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  • AC, doxorubicin, cyclophosphamide; CHF, congestive heart failure; Cum Inc, cumulative increase; H, Herceptin; T, paclitaxel.
  • BCIRG, Breast Cancer International Research Group; TCH, paclitaxel, cyclophosphamide, Herceptin.
  • CEF, cyclophosphamide/epirubicin/5-flourouracil; PgR, progesterone receptor.
  • DFS, disease-free survival; OS, overall survival; FinHer, The Finland Herceptin trial.
  • HER2, human epidermal growth factor receptor 2
  • ADCC, antibody-dependent cell-mediated cytotoxicity. Like trastuzumab, pertuzumab was among the first-line anti-HER2 antibodies tested preclinically in vitro and in vivo that showed that antibodies against the HER2 extracellular domain could growth-inhibit these tumors preclinically. Although they are both HER2-targeting agents, pertuzumab and trastuzumab have some distinct differences, listed here. The most important difference is that pertuzumab binds to a different epitope in the HER2 extracellular domain that inhibits the HER2 dimerization with other HER family receptors. In particular, pertuzumab more strongly inhibits the most effective signaling dimerization partner complex, HER2 plus HER3.
  • Figure 1: The ER Pathway. Estrogen exerts its effects through the classical pathway where the estrogen receptor (ER) dimerizes with itself and associates with coactivators (CoA) to subsequently promote transcription through a direct genomic effect. In the non-genomic pathway ER can bind other protein complexes or adaptor proteins to either activate tyrosine kinase receptors or their downstream effectors such as AKT or mitogen activated protein kinase (MAPK). Likewise, ER can be phosphorylated/activated by AKT or other proteins in an estrogen independent fashion causing ER to bind to transcription factors (TF) and promote transcription.
  • Figure 1: The ER Pathway. Estrogen exerts its effects through the classical pathway where the estrogen receptor (ER) dimerizes with itself and associates with coactivators (CoA) to subsequently promote transcription through a direct genomic effect. In the non-genomic pathway ER can bind other protein complexes or adaptor proteins to either activate tyrosine kinase receptors or their downstream effectors such as AKT or mitogen activated protein kinase (MAPK). Likewise, ER can be phosphorylated/activated by AKT or other proteins in an estrogen independent fashion causing ER to bind to transcription factors (TF) and promote transcription.
  • Mention response rates with chemotherapy
  • Figure 2: Receptor Tyrosine Kinase Pathway. Receptor tyrosine kinases, such as epidermal growth factor (EGFR), HER2, fibroblast growth factor (FGFR), and insulin like growth factor 1 (IGF-1R) have an extracellular receptor domain, a transmembrane domain, and an intracellular domain with tyrosine kinase activity. They can form homo or heteromers which are activated upon binding a ligand and undergoing phosphorylation of their kinase domain. Downstream pathways are then activated such as mitogen activated protein kinase (MAPK) and AKT which result in regulation of transcription (TF = transcription factor) and modulation of other cellular processes.
  • Figure 3: PI3K/AKT/mTOR Pathway. Phosphoinositide 3-kinase (PI3K) is activated by tyrosine kinases (TK) and can also be activated by Ras. Its p85 regulatory subunit interacts with the TK and subsequently releases its inhibition over the catalytic domain p110. p110 then converts Phosphatidylinositol (3,4,5)-triphosphate (PIP3) to Phosphatidylinositol (4,5)-bisphosphate (PIP2). PIP2 then recruits adaptor proteins such as 3-phosphoinositide-dependent protein kinase-1 (PDK1) and AKT. Tensin homolog deleted on chromosome ten (PTEN) degrades PIP3 to PIP2. Mammalian target of rapamycin (mTOR) serves to fully activate AKT (mTORC2) while mTORC1 is activated by AKT. Activation of AKT, mTOR, and mitogen activated protein kinase (MAPK) all lead to modulation of cellular processes which affect growth, invasion, and proliferation.
  • PI3K increased concomitantly with endocrine resistance in LTED

Trastuzumab Trastuzumab Presentation Transcript

  • QUESTION• Trastuzumab: – A. Is indicated for all adjuvant breast cancer treatment – B. Marginally improves overall survival – C. Requires Her 2 neu overexpression for efficacy – D. Is not yet approved for breast cancer treatment
  • ANSWER• Trastuzumab requires Her 2 neu overexpression for efficacy – Trastuzumab is indicated only for breast cancers that overexpress Her 2 neu, is associated with a significant improvement in overall survival in the adjuvant setting, and is FDA approved for adjuvant and metastatic breast cancerCobleigh, MA, J Clin Oncol 1999 Sep; 17(9):2639-48Slamon, DJ, N Eng J Med 2001 Mar 15;
  • HER 2 & TOP II ᾀ CO AMPLIFICATIONQUESTION1. 50%2. 73%3. 35%4. 30%
  • HER2 Gene: Background • Localized to chromosome 17q • Tyrosine kinase transmembrane growth factor receptor • Member of EGFR gene family • In 85% of 120 publications (> 20,000 patients total), abnormal HER2 expression has been linked with adverse outcome in breast cancerRoss and Fletcher. Semin Cancer Biol. 1999;9:125.Pegram and Slamon. Semin Oncol. 2000;27(suppl 9):13.Data on file, Genentech BioOncology.
  • HER2 Overexpression in Breast Cancer HER2 is overexpressed in ~ 25% of breast cancers Normal (1x) ~ 25,000-50,000 HER2 receptors Overexpressed HER2 (10-100x) up to ~ 2,000,000 HER2 receptorsPegram MD, et al. Cancer Treat Res. 2000;103:57-75.Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1): Excessive cellular divisionSlamon DJ, et al. Science. 1987;235:177-182.
  • HER2 Overexpression Shortens Survival HER2 oncogene amplification HER2 oncoprotein overexpression Shortened survival Median Survival From First DiagnosisSlamon DJ, et al. Science. HER2 overexpressing 3 yrs1987;235:177-182. Slamon DJ, et al. HER2 normal 6-7 yrsScience. 1989;244:707-712.
  • Methods for Testing HER2 Status
  • ASCO/College of American Pathologists Guidelines for HER2 Testing in Breast CancerPositive for HER2 is either immunohistochemistry (IHC) HER2 3+ (defined as uniform intense membrane staining of >30% of invasive tumor cells) or FISH amplified (ratio of HER2 to CEP17 of >2.2 or average HER2 gene copy number >6 signals/nucleus for those test systems without an internal control probe)Equivocal for HER2 is defined as either IHC 2+ or FISH ratio of 1.8–2.2 or average HER2 gene copy number 4–6 signals/nucleus for test systems without an internal control probeNegative for HER2 is defined as either IHC 0–1+ or FISH ratio of <1.8 or average HER2 gene copy number of <4 signals/nucleus for test systems without an internal control probe
  • HER2 TESTING CHALLENGES• Unclear which patients benefit most from targeted therapy[1-3]• Determination of HER2 status reliant on testing infrastructure – ie, central vs local testing, FISH vs IHC• Potential benefit from adding trastuzumab for treatment of patients with tumors < 3+ IHC and FISH negative• Disparate results with local vs central testing – Patients in NCCTG 9831 (adjuvant chemotherapy trastuzumab) were assessed for HER2 by local testing – Central testing identified subset of patients who were protein negative and gene negative with HR of 0.51 for DFS (P = 0.13)
  • Disease-free-Survival According to Local Immunohistochemistry for HER2 and Central FISH for Patients Treated with Adjuvant Chemotherapy with/without Trastuzumab in the HERA Trial _____________________ McCaskill-Stevens W, Procter M, Azambuja E, Dafni U,Leyland-Jones B, Ruschoff J, Dowsett M, Jordan B, Dolci S,Abramovitz M, Stoss O, Viale G, Gelber RD, Piccart-Gebhart M, for the HERA Study Team
  • HER2 STATUS TESTING Local IHC 3+ → central IHC 3+ Prospective testing for Local IHC 2+ → central FISH+eligibility before randomization Local FISH + → central FISH+Central FISH results are available for:1131 pts. prospectively (eligibility screening)940 pts. retrospectively (assay bankedspecimens)2071 (61%) total out of the 3401 patients central FISH+ = FISH Ratio ≥ 2.0
  • Biology of Her2 RTKsHER family, also known as ErbB family – HER1, HER2, HER3, HER4 – Transmembrane receptor kinases with extracellular domain – Receptor-specific growth factor ligands identified for all but HER2 Activated HER molecules – dimerize upon ligand binding – Result in signal transduction and cell growthSlamon D, et al. N Engl J Med. 2001;344:783-792. Valabrega G, et al. Ann Oncol. 2007;18:977-984. Pegram MD, et al. Semin Oncol. 2000;27(suppl 11):21-25. 3.
  • HER2-Targeted Agents
  • Trastuzumab Development History 1981 1985 1987 1990 1991 1992 1993 1994 1995 199 1997 1998 6Murine Associatio Phase I Phase PhaseHER2/n n of HER2 IND for II IIIeu gene with poor rhuMAb cloned clinical HER2 outcome Human muMA trastuzumab HER2 b 4D5 FDA gene approval cloned 9/25/98
  • Trastuzumab: Humanized Anti-HER2 Antibody HER2 epitopes recognized by • Targets HER2 protein hypervariable murine antibody fragment • High affinity (Kd = 0.1 nM) and specificity • 95% human, 5% murine – Decreases potential Human for immunogenicity IgG-1 – Increases potential for recruiting immune effector mechanismsBaselga. Satellite Symposium, 23rd Annual San Antonio Breast CancerSymposium 2000.
  • Trastuzumab: Mechanism of Action
  • 1. Trastuzumab mediates ADCC Once bound to the Fc domain of trastuzumab, the NK cells release substances……that perforate the tumourcell membrane and promotecell death Nahta R, Esteva FJ. Breast Cancer Res 2006; 8: 215 Clynes RA, et al. Nat Med 2000; 6: 443-446 Gennari R, et al. Clin Cancer Res 2004; 10: 5650-5655 Arnould L, et al. Br J Cancer 2006; 94: 259-267
  • 2. Trastuzumab prevents formation of p95HER2 Formation of the active p95 fragment, through proteolytic cleavage of the extracellular domain of HER2……is prevented bytrastuzumab Molina MA, et al. Cancer Res 2001; 61: 4744-4749 Nahta R, Esteva FJ. Cancer Lett 2006; 232: 123-138
  • 3. Trastuzumab blocksHER2-activated cell proliferation HER2 signalling induces cell proliferationTrastuzumab interruptsthis process Nahta R, Esteva FJ. Cancer Lett 2006; 232: 123-138 Fry MJ. Breast Cancer Res 2001; 3: 304-312 Gershtein ES, et al. Clin Chim Acta 1999; 287: 59-67 Yakes FM, et al. Cancer Res 2002; 62: 4132-4141 Longva KE, et al. Int J Cancer 2005; 116: 359-367
  • 4. Trastuzumab inhibitsHER2-regulated angiogenesis HER2 signalling induces angiogenesis Trastuzumab inhibits this process Izumi Y, et al. Nature 2002; 416: 279-280 Nahta R, Esteva FJ. Cancer Lett 2006; 232: 123-138 Wen XF, et al. Oncogene 2006; 25: 6986-6996 Klos KS, et al. Cancer 2003; 98: 1377-1385
  • Trastuzumab: 1 target 4 mechanisms of actionActivation of ADCC Prevention of formation of p95HER2Inhibition of cell Inhibition of proliferation HER2-regulated angiogenesis
  • ADCC is a key mechanism of Herceptin’s antitumour activity in vivo HER2 Tumour + Herceptin cell NK cell ADCC FcgRIII• Once bound to HER2, the Herceptin Fc domain recruits immune cells to target and destroy the tumour
  • Lapatinib Blocks Signaling Through Multiple Receptor Combinations Blocks signaling through 1+1 2+2 1+2 ErbB1 and ErbB2 homodimers and heterodimers Might also prevent signaling through heterodimers between these receptors and other ErbB family members Potentially blocks multiple ErbB signaling pathways Downstream signaling cascade
  • ® Herceptin in the adjuvant setting: rationale• HER2 overexpression is an early event in breast cancer development and is associated with aggressive disease ® Herceptin offers• A new mechanism of antitumour activity• Proven clinical benefits in the metastatic setting, including increased survival when used in combination with chemotherapy• Greater benefit when used earlier in metastatic disease• A favourable safety profile and good tolerability
  • HER2 and Adjuvant• Benefit estimates for use of trastuzumab available in Adjuvant! Version 9.0 – HER2 included as a variable• HER2 expression prognostic for breast cancer – Modest independent relative risk of 1.5• Trastuzumab now included as adjuvant therapy option – Projections of benefit for trastuzumab only for 3 years because of short follow- up on current trials
  • Adjuvant! Limitations• Many estimates are based on as yet incomplete evidence and as yet strongly debated assumptions• For example – No impact of HER2 status on estimates of hormonal therapy efficacy – No impact of HER2 status on estimates of efficacy of adjuvant anthracyclines and/or taxanes
  • Adjuvant! Version 9.0
  • Adjuvant! Projection for Trastuzumab
  • Four major ongoing Herceptin ® adjuvant trials• The extensive Herceptin adjuvant ® trial programme will – investigate complementary strategies – establish the efficacy and role of Herceptin in the adjuvant setting ® – establish the safety profile of Herceptin ® – determine the optimal duration of adjuvant Herceptin therapy ®
  • âHerceptin in the adjuvant setting: major trials Four main trials are currently investigating Herceptin in the ® adjuvant setting• HERA (Herceptin Adjuvant) Trial ®• NSABP (National Surgical Adjuvant Breast Project) trial B31• Intergroup trial N9831• BCIRG (Breast Cancer International Research Group) trial 006
  • Comparison of the four large Herceptin adjuvant trials ® Accrual Follow-up Target Patient phase phase PrimaryTrial accrual selection (years) (years) endpointNSABP B31 2,700 Node+, 4.75 15 OS IHC 3+ or FISH+Intergroup 3,000 Node+, 4.5 15 DFSN9831 IHC 3+ or FISH+BCIRG 006 3,000 Node+ and – NA NA DFS FISH+HERA Trial 3,192 Node+ and – 4 10 DFS IHC 3+ or FISH+
  • North American Trastuzumab Adjuvant Trials in Breast Cancer NSABP B-31 4 cycles 52 wks T HD every 3 wks 4 cycles Trastuzumab AC 4 cycles T HD every 3 wks NCCTG 9831 12 wks 52 wks T LD/wk 64 wks 4 cycles Trastuzumab AC T LD/wk Trastuzumab T LD/wkRomond EH, et al. N Engl J Med. 2005;353:1673-1684.
  • NSABP TRIAL B31: TREATMENT PLAN Doxorubicin 60mg/m 2 Cyclophosphamide 600mg/m 2 Paclitaxel 175mg/m q3w 2 Herceptin ® – loading dose 4mg/kg on week 1 – maintenance dose 2mg/kg x 51 weeks
  • NSABP TRIAL B31:PRIMARYOBJECTIVES Stage I: (n=1,000) – evaluation of cardiac safety Stage II: (n=1,700; total=2,700) – evaluation of efficacy • survival: primary endpoint • disease-free survival (DFS): secondary endpoint
  • NSABP TRIAL B31: SECONDARYOBJECTIVES Prognostic and predictive value of phosphorylated HER2 receptor Prognostic and predictive value of shed extracellular domain (ECD) Concordance between different HER2 assays, i.e. IHC versus FISH Change in HER2-phosphorylated receptor, ECD level or HER2 overexpression upon relapse
  • NSABP TRIAL B31: KEY INCLUSIONCRITERIA  Histologically/cytologically proven invasive adenocarcinoma of the breast  At least one positive axillary node  Axillary dissection AND either total mastectomy OR lumpectomy  HER2 overexpression (IHC 3+ or FISH positive)  Known hormone receptor status (ER/PgR)  No more than 84 days since prior surgery for breast cancer  No prior chemotherapy, radiotherapy or hormonal therapy for breast cancer  Normal cardiac, renal and hepatic function
  • Disease-Free Survival B-31 N9831 100 100 90 87% 87% 85% 90 86%Patients (%) 80 AC  T 80 78% AC  TH 74% 70 66% 70 68% Patients Events Treatment 60 60 AC  T (n = 807) 872 171 AC  T 864 83 AC  TH AC  TH (n = 808) 50 HR: 0.45; 2P = 1 x 10-9 50 HR: 0.55; 2P = .0005 0 1 2 3 4 5 0 1 2 3 4 5 Years From Randomization Years From RandomizationRomond EH, et al. N Engl J Med. 2005;353:1673-1684.
  • DISEASE-FREE SURVIVAL B-31 N9831100 100 AC->T+H AC->T+H90 90 AC->T AC->T80 8070 70 N Events N Events60 60 AC->T 807 90 AC->T 872 171 AC->T+H 864 83 AC->T+H 808 51 HR=0.55, 2P=0.000550 50 HR=0.45, 2P=1x10-9 0 1 2 3 4 5 0 1 2 3 4 5 Years Years
  • NSABP B-31: CARDIOTOXICITY DATA Years Cum Inc Cum Inc No. at Arm 2: AC  T + H After Arm 1, % Arm 2, % Risk 6 Day 1 n = 850, 31 CHFs, Cycle 5 no cardiac deaths 0.5 0.3 2.6 1472 4.1%Percentage 4 1.0 0.5 3.6 1202 HR: 5.9 1.5 0.5 3.9 983 Arm 1 evaluable cohort Arm 2 evaluable cohort 2.0 0.5 4.1 775 2 Arm 1: AC  T 2.5 0.8 4.1 595 n = 814, 4 CHFs, 0.8% 3.0 0.8 4.1 405 1 cardiac death 0 0.5 1.0 1.5 2.0 2.5 3.0 Years After Day 1 Cycle 5Tan-Chiu E, et al. J Clin Oncol. 2005;23:7811-7819. Reprinted with permissionfrom the American Society of Clinical Oncology.
  • Intergroup trial N9831: treatmentplan Herceptin® – 4mg/kg loading dose (90 minutes i.v. infusion) followed by 4mg/kg weekly (90 minutes i.v. infusion or 30 minutes i.v. infusion based on toxicity) Doxorubicin 60mg/m2 every 3 weeks Cyclophosphamide 600mg/m2 every 3 weeks Paclitaxel 80mg/m2 weekly
  • Intergroup trial N9831: objectives Primary – disease-free survival – cardiotoxicity Secondary – overall survival – evaluation of whether sHER1 or sHER2 levels at baseline are prognostic for disease-free and overall survival ® – concordance of IHC (HercepTest ) with FISH TM (Vysis ); disease-free survival; and overall survival
  • Intergroup trial N9831: inclusion criteria• Operable, histologically confirmed adenocarcinoma of the breast• Node-positive disease• Hormonal status known (ER/PgR)• HER2 overexpression (IHC 3+ or FISH positive)• No prior chemotherapy – hormonal therapy allowed for up to 4 weeks but discontinued prior to enrolment• No more than 84 days from mastectomy or axillary node dissection• LVEF normal
  • Intergroup trial N9831: exclusion criteria• Locally advanced tumours• Prior history of breast cancer• Prior chemotherapy or radiotherapy for breast cancer• Cardiac disease including: – myocardial infarction – history of congestive heart failure – medication for arrythmia or angina pectoris• Prior anthracycline or taxane therapy for any malignancy
  • HERA TRIAL: STUDY DESIGN Primary management (surgery, [neo]adjuvant chemotherapy ± adjuvant radiotherapy) Stratification Randomisation Herceptin ® Herceptin ® q3w x 1 year q3w x 2 years Observation* ®*Observation group to receive the same follow-up as the Herceptin treatment groups
  • HERA: Trastuzumab in HER2- Positive Early-Stage Breast Cancer Observation* Women with HER2- (n = 1698) positive invasive early-stage breast Interim follow-up: cancer, who median 2 years received surgery Trastuzumab and adjuvant or 8 mg/kg loading dose, neoadjuvant 6 mg/kg every 3 weeks chemotherapy for 1 year radiotherapy (n = 1703) (N = 3401) *All patients given the option to switch to trastuzumab May 2005 after positive interim data review.Piccart-Gebhart MJ, et al. N Engl J Med. 2005 ;353:1659-1672.
  • HERA TRIAL: PRIMARY OBJECTIVES• Compare disease-free survival (DFS) in patients with HER2-overexpressing breast ® cancer who received Herceptin versus® those who did not receive Herceptin – in patients treated for 1 year – and those treated for 2 years
  • HERA TRIAL: SECONDARY OBJECTIVES Overall survival, relapse-free survival and distant DFS – 1 year of Herceptin versus observation ® – 2 years of Herceptin versus observation ® Safety and tolerability – Herceptin versus ® observation Incidence of cardiac dysfunction – Herceptin versus observation ® Treatment duration (efficacy and safety) – 1 year versus 2 years of Herceptin ®
  • HERA TRIAL: STUDY SIZE AND DURATION Sample size: 3,192 (1,064 per arm) Target population: women with HER2- positive primary breast cancer (IHC 3+ or FISH positive) Study duration – recruitment 48 months – follow-up until 10 years after last patient enrolled Number of centres: ~600
  • HERA TRIAL: KEY INCLUSION CRITERIA Invasive, non-metastatic, operable primary breast cancer – histologically confirmed and adequately excised Axillary node positive, or node negative with tumour size >1cm Known hormone receptor status (ER/PgR or ER alone) Completed 4 cycles of approved (neo)adjuvant chemotherapy Baseline LVEF >55% (echocardiography or MUGA scan) Completed radiotherapy if indicated Centrally confirmed HER2 overexpression (IHC 3+ or FISH positive) in invasive component of primary
  • HERA TRIAL: KEY EXCLUSION CRITERIA Clinical T4 tumour, including inflammatory breast cancer 2 Cumulative dose of doxorubicin >360mg/m or epirubicin 2 >720mg/m (Neo)adjuvant chemotherapy with peripheral blood/bone marrow stem cell support Supraclavicular lymph node involvement Any prior malignant neoplasms (including primary invasive breast cancer), except – curatively treated basal/squamous cell carcinoma of skin – curatively treated in-situ cervical carcinoma
  • HERA: Trastuzumab in HER2- Positive Early-Stage Breast Cancer (cont’d) DFS (Censored) OS (Censored) 100 100 Patients Alive (%) 80 80 Patients (%) 60 60 1-year trastuzumab 1-year trastuzumab 40 Observation 40 Observation 20 3-year DFS: 80.6% vs 74.0% 20 3-year OS: 92.4% vs 89.2% HR: 0.63 (95% CI: 0.53-0.75; P < .0001) HR: 0.63 (95% CI: 0.45-0.87; P < .0051) 0 0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Months From Randomization Months From Randomization 1703 1127 140 1703 1190 146 1698 930 114 1698 1042 126Smith IE, on behalf of HERA. ASCO 2006. Clinical Science Symposium.
  • HERA: DFS Benefit in Subgroups n HR All 3387 0.54 Nodal status Any, neoadjuvant chemotherapy 358 0.53 0 pos, no neoadjuvant chemotherapy 1100 0.521-3 pos, no neoadjuvant chemotherapy 972 0.51 4 pos, no neoadjuvant chemotherapy 953 0.53 Adjuvant chemotherapy regimen No anthracycline or taxane 203 0.64 Anthracycline, no taxane 2307 0.43 Anthracycline + taxane 872 0.77 Receptor status/endocrine therapy Negative 1674 0.51 Pos + no endocrine therapy 467 0.49 Pos + endocrine therapy 1234 0.68 0 1 2 Favors Favors Trastuzumab Observation HR: 1-Year Trastuzumab vs ObservationSmith IE, on behalf of HERA. ASCO 2006. Clinical Science Symposium.
  • HERA TRIAL: UNIQUE FEATURES Investigating the role of Herceptin independently from ® chemotherapy regimen Investigating 2 years of Herceptin treatment ® 3-weekly schedule from the start – more convenient – gives similar exposure to Herceptin as weekly ® administration of lower doses New model of partnership between academia and pharmaceutical industry
  • HERA: Cardiac Safety Patients, n (%) Observation 1-Yr Trastuzumab Cardiac death* 1 (0.1) 0 (0) Severe CHF* 1 (0.1) 10 (0.6) Symptomatic CHF* (including severe) 3 (0.2) 36 (2.1) Confirmed significant LVEF decline* 9 (0.5) 51 (3.0) Any type of cardiac endpoint* 10 (0.6) 61 (3.6) At least 1 significant LVEF decline†‡ 35 (2.3) 118 (7.4) *Observation, n = 1678; trastuzumab, n = 1708. †Observation, n = 1545; trastuzumab, n = 1600. ‡Many were single observations, not confirmed at subsequent time points.Smith IE, on behalf of HERA. ASCO 2006. Clinical Science Symposium.
  • BCIRG 006 4 x AC 4 x Docetaxel 60/600 mg/m2 100 mg/m2 HER2+ (Central FISH) AC  T 4 x AC 4 x Docetaxel 60/600 mg/m2 100 mg/m2 N+ or High-Risk N- AC  TH 1-Yr Trastuzumab 6 x Docetaxel and Carboplatin 75 mg/m2 AUC 6 N = 3222 TCH Stratified by nodes and hormone receptor status 1-Yr TrastuzumabSlamon D. SABCS 2005. General Session 1.
  • BCIRG TRIAL 006: OBJECTIVES • Primary – disease-free survival • Secondary – overall survival – safety – cardiac toxicity – quality of life – prognostic value of HER2 overexpression
  • BCIRG TRIAL 006: TREATMENT PLAN• Doxorubicin 60mg/m2• Cyclophosphamide 600mg/m2• Docetaxel 100mg/m2• Platinum salt – carboplatin AUC 6 – cisplatin 75mg/m2• Herceptin ® – 6mg/kg every 3 weeks
  • BCIRG trial 006: key inclusion criteria• Histologically proven breast cancer• Definitive surgical treatment• Node-positive/negative disease• HER2 overexpression (FISH positive)• Normal renal, hepatic and cardiac function• No prior systemic therapy or radiotherapy for breast cancer
  • BCIRG 006 DISEASE-FREE SURVIVAL:2ND INTERIM ANALYSIS 1.0 Absolute DFS benefits (from Year 2 to 4): 93% AC  TH vs AC  T: 6% 0.9 87% TCH vs AC  T: 5% 92% Disease Free (%) 83% 87% 86% TCH 0.8 82% 81% AC  TH AC  T 77% 0.7 Patients Events 1073 192 AC  T 0.6 1074 128 AC  TH HR (AC  TH vs AC  T): 0.61 (0.48-0.76; P < .0001) 1075 142 TCH HR (TCH vs AC  T): 0.67 (0.54-0.83; P = .0003) 0.5 0 1 2 3 4 5 Year From Randomization Slamon D. SABCS 2006. Abstract 52.
  • BCIRG 006 Overall Survival: 2nd Interim Analysis 1.0 99% 97% 98% 92% 0.9 97% 95% AC  TH 93% 91% TCH AC  T 86% Survival (%) 0.8 0.7 Patients Events 1073 80 AC  T 0.6 1074 49 AC  TH HR (AC  TH vs AC  T): 0.59 (0.42-0.85; P < .004) 1075 56 TCH HR (TCH vs AC  T): 0.66 (0.47-0.93; P = .017) 0.5 0 1 2 3 4 5 Year From RandomizationSlamon D. SABCS 2006. Abstract 52.
  • BCIRG 006: EFFICACY RESULTS  Both AC  TH and TCH arms – Statistically significantly improved DFS compared with AC  T (HR: 0.61 with AC  TH and 0.67 with TCH)  At this time – No statistically significant difference between AC  TH and TCH – Insufficient information to evaluate overall survival (secondary endpoint)Slamon D. SABCS 2006. General Session 1.
  • SECOND INTERIM ANALYSIS OFADVERSE EVENTS FOR PHASE IIIBCIRG 006  Adverse events less common and safety better in anthracycline-free TCH arm of BCIRG 006 – Significantly lower rates of sensory neuropathy and myalgias – No leukemias – More grade 3/4 thrombocytopenia and anemia  Benefit of anthracyclines in adjuvant treatment of breast cancer now questioned Slamon D, et al. SABCS 2006. Abstract 52.
  • HER2 and Topo IIα in BCIRG 006 2990 of 3222 patients analyzed 17 q 12 17 q 21.1 17 q 21.2 HER2 Topo IIα N = 2990 Core region region Topo IIα non- 1788 pts (60%) coamplified 145 pts (5%) Coamplified 1057 pts (35%) Most recent analysis Normal Amplified DeletionSlamon D, et al. SABCS 2006. Abstract 52.
  • HER2/neu Overexpression: Predictive of Response Topoisomerase IIα gene (Topo IIα) Located close to HER2/neu on the 17q chromosome Integrally involved in the antitumor action of anthracyclines Topo IIα is essential for DNA replication and recombination Anthracyclines target Topo IIα enzyme
  • The Topo IIα GeneFunctions Resolves topological problems in DNA Is critical in RNA transcription from DNA Makes transient protein-bridged DNA breaks on one or both DNA strands during replication Plays critical roles in segregation, condensation, and superhelicity
  • Implications for HER2-Negative and HER2-Positive Breast Cancers• Superior efficacy benefits for anthracyclines (when present) derives from their effects on Topo IIα amplification and/or overexpression• To date, Topo IIα amplification occurs only in 35% of the 25% of breast cancer patients with HER2 amplification, ie, a subset of a subclass (tested in > 4500 patients)• Data support their preferential use in a HER2- negative breast cancer population that is ~ 75% of all breast cancers• For HER2-positive breast cancers, trastuzumab and lapatinib appear to replace the gained efficacy of anthracyclines in the 1/3 of patients with coamplification of HER2 and Topo IIα without risking their known and well-established toxicities
  • HER2 is Predictive of Paclitaxel BenefitBy Estrogen ReceptorDisease Free Survivaln = 1322 ER DFS: Her2 CB11 < 50% Neg ER DFS: Her2 CB11 < 50% Pos / ER negative / ER positive 1.0 1.0 paclitaxel paclitaxel 0.8 0.8 HER2 NEG No paclitaxel 0.6 0.6 Proportion Proportion 0.4 0.4 No paclitaxel n=390 n=703 No Taxol No Taxol 0.2 0.2 Taxol Taxol (29%) (53%) 0.0 0.0 0 2 4 6 8 10 0 2 4 6 8 10 Years DFS: Her2 Years >= 50% CB11 DFS: Her2 CB11 >= 50% / ER negative / ER positive 1.0 1.0 paclitaxel HER2 POS paclitaxel 0.8 0.8 0.6 0.6 Proportion Proportion 0.4 0.4 n=144 No paclitaxel No paclitaxel No Taxol n=79 (11%) No Taxol 0.2 0.2 Taxol Taxol (6%) 0.0 0.0 0 2 4 6 8 10 0 2 4 6 8 105 10Hayes D.F., et al. N Engl Years Years 357:1496-506, 2007 J Med. Years
  • FINHER TRIAL First randomization Second randomization Trastuzumab Docetaxel once wkly for 9 wks; 100 mg/m2 3 cycles, first dose 4 mg/kg followed by 3 cycles CEF then 2 mg/kg with CEF + (n = 502) docetaxel or vinorelbine Patients with node- (n = 116) positive or node-negative disease; tumor Patients with HER2 > 20 mm and PgR- amplification negative (n = 232) Vinorelbine (N = 1010) CEF + 25 mg/m2 8 cycles, then docetaxel or vinorelbine 3 cycles CEF (n = 115) (n = 507)Joensuu H. SABCS 2006. Abstract 2.
  • FINHER TRIAL: EFFICACY  At 36 months of median follow-up, the following was observed in the trastuzumab arm – 58% improvement in DFS – A trend for improvement in OS – No major increase in cardiotoxicity  Established short duration trastuzumab as an option for patients unable to complete a 1-year courseJoensuu H, et al. N Engl J Med. 2006;353:809-820..
  • ECOG TRIAL E2198: INCLUSION CRITERIA• Histologically confirmed stage II or IIIa adenocarcinoma of the breast• HER2 overexpression (IHC 2+/3+)• Axillary node dissection AND mastectomy or lumpectomy within 12 weeks prior to enrolment• No prior chemotherapy, hormonal therapy (at least one year since tamoxifen therapy) or radiotherapy• No history of cardiac disease
  • ECOG TRIAL E2198: OBJECTIVES• Evaluate the incidence of cardiotoxicity associated with paclitaxel plus ® Herceptin in women with HER2- positive breast cancer• Assess the long-term safety of ® Herceptin in this patient population
  • ECOG TRIAL E2198: CARDIOTOXICITY LVEF LVEF LVEF >10% < normal grade 3/4Post paclitaxel 9.5 (18/189) 2.1 (4/189) –+ Herceptin®Post AC 12.5 (16/128) 5.5 (7/128) 8
  • BIG 2.06/N063D Adjuvant HER2+ (paclitaxel) trastuzumab (trast for 1 yr) HER2+ BC R Tumors 1 A cm after N (paclitaxel) lapatinib (lap for 1 yr) completion D of O (paclitaxel) trastuzumab+ lapatinib anthracycline M (trast + lap for 1 yr) based I therapy with Z (paclitaxel) trastuzumab (12 weeks), LVEF 50% E 6-week wash out , lapatinib (34 weeks) Treatment Schema 1: No taxane: all neoadjuvant/adjuvant chemo before targeted therapy.N = 8,000 Treatment Schema 2: Taxane included: targeted therapy after neoadjuvant/adjuvant anthracycline-based chemo, and concurrent with weekly paclitaxel.
  • Adjuvant Regimens Prescribed for HER2+ Disease AC-TH Vinorelbine/trastuzumab* Endocrine Rx +/- trastuzumab* Vin/trastuz. then FECAC/EC then trastuzumab FAC/FEC then trastuzumab Trastuzumab alone* TCH Docetaxel/cyclophos + trastuzumab*Chemo then “short course” trastuzumab**not based on phase III data
  • HERCEPTIN TREATMENT BEYOND PROGRESSION ENHANCES EFFICACY OF COMBINATION CHEMOTHERAPY• HER2 remains overexpressed and active in progressive disease• HER2 may contribute to an even more aggressive tumour growth if Herceptin treatment is discontinued• Inhibition of HER2 signalling may sensitise tumours to chemotherapy in tumours progressing on Herceptin alone
  • HERCEPTIN TREATMENT BEYOND PROGRESSION ENHANCES EFFICACY OFCOMBINATION THERAPY WITH TARGETED AGENTS• Herceptin synergistically enhances the antitumour effect of Avastin in tumours progressing on Herceptin• Herceptin synergistically enhances the antitumour effect of pertuzumab in tumours progressing on Herceptin• Lapatinib enhances the antitumour effect of Herceptin Scheuer et al 2006; Friess et al 2006; Scaltriti et al 2008
  • Treatment Options AfterTrastuzumab Trastuzumab use after disease recurrence has not been evaluated in clinical studies In a retrospective evaluation[1] – Response rate was 26% when trastuzumab was used in the second-line setting vs 43% in the first-line setting – In another review, TTP was extended from 7.1 months to 10.2 months in patients who continued trastuzumab A phase III study of lapatinib plus capecitabine compared with capecitabine alone provides evidence for lapatinib therapy following progression on trastuzumab[2] 1. Extra JM, et al. SABCS 2006. Abstract 2064. 2. Geyer C, et al. N Engl J Med. 2006;355:2733-2743.
  • PERTUZUMAB Monoclonal antibody to HER2 – Recognizes different epitope than trastuzumab – Inhibits homo- and heterodimerization of HER2 – Potentially useful for patients who have progressed on trastuzumab Interim phase II study results combining trastuzumab and pertuzumab indicate combination is well tolerated – Overall response rate is 18.2% in this pretreated population – Results suggest new HER2 monoclonal antibodies are promising in HER2-positive breast cancer
  • PERTUZUMAB AND TRASTUZUMAB BINDTO DISTINCT EXTRACELLULAR HER2EPITOPES Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex Pertuzumab I I Dimerization domain I I II I II I I I Trastuzumab I I V V  Inhibits HER2 dimerization with other HER  Activates ADCC family receptors (particularly HER3)  Inhibits HER-mediated signaling pathways  Activates ADCC  Prevents HER2 domain cleavage  Inhibits multiple HER-mediated signaling pathwaysHubbard SR. Cancer Cell. 2005;7:287-288.
  • ESTABLISHED CHEMOTHERAPYRESISTANCE MECHANISMS  Impaired drug uptake  Active drug efflux, eg by ABC transporters (P-glycoprotein, MDR2, BCRP, MRP1-6 etc)  Enhanced drug metabolism, eg by P450 enzymes  Alterations of intracellular target, eg tubulin  Upregulation of DNA repair in tumour cells  Upregulation of signalling pathways, eg anti-apoptotic genes (bcl-2, XIAP etc)
  • Hypothetical mechanisms of resistance to Herceptin (1) • Selection of HER2-negative cells in a heterogeneous tumour – Outgrowth of HER2-negative tumours from an originally mixed tumour cell population • Defective interaction of Herceptin with HER2 – Masking of Herceptin-binding epitope of HER2 – Alterations in Herceptin-binding epitope of HER2 – Loss of HER2 ECD by shedding or alternative initiation of translation on HER2 gene Kunitomo et al 2004; Nagy et al 2005;HER2, human epidermal growth factor Tanner et al 2004; Stephens et al 2004;receptor 2; ECD, extracellular domain Stephens et al 2005; Anido et al 2006
  • Hypothetical mechanisms of resistance to Herceptin (2) • Changes in downstream signalling proteins which eventually disconnect growth regulation from HER2 – PIK3CA mutations resulting in constitutively active PI3-kinase – Loss of PTEN function leading to persistent signalling activity via the PI3K/Akt survival pathway – Changes in cyclin-dependent kinase inhibitor p27kip1 Berns et al 2007; Nagata et al 2004; Crowder et al 2004; Pandolfi 2004; Kute et al 2004; Nahta et al 2004
  • IN VITRO STUDIES ARE NOT PREDICTIVE OF IN VIVO RESISTANCE • In vitro resistance was observed in cell lines exposed to Herceptin • In vitro resistance models tend to focus on just one biological feature • In vitro resistance represents intrinsic insensitivity or artificial manipulation of cells • Conclusions from in vitro resistance models cannot be translated to clinical settings – ADCC is a key mechanism of Herceptin efficacy in vivoADCC, antibody-dependent Gennari et al 2004; Arnould et al 2006;cellular cytotoxicity Musolino et al 2008; Gianni 2008
  • Trastuzumab-DM1: Novel Antibody- Drug Conjugate Target expression: HER2Monoclonal antibody: Trastuzumab Trastuzumab Cytotoxic agent: DM1 Highly potent cytotoxic agent DM1 MCC Linker: SMCC T-DM1 Average drug:antibody Systemically stable ratio ≅ 3.5:1
  • Targeted Agents for HER2+ Breast Cancer Trastuzumab Bevacizumab phase III VEGF T-DM1 phase III Sunitinib EGFR Pertuzumab phase II VEGFR HER2 phase III P P P P P P PI3-K P P Akt/PKB Lapatinib PTEN phase III Everolimus phase III mTOR Neratinib phase III 4E-BP1 S6K1 Gefitinib elF-4E phase II Protein synthesis Cell growth, proliferation, survival, metastasis, angiogenesis
  • Clinical Significance of Polysomy 17 in the HER2+ NCCTG N9831 Intergroup Adjuvant Trastuzumab Trial Reinholz MM, Jenkins RB, Hillman D, LingleWL, Davidson N, Martino P, Kaufman P, Kutteh L, and Perez EA. NCCTG, ECOG, SWOG, CALGB Reinholz et al: SABCS 2007 (abstract #36) CP1270832-139
  • Adjuvant Trastuzumab May Benefit Pts with Normal HER2 Breast Tumors (n=103) IHC 0,1,2+ HER2 FISH ratio < 2.0 100 100 AC→T+H 90 90 AC→T+H 80 p = 0.26Percent 80 p = 0.12 Percent 70 AC→T N Events DFS 70 N Events DFS AC→T 60 3 yr 5 yr 3 yr 5 yr 60 50 AC→T 142 20 88.2 67.6 AC→T 74 19 82.0 63.7 AC→T+H 191 19 89.1 82.3 50 AC→T+H 82 11 91.0 80.8 40 40 0 1 2 3 4 5 0 1 2 3 4 5 Time (years) IHC 0,1,2+ and HER2 FISH ratio <2.0 Time (years) 100 90 AC→T+H 80 Percent p = 0.14 70 N Events DFS AC→T 60 3 yr 5 yr 50 AC→T 44 14 82.6 60.9 AC→T+H 59 9 90.2 81.2 40 0 1 2 3 4 5 Time (years) CP1270832-140
  • •p-value for interaction = 0.38 (HER2 copy ≥ 4 only)
  • RR of ACTH/ACT for DFS (NSABP B-31) FISH+ (1588)Categories (N) FISH- (207) Interaction p=0.60 for FISH IHC 3+ (1488) Interaction p=0.26 for IHC IHC <3 (299) FISH- & IHC <3 (174) 0.00 0.25 0.50 0.75 1.00 1.25 1.50 RR Note: RR adjusted for ER and nodal status
  • HER2 Amplification and Polysomy • Retrospective tissue analysis of CALGB 9840 patient subset • Polysomy 17 may be associated with increased response to trastuzumab • More study warranted to evaluate this response marker • Counting centromeres may not correlate with degree of HER2 amplification Response Rate, % P Value Paclitaxel Paclitaxel + TrastuzumabPolysomy 17 and FISH ratio < 2 (n = 38) 26 63 .043Kaufman PA, et al. ASCO 2007. Abstract 1009.CEP 17 < 2.2 and FISH ratio < 2 (n = 103) 36 36 NS
  • This Situation is Quite Common• Common clinical scenarios: – FISH neg and IHC 1+/2+ = 40% of cases – FISH ratio 1-2 = 25%-40% of cases – Polysomy 17 = 8%-27% of cases• Does give one pause… – Retest negatives? – Consider trastuzumab if the FISH – ratio = 1-2, or if polysomy 17?
  • ANTI HR + & ANTI HER2 + CROSS TALK• TAMOXIFEN – Oldest targeted agent (1896/1960)• TRASTUZUMAB- Newest targeted agent (1998)
  • CROSS TALK• Endocrine resistance presents major problem• 70% Percent ER positive• develop endocrine resistance eventually
  • The ER Pathway Estrogen Cell Surface E R Cytoplasm Co Nucleus E E A R R DNA .Roop R., Ma C., Future Oncology, In press Transcription of genes
  • Steroid receptor coactivators and ER-dependent gene transcription Histone P/CAF Acetylase CBP Activity SRC Family AIB1 TranscriptionEstradiol-bound ER
  • SERM sensitive estrogen tamoxifen Corepressors Coactivators N-CoR/SMRT NH2 A/B C D E/F COOH AF-1 DBD AF-2/HBD transcription
  • SERM resistant estrogen Coactivators tamoxifen (AIB1,etc.) Corepressors NH2 A/B C D E/F COOH AF-1 DBD AF-2/HBD transcription
  • HER2/neuJNK PI3K-Akt src MAPK estrogen Coactivators N-CoR (AIB1,etc.) tamoxifen SMRT PSer118 NH2 A/B C D E/F COOH AF-1 DBD AF-2/HBD transcription
  • Non-classic Effects of ER RTK: FGFR, IGF- Estrogen 1R, EGFR, HER2 Cell Surface E R E Cytoplasm R Ad P E E R E p R R P MAP AKT C K Nucleus E CoA R E E E T T R R R F F DNARoop R, Ma C. FutureOncology, In press. Transcription of genes
  • Cross-talk between signal transduction and endocrine pathways Growth factor Estrogen IGFR HER2 Trastuzumab Plasma P P membrane P P P AI P SOS PI3-K RAS RAF Cell P survival Akt MEK P ER p90RSK P MAPK P Cytoplasm Cell P P P Basal growth P transcription ER p160 CBP machinery ER Nucleus ERE ER target gene transcription Adapted from Johnston
  • Ligand E ErbB ErbB P P P Ep85 p110 Ras ER Akt MAPK P E P ER Transcription ER-Responsive Element
  • Crosstalk with TK pathways• Endocrine resistance – Cross talk with growth factor (GF) pathways • EGFR, HER2, AKT, MAPK, PI3K • Ligand independent pathway – GF pathways also cause ER independent endocrine resistance – Novel targeted agents to inhibit these pathways • Goal of restoring endocrine sensitivity
  • Her2 and Endocrine Resistance • ER+ and Her2+ breast cancer = 10% – Less than you expect by chance • Interaction between Her2 and ER expression • ERE exist on promoter region of HER2 gene • Her2 pathway facilitates endocrine resistance – Increases ER phosphorylation – Disrupt interaction of ER and co-repressors – AKT and MAPK pathways (both activated by ER and HER2)
  • Adjuvant Endocrine Therapy Study TransATAC: Time to Recurrence by HER2 Status Tamoxifen Patients Anastrozole Patients 35 35 HER2+ n=839 HER2+ n=877 30 HER2 HR=2.30 30 HER2 HR=3.23 P=0.001 P<0.0001 Patients (%) 25 25 20 20 15 15 10 10 5 5 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years Years • HER2+ status was significantly associated with reduced time to recurrence for both tamoxifen and anastrozoleHR = hazard ratio.Update of Dowsett and Allred. Breast Cancer Res Treat. 2006;100(suppl 1):S21. Abstract 48.
  • TransATAC: Time to Recurrence by HER2 Status Patients Events HR HER2– 1526 149 0.66 HER2+ 190 45 0.92 Combined 1786 200 0.72 0.5 1.0 2.0 HR (ANA:TAM) and 95% CI ANA TAM better better • HER2+ statuswas associated with substantially reduced benefit in time to recurrence with adjuvant anastrozole compared with tamoxifenUpdate of Dowsett and Allred. Breast Cancer Res Treat. 2006;100(suppl 1):S21. Abstract 48.
  • TANDEM• Combination ER/HER2 blockade (TANDEM) – 207 patients postmenopausal ER+/HER2+ – Anastrazole +/- trastuzumab for metastatic disease – PFS prolonged for combination • 4.8 vs. 2.4 months – Clinical Benefit Rate 40.7 vs. 20.3 – Increased SAE’s (28% vs. 16%) • Mostly GI toxicities, arthralgias
  • Kaufman, B., et. al., J Clin Oncol, 27:5529-5537 (2009).TANDEM
  • ER+/HER2+ br ca is less responsive to endocrine therapy N=1,925 De Laurentiis et al. Clin. Cancer Res. 11:4741, 2005
  • ER+/PR tumors are resistant totamoxifen (ATAC) From Cui et al. JCO 23:7721, 2005
  • Negative PR is a marker of high HER1/HER2 levels and tamoxifen resistance ER+/PR+ ER+/PR+ Arpino et al. JNCI 97:1254, 2005
  • Negative PR is a marker of high HER1/HER2 levels and tamoxifen resistance ER+/PR+ ER+/PR ER+/PR+ ER+/PR Arpino et al. JNCI 97:1254, 2005
  • Randomized Phase II Trial of Tamoxifen ± Gefitinib in MBC (ZD1839IL/0225) Primary Endpoint 274 Pts R • TTP a Tamoxifen + Gefitinib 20 mg/day 250 mg/day n Secondary Strata 1 d•No prior Tam o • ORR & CBR•Prior Tam > m1yr i Tamoxifen + Placebo Exploratory Strata 2 z 20 mg/day • IHC study of•Prior AI e downstream effectors of erbB family and ER & co-activators (AIB1) Study Chair: Kent Osborne, Baylor College Medicine.PI CK Osborne, Baylor College Medicine
  • Tamoxifen-resistant breast tumors acquire ErbB receptor overexpression Tam-S Tam-R EGFR HER2 Knowlden et al. Endocrinology 144:1032, 2003 10% ‘conversion rate’ to HER2 overexpression in breast cancers that recur (early) on adjuvant tamoxifen (Gutierrez et al. J. Clin. Oncol. 23:2469, 2005)
  • Neoadjuvant aromatase inhibitors (AI) are betterthan tamoxifen against ER+/HER2+ breast cancer Osborne and Schiff J. Clin. Oncol. 23:1616, 2005
  • Gefitinib blocks HER2 signaling and restores letrozole-mediated growth inhibition of breast cancer cells HER2 IP:HER2 P-Tyr Akt 40 35 Ser473 P-Akt Colonies (10-1) 30 25 MAPK 20 15 P-MAPK 10 5 ER 0 AD - + + + + Ser167 P-ER Letrozole - - + - + Gefitinib - - - + + Ser118 P-ER LY294002 - + - - U0126 - -+ - Gefitinib - - - + Shin et al. Submitted
  • Is EGFR/HER2 signaling upregulated after escape from estrogen depletion? Estrogen depletion upregulates EGFR transcription (EGFR gene contains a 96-bp intron fragment that is repressed by estradiol) – Wilson and Chrysogelos, J. Cell Biochem. 85:601, 2002 ER+ breast cancer cells selected for resistance to fulvestrant show EGFR and P-MAPK levels – McClelland et al., Endocrinology 142:2776, 2001 Resistance to fulvestrant does not occur if selection is done in the presence of gefitinib or MAPK inhibitors MCF-7/aromatase cells that become resistant to letrozole overexpress HER2 and P-MAPK; resistance is reversed by gefitinib or MEK inhibitors – Jelovac et al. Cancer Res. 65:5380, 2005; Sabnis et al. ibid 65:3903, 2005
  • Serum HER2 converts to positive at disease progressionin patients with breast cancer on hormonal therapy Letrozole 29/111 (26%) Tamoxifen 32/129 (25%) Lipton et al. Cancer 104:257, 2005
  • EGFR Interaction of with ER less studied than HER2 Like HER2 can activate downstream pathways – MAPK Can form heterodimers with HER2 receptors – Gefitinib prevented heterodimer formation/phosphorylation – Reversed tamoxifen resistance MCF-7 cell line
  • Clinical data 56 postmenopausal patients ER+ and EGFR+ – Gefitinib + Anastrazole or placebo – 4-6 weeks prior to surgery – Primary endpoint cell cycle inhibition (Ki67) – Combination arm showed higher Ki67 reduction – 5.6% relative difference P=0.0054 – Tumor response rates were similar – Showed that combination is tolerable Polychronis, A., et. al., Lancet oncology 6:383-91 (2005).
  • IGF-1 Pathway TK receptor TK activity on transmembrane subunit Has homology with the insulin receptor – IGF-1R and IR can form hybrid receptors – IGF-1R and IR can bind each other’s ligands IGF-1R expressed in ~45% of breast cancers (by IHC)
  • Belinsky, M.G., et. al., Cell Cycle 7:19, 2949-2955 (2008).
  • IGF-1 system and EndocrineResistance Crosstalk with ER pathway similar to other TK IGFR inhibitors + endocrine therapy – Negative trials (two monoclonal Ab) – At least two ongoing (one small molecule TKI, one monoclonal Ab) Data too sparse to make any judgments
  • FGF Pathway Fibroblast growth factor pathway TKR FGF1-FGF4 (4 different genes) – Alternate splicing results in many isoforms – At least 18 ligands that can bind FGF receptors – Activates downstream pathways similar to other TKI
  • FGF pathway 18 different ligands FGFR(1-4) Cell Surface Cytoplasm PI3 Ras K MAP AKT K Gene Growth TF p Expression InvasionRoop R, Ma C., Future Oncology, In press.
  • FGF and endocrine resistance Amplification of FGFR1 in 10% breast CA – FGFR1 amplified cell line resistant to tamoxifen FGFR1 amplified ER+ tumors usually PR- – Tend to have higher Ki67 – ? Role in luminal B breast cancers FGFR3 activation in cell lines decreased sensitivity to endocrine therapy FGFR4 transcription predicts Tamoxifen sensitivity clinically
  • PI3K Activated by TK or G-protein Divided into 3 subclasses (I-III) – Subclass I divided Ia and Ib Heterodimers p110 and p85 – Three isoforms p110 exist (α, β, δ) PI3K activation – Activates AKT and interacts with mTOR
  • Roop R., Ma C., Future Oncology, In press.PI3K/AKT/mTOR Pathway RTK: FGFR, IGF- 1R, EGFR, HER2 PIP p8 2 PTE 5 RAS p110 N PIP 3 PDK1 MAPK mTOR- AKT mTOR- C2 C1 Downstream Target growth, Invasion Proteins
  • Increased PI3K Pathway Activity Promotes endocrine resistance (LTED cells) Ways PI3K can be overactivated – PIK3CA (encodes p110α) mutated 30-40% time – Loss of PTEN – Amplification PIK3CB (encodes p110β) – Mutations in AKT
  • PI3K Inhibition Cell line experiments – ER+ and PIK3CA or PIK3CB silenced (RNAi) – Apoptosis and growth inhibition – PIK3CA ≥ PIK3CB – Combined PIK3CA and PIK3CB greatest – Apoptosis dependent on estrogen depletion – ER negative cell line had no effect
  • Clinical trials PI3K A few clinical trials underway – Endocrine therapy + BKM120 or BEZ235 – Letrozole + XL147 or XL765 Data is very early for this class of drugs
  • mTOR Downstream of PI3K pathway Rational target for treating endocrine resistance Phase III letrozole +/- temsirolimus (metastatic) – negative Phase II trial neo-adjuvant letrozole +/- everolimus – positive TAMRAD – phase II tamoxifen +/- everolimus – positive
  • ONCOGENES AND SIGNALINGMOLECULES THAT BEEN ASSOCIATEDWITH ANTIESTROGEN RESISTANCE Ha-Ras Cox-2 IGF-II Src Heregulin FGF-1/4 Erk (MAPK) VEGF p38Mapk IGF-I receptor Cyclin D1 AIB-1 (SRC-1) and IRS-1 Cyr61 (ligand for Activated Akt p130Cas avb3)
  • Summary/Conclusions High ER and PR+ predict good response to tamoxifen Negative PR and high EGFR/HER2 predict early escape ER+/HER2+ tumors are initially more responsive to AIs than tamoxifen EGFR/HER2 overexpression occurs at the time of escape from hormonal therapy Blockade of EGFR/HER2 is one of many approaches to enhance hormonal therapy action We need new clinical paradigms to elucidate the preferential mechanisms of escape from endocrine therapy as well as to prioritize combinatorial molecular strategies
  • In summary Her2+ Her2- Agressive Non agressive Agressive Non agressive Trastuzumab Trastuzumab +RH+ + CT Hormono PolyCT Hormono Trastuzumab Sequentiel Trastuzumab PolyCTRH- + CT +/- CT MonoCT, PolyCT?
  • Prognosis for Patients WithHER2+ Breast Cancer• HER2 positivity is an independent predictor of poor prognosis• HER2 positivity predicts response and survival• HER2 positivity also correlates with other clinical pathologic variables – Short disease-free interval – Larger tumour size – Positive nodal status – Ductal rather than lobular histology – Ploidy – High S-phase fraction – High nuclear grade – Mutated p53 – Decreased ER and PgR expression HER = human epidermal growth factor receptor; ER = oestrogen receptor; PgR = progesterone receptor. Berger et al. Cancer Res. 1988;48:1238; Chazin et al. Oncogene. 1992;7:1859; Hynes and Stern. Biochim Biophys Acta. 1994;1198:165; O’Reilly et al. Br J Cancer. 1991;63:444; Paik et al. J Clin Oncol. 1990;8:103; Press et al. J Clin Oncol. 1997;15:2894; Slamon et al. Science. 1987;235:177; van de Vijver et al. N Engl J Med. 1988;319:1239.
  • All HER2/neu Might Not Be Created Equal . . .
  • Multiple Approaches to Targeting theHER Pathways Extracellular Trastuzumab domain binding site HER2 receptors Lapatinib Intracellular binding site domain Activation mediates multiple processes
  • Multiple Approaches to Targeting theHER Pathways (cont’d) Truncation of HER2 Truncated HER2 continues to mediate multiple processes
  • Adjuvant Node+, HER2+Unresolved Clinical Questions• Concurrent vs sequential trastuzumab• Which chemotherapy regimen?• Anthracycline or not?• Duration of trastuzumab?• Endocrine therapy plus trastuzumab only?• Trastuzumab alone?
  • Traditional approach Node Node positive negative New Approach ER-, PR- ER+HER-2+ ER++ HER-2- Luminal A Luminal BVirulent Basal-like Virulent Indolent Virulent
  • Indolent ER and PR-Positive BreastCancer E2 ER Breast Cancer •Tamoxifen and P Aromatase Inhibitor- responsive PR
  • More Virulent ER+ Breast Cancer TAM IGFR Her- Her-2 1 ER + AIB1 An estrogen response coactivator PR Schiff R, J Natl Cancer Inst 2003;95:353 - 361
  • Cancer stem cells: are we missing the target? Jones et al. JNCI 96:583, 2004Courtesy of Jenny Chang, MD
  • Cancer stem cells: are we missing the target? Jones et al. JNCI 96:583, 2004
  • Cancer stem cells: are we missing the target? Jones et al. JNCI 96:583, 2004
  • Breast Stem Cell Survival Hedgehog Notch family TGFβ family family Wnt Growth family Hormone /Insulin-like GF EGF Estrogenfamily Progesterone Self-renewal FGFfamily Prolactin Stem Cell Modified from Clarke et al 2005
  • Breast Cancer Lab Report of the FutureJones, Mary A. DOR: 01/31/25MR#:555690 Dx: Breast cancerReceptor status: ER-, Her2-, PR-, AR-Activated pathway: Insulin-like growth factor receptor, AKT,mTOR Basal-like Breast CancerPercentage of patients that have had this pathwayactivated in breast cancer: 16%
  • Breast Cancer Lab Report of the FutureJones, Mary A. DOR: 01/31/25MR#:555690 Dx: Breast cancerReceptor status: ER-, Her2-, PR-, AR-Activated pathway: Insulin-like growth factorreceptor, AKT, mTOR Basal-like Breast Cancer Percentage of patients that have had this pathway activated in breast cancer: 16%Potential therapies:RAD0001ImatinibAnti-IGFR antibodyMetforminExercise, low fat diet
  • Breast Cancer Mortality Will the Progress Continue? Queen- Clinical size panty Trials in Hose – Breast one Cancer size does not fitSubtypes all !
  • The Future Is PossibleI don’t know if heavier than air flightis possible, but I’m committed to livingmy life dedicated to its possibility. - Wilbur Wright