortality - US Screening: 50% Adjuvant Therapy: 50% Rates of Death from Breast Cancer among Women 30 to 79 Years of Age from 1975 to 2000 under Hypothetical Assumptions about the Use of Screening Mammography and Adjuvant Treatment Berry Det al. N Engl J Med 2005;353:1784-1792

  47. Outline Endocrine Receptors and Breast Cancer Potential Mechanisms of Resistance to Endocrine Manipulation Clinical Trials Future Developments Ongoing Trials VIII Simposio Internacional GEICAM – A Coruña 2011

  48. Tamoxifen improves 15-y outcomes in ER+/unknown 60 60 10 386 women: 20% ER-unknown, 30% node-positive. 50 50 45.0 38.3 40 40 34.8 26.5 Breast cancer mortality (%) Recurrence (%) 30 30 25.7 25.6 24.7 20 20 11.9 17.8 15.1 10 10 8.3 0 0 0 5 10 15 0 5 10 15 Years Years 33.2 Control Tamoxifen Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

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