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Targeted therapy in breast cancer

This document discusses targeted therapy for breast cancer. It begins by providing background on declining mortality rates for breast cancer over time. It then discusses how cancers develop multiple alterations that allow uncontrolled growth and outlines six essential alterations in cell physiology that contribute to malignancy. The document discusses molecular alterations that occur in breast cancer progression. It defines targeted therapy as drugs that target uniquely disrupted pathways in cancer cells. The document outlines several targeted therapies for breast cancer including hormonal therapies like tamoxifen, aromatase inhibitors, and fulvestrant. It discusses clinical trials demonstrating the benefits of these therapies. It also discusses therapies that target the HER2 receptor like trastuzumab and lapatinib. In summary, the document provides an overview of targeted

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Targeted Therapy in Breast Cancer Dr N Kannan
Turnaround: decline in mortality rates 35 30 20 15 UK Netherlands Sweden Italy France 10 5 0 19 51 19 54 19 57 19 60 19 63 19 66 19 69 19 72 19 75 19 78 19 81 19 84 19 87 19 90 19 93 19 96 19 99 20 02 Mortality rate 25 Year Veronesi et al 2005
Cancer is a multistep process Cures need to attack many features of tumors Creating own instructions to grow Ignoring body’s own orders to stop growing  Avoiding cell death Growing new blood supply Tissue invasion & metastasis ∞ Endless potential to replicate Adapted from Hanahan and Weinberg, Cell 2000
Six Essential Alterations in Cell Physiology in Malignancy Self-sufficiency in growth signals Evading apoptosis Hanahan & Weinberg, Cell 100:57 (2000) Insensitivity to anti-growth signals Targets for classical drugs? Targets for novel drugs? Sustained angiogenesis Tissue invasion & metastasis Limitless replicative potential
Molecular alterations in breast cancer progression p53 BRCA1 BRCA2 Normal Growth factor, hormone, ER deregulation? Hyperplasia Dysplasia - p53 - BRCA 1, 2 +HER-2 +Cyclin-D +myc In Situ Carcinoma - p53 - BRCA 1, 2 +HER-2 +Cyclin-D +myc Invasive Carcinoma
Targeted Therapy: A definition • Drugs targeted at pathways, processes and physiology which are uniquely disrupted in cancer cells: – – – – Receptors Genes Angiogenesis Tumor pH • these pathways etc. are not so distinct or unique • Smart bombs can cause collateral damage
New cancer treatments present a complex picture… Metastases Inhibitors AntiAngiogenesis EGFR inhibitors mTOR inhibitors HIF inhibitor Proteasome inhibitor Tubulininteracting agents MUC-1 Directed antibodies Src inhibitor MEK inhibitors Raf inhibitor Death Receptors IGF-1R inhibitors HER2-R inhibitors Cell Cycle inhibitors HSP90 inhibitors Mdm2 inhibitor Pro-apoptotic drugs HDAC Inhibitors Farnesyl Transferase Inhibitors Aurora Kinase inhibitor Kinesins
The Homing Pigeons • • • • • Hormonal receptor HER2 inhibitors Tyrosine Kinase Inhibitors VEGF inhibitors PARP inhibitors
Hormonal therapy
Rationale for Hormonal Treatment of Breast Cancer • Endocrine manipulation can: – Decrease levels of estrogen that stimulate tumor growth – Block estrogen interaction with estrogen receptors • Less toxicity • Response rates in metastatic disease: – 30% of unselected patients – ≥50% of ER-positive patients
Hormonal Therapies (FDA indications) • 1st line therapy: – Tamoxifen, anastrozole (Arimidex), letrozole (Femara) • 2nd line therapy: – Fulvestrant (Faslodex), toremifene (Fareston), exemestane (Aromasin) • “Palliative” – Goserelin (LHRH analog, Zoladex)
Hormonal Therapies for Postmenopausal Metastatic • Tamoxifen 20 mg po daily • Aromatase inhibitors: • anastrozole 1 mg po daily, • letrozole 2.5 mg po daily • exemestane 25 mg po daily • Fulvestrant 250 mg IM q month • Megace 40 mg po QID • Aminoglutethimide 250 mg po QID with hydrocortisone
Hormonal therapy for Premenopausal Metastatic • LHRH analog 7.5 mg depot every 28 days • Tamoxifen 20 mg po daily • May be considered with LHRH analog: • anastrozole 1 mg po daily, • letrozole 2.5 mg po daily • exemestane 25 mg po daily • Fulvestrant 250 mg IM q month ?? • Premenopausal dose may be higher? • Megace 40 mg po QID
Treatment Sequence for Postmenopausal Women With Metastatic Breast Cancer First line Second line Antiestrogen or Nonsteroidal Aromatase Inhibitor (AI) Nonsteroidal AI or Antiestrogen if response Third line Steroidal AI if response Fourth line Progestin if response Fifth line Androgen No Response Chemotherapy
Proportion of patients Breast cancer events in ER+/PgR+ subgroup (n=5704) (ATAC) 1.0 0.95 0.9 0.85 HR (95% CI) 0.8 A vs T 0 6 P-value 0.82 (0.65–1.03) 0.091 12 18 24 30 36 - Anastrozole - Tamoxifen - Combination 42 Time to event (months) 48 54
Proportion of patients Breast cancer events in ER+/PgRsubgroup (ATAC) 1.0 0.95 0.9 0.85 0.8 0.75 HR (95% CI) 0.7 A vs T 0 6 0.48 (0.33–0.71) - Anastrozole - Tamoxifen - Combination P-value <0.001 12 18 24 30 36 42 Time to event (months) 48 54
FIRST (Fulvestrant fIRst-line Study Comparing Endocrine Treatments) Phase II, randomized, open-labeled, multi-center Advanced breast cancer ER positive First line Ellis et al SABCS 2008, Abst 6126 Fulvestrant HD (500 mg/mos plus 500 mg D14) Anastrozole 1 mg/d
Kaplain Meier Plot for Time to Progression (TTP)
TEAM Trial DFS: 5 Yrs (ITT) no difference on OS, DFS 1.0 Probability 0.8 HR: 0.97 (95% CI: 0.88-1.08; P = .604) 0.6 0.4 0.2 0 T→E E 1 0 Patients at Risk, n T → E: 4868 E: 4898 5 yrs T → E = 85.4% 5 yrs E = 85.7% 4 3 2 Yrs Since Randomization 111/4660 109/4716 Rea D, et al. SABCS 2009. Abstract 11. 160/4436 117/4533 5 155/4140 108/3377 100/2529 166/4272 133/3575 107/2564
IES Trial ER+/Unknown DFS 100 Exemestane Tamoxifen E = 530/2294 80 70 Absolute difference at 5 yrs = 3.0% (95% CI: 1.3-4.6) 60 50 T = 622/2305 40 30 20 10 0 0 1 Events/Patients at Risk, n E 0/2294 55/2193 81/2193 T 0/2305 2 t ne maert f o dn E t Women Surviving , Alive and Disease Free (%) 90 59/2124 101/2077 Bliss JM, et al. SABCS 2009. Abstract 12. Absolute difference at 8 yrs = 4.4% (95% CI: 1.8-7.2) HR: 0.82 (95% CI: 0.73-0.92; P = .0009) 3 80/2017 98/1948 4 5 Yr From Randomization 70/1915 69/1847 67/1810 65/1745 6 7 8 9 61/1662 70/1596 51/1333 65/1244 53/758 44/676 27+7*/267 22+7*/255
Estrogen signaling interacts with EGFR/HER pathways EGFR/HER estrogen shc ER Src MNAR ER ARO cytoplasm ER ER MAPK/AKT Ligand-independent Ligand-dependent SRC-3 ER nucleus ER ER P TF Growth Survival Angiogenesis
The importance of EGFR as a target EGFR activation Survival/protection from apoptosis Dedifferentiation Signalling cascade Angiogenesis • • • • • • • • Gene activation M G2 G1 S Cell proliferation Metastasis: cell migration and invasion
EGFR Expression associated with poorer prognosis Colon Head and Neck Pancreatic NSCLC Renal cell carcinoma Breast Ovarian Glioma Bladder 25-77% 95-100% 30-89% 40-80% 50-90% 14-91% (45%) 35-70% 40-63% 31-48%
The erB Family • 4 tyrosine kinase receptors • act as signal transductors for cell proliferation and differentiation via the MAPK path – erB-1: aka EGFR and HER1 – erB-2: aka HER2 (no ligands; potent signal) – erB-3: aka HER3 (no TK; uses PI3K/AKT) – erb-4: aka HER4
Multiple Activation Mechanisms for EGFRTK1-4 1. Overexpression of EGFR protein 2. Increased ligand expression/autocrine loop 3. Heterodimerization 4. Lateral signal propagation, cross talk (G-protein coupled receptors, cytokine receptors, cell stress) 5. Mutant EGFR – constitutive activation 6. Decreased phosphatase 7. Altered downstream signal function 1. Raymond E et al. Drugs. 2000;60(suppl 1):15-23. 2. Velu TJ. Mol Cell Endocrinol. 1990;70:205-216. 3. Wells A. Int J Drugs. Endocrinol. Biochem Cell Biol. 1999;31:637-643. 4. Moghal N et al. Curr Opin Cell Biol. 1999;11:190-196. Biol. Biol.
HER2 • HER2 gene (neu, c-erb-2) ecodes a transmembrane gycoprotein receptor • HER 2 is over expressed by 1/4 human breast cancer and correlates with poorer outcome • MoAb against the receptor inhibits the growth of overexpressing cells • 15% chance of PR and 4% Cr as single therapy
Trastuzumab Trials in EBC
Unanswered ? • • • • Duration of trastuzumab Ideal chemotherapy combination Role in equivocal HER2 by FISH Can Anthracyclines be omitted to reduce cardiotoxicity
Trastuzumab Resistance Virtually all HER2+ metastatic breast cancers develop resistance Adjuvant trastuzumab reduces the annual hazard rate by 1/2, ie, 1/2 of recurrences are not prevented Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.
Possible Causes of Trastuzumab Resistance  Suboptimal drug delivery  Altered target expression persistant signaling by full length or trunkated C terminal end  Activation of other receptors EGFR and IGFR  Modified target-regulating proteins PTEN mutation leading to uncoupling of PI 3 kinase pathaway  Alternative pathway signaling Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.
Phase I/II trial of trastuzumab + bevacizumab in relapsed/MBC Phase I COHORT 1 (N=3) Trastuzumab qw + bevacizumab 3 mg/kg day 7 then q2w HER2+ (FISH+) N=9 COHORT 2 (N=3) Trastuzumab qw + bevacizumab 5 mg/kg day 7 then q2w COHORT 3 (N=3) Trastuzumab qw + bevacizumab 10 mg/kg day 7 then q2w • • • Investigator-initiated, investigator held IND First report of 2 humanized MAbs in human subjects Primary endpoints: PK – no evidence for a PK interaction between these humanized MAbs Safety – generally well tolerated, one pt with ↓LVEF Pegram et al. Breast Cancer Res Treat. 2004;88(suppl 1):S124. Abstract 3039.
Phase I trastuzumab + bevacizumab clinical efficacy: 2CR, 3PR, 2SD (>6months) Day 0 9 months Pre-treatment Post-treatment Pegram, et al., SABCS (2004) #3039
Updated Analysis: Phase III Trial of Lapatinib ± Trastuzumab in HER2+ MBC EGF104900 Lapatinib 1500 mg PO QD (n = 148) Heavily pretreated patients with HER2-positive metastatic breast cancer and progression on trastuzumab (N = 296) Optional crossover to trastuzumab arm if PD after 4 wks (n = 77) Lapatinib 1000 mg PO QD + Trastuzumab 4 mg/kg loading dose, then 2 mg/kg IV wkly (n = 148) Stratified by visceral disease and hormone receptor status Blackwell K, et al. SABCS 2009. Abstract 61. Primary endpoint: PFS Secondary endpoints: OS ORR CBR
Updated Analysis: Phase III Trial of Lapatinib ± Trastuzumab in HER2+ MBC • Lapatinib + trastuzumab associated with 26% improvement in OS vs lapatinib alone – Significant survival benefit despite 52% crossover to combination therapy at disease progression • Lapatinib + trastuzumab well tolerated – AEs comparable to lapatinib alone – Higher incidence of serious cardiac AEs with combination vs lapatinib alone • Findings support continued use of trastuzumab • Offers possible options for heavily pretreated patients who progress on trastuzumab
A Phase II Study of Trastuzumab-DM1 (T-DM1), a HER2 Antibody-Drug Conjugate, in Patients with HER2Positive Metastatic Breast Cancer (MBC): Interim Results • DM1 Mertansine is conjugated to trastuzumab via a nonreducible thioether bond to a linker molecule (MCC).1 Average number DM1 molecules/monoclonal antibody=3.5 1. Beeram M., et al. J Clin Oncol. 2008; 26 (May 20 suppl; abstr 1028).
Trastuzumab-DM1 in Heavily Pretreated HER2+ MBC • T-DM1 demonstrated significant clinical benefit in heavily pretreated HER2+ metastatic breast cancer patients – ORR (by independent review): 32.7% – CR + PR + SD ≥ 6 mos (by independent review): 44.5% – Median PFS: 7.3 mos • T-DM1 well tolerated with manageable adverse effects • Offers therapeutic option for heavily pretreated HER2+ patients – Possible utility in earlier therapeutic strategies
Trastuzumab + Heat Shock Protein (HSP) Inhibitor: Tanespimycin  Inhibition of HSP90 chaperone function induces degradation of client protein like HER2  Phase I trial of KOS-953, an HSP90 inhibitor, plus trastuzumab: 17 HER2+ patients with trastuzumab-resistant metastatic breast cancer – 1 partial response, 3 minimal response, 5 prolonged (>4 mo) stable disease  Phase II trial under way Modi S, et al. 42nd ASCO; June 2-6, 2006. Abstract 501.
Change in Serum HER2 and Outcome Change in HER2 Serum Levels DR (median/d) TTP (median/d) OS from Baseline ORR (median/d) <20% decrease 28.4% 230 182 593 >20% decrease 56.5% 369 320 898 P value <.001 .008 <.001 .018 Patients with <20% decrease in serum HER2 have decreased benefit from trastuzumab and should be considered for additional HER2-targeted therapies ORR = objective response rate; DR = duration of response; TTP = time to tumor progression; OS = overall survival. Ali SM, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 500. Reprinted with permission from the American Society of Clinical Oncology.
ER+/PR- Status Compared with ER+/PR+ disease, ER+/PRbreast cancer has – Lower response rate to estrogen deprivation – Worse prognosis – May be dependent on other signaling pathways ER = estrogen receptor; PR = progesterone receptor. Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.
ER+/PR- Breast Cancer and EGFR Inhibition  Presurgical exposure to short-term gefitinib, an EGFR inhibitor, in 43 patients with operable breast cancer  Tissue obtained at surgery – ER+/PR- tumors more likely to show molecular growth inhibition – ER+/PR+ tumors more likely to show molecular growth proliferation  Conclusions – ER+/PR- breast cancer is growth factor dependent – ER+/PR- patients may be more likely to benefit from EGFR inhibition ER = estrogen receptor; PR = progesterone receptor; EGFR = epidermal growth factor receptor. Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.
VEGF inhibition
Vascularization is required to convert an in-situ carcinoma into a rapidly growing malignancy Premalignant stage Malignant tumor (Avascular tumor) (Angiogenic switch) Tumor growth (Vascularized tumor) Vascular invasion Dormant micrometastasis Overt metastasis (Tumor cell intravasation) (Seeding in distant organs) (Secondary angiogenesis) Stages at which angiogenesis plays a role in tumor progression Adapted from Poon RT, et al. J Clin Oncol. 2001;19:1207–25
Tumor characteristics and environment promote VEGF expression Hypoxia EGF PDGF IGF-1 IL-8 bFGF Binding and activation of VEGFR VEGF release COX-2 NO Oncogenes Increased expression (MMP, tPA, uPA, uPAr, eNOS, etc.) P– P– –P –P Survival Proliferation Migration ANGIOGENESIS PDGF = platelet-derived growth factor; IGF-1 = insulin-like growth factor 1 IL-8 = insulin-like growth factor 8 Permeability
Bevacizumab (Avastin)- first effective anti-VEGF targeted agent • Bevacizumab (Avastin) - a major breakthrough in cancer treatment – Monoclonal antibody – Mode of action that differs fundamentally from chemotherapy – Novel target – antiVEGF/angiogenesis – First agent to specifically target VEGF and show improved survival
Progression-free survival proportion E2100 MBC: progression-free survival 1.0 0.9 0.8 Paclitaxel + Avastin: 10.97 months 0.7 Paclitaxel: 6.11 months 0.6 0.5 0.4 HR=0.49 p=<0.001 0.3 0.2 0.1 0 6.11 0 10.97 10 20 Months 30
AVADO: Bevacizumab + Docetaxel in First-line Treatment of Advanced Breast Cancer • Adding bevacizumab to docetaxel in first-line treatment of advanced breast cancer improves PFS but not OS[1] – Previous analysis: addition of bevacizumab to docetaxel significantly improved PFS in locally recurrent or metastatic breast cancer with both 7.5-mg/kg and 15.0mg/kg doses[2] • Updated results confirmed preliminary findings: addition of bevacizumab 15 mg/kg to docetaxel – Significantly increased ORR – Prolonged PFS – Toxicity profile similar among treatment arms 1. Miles DW, et al. SABCS 2009. Abstract 41. 2. Miles D, et al. ASCO 2008. Abstract LBA1011.
RIBBON-2: Phase III Trial of SecondLine Bevacizumab + Chemotherapy: PFS Primary Endpoint of PFS, ITT Population Proportion of Progression Free 1.0 Chemo/placebo (n = 225) Chemo/bevacizumab (n = 459) 0.8 0.6 Median PFS: 7.2 vs. 5.1 mos HR: 0.78 (P = .0072) 0.4 0.2 0 0 2 4 6 8 10 12 Patients at Risk, n Chemo/placebo 225 165 129 93 77 44 Chemo/bev 459 381 334 254 190 130 33 87 Brufsky A, et al. SABCS 2009. Abstract 42. 14 16 18 20 22 Duration of PFS (Mos) 19 47 12 27 8 18 5 9 4 5 24 26 28 30 32 34 3 2 1 1 1 1 0 0 0 0 0 0
RIBBON-2: Phase III Trial of SecondLine Bevacizumab + Chemotherapy: ORR* 45 40 Response (%) 35 CR PR 30 ORR = 29.6% 1.1% 25 P = .0193† ORR = 39.5% 2.2% 28.5% 37.3% 20 15 10 5 0 Chemo/Placebo Chemo/Bevacizumab *Includes only patients with measurable disease at baseline. † Not significant at pre-specified α = 0.01 Duration of response: 7.3 mos in chemo/bevacizumab vs 7.5 mos in chemo/placebo Brufsky A, et al. SABCS 2009. Abstract 42.
RIBBON-2: Phase III Trial of SecondLine Bevacizumab + Chemotherapy in MBC • Study met primary endpoint – Improved PFS with combination bevacizumab + standard chemotherapy vs chemotherapy alone for second-line treatment of HER2-negative MBC • Observed improvement in PFS supported by secondary endpoint of ORR – OS data immature • Bevacizumab combination chemotherapy regimens well tolerated with no unexpected adverse events • Feasible to consider bevacizumab in second-line setting Brufsky A, et al. SABCS 2009. Abstract 42.
RIBBON-2: Phase III Trial of SecondLine Bevacizumab + Chemotherapy in MBC • Study met primary endpoint – Improved PFS with combination bevacizumab + standard chemotherapy vs chemotherapy alone for second-line treatment of HER2-negative MBC • Observed improvement in PFS supported by secondary endpoint of ORR – OS data immature • Bevacizumab combination chemotherapy regimens well tolerated with no unexpected adverse events • Feasible to consider bevacizumab in second-line setting Brufsky A, et al. SABCS 2009. Abstract 42.
Tyrosine Kinase Inhibitors
Turning Off the EGFR-TK Signal At the Source1-3  Inhibition of the EGFR-TK itself—inside the cell— completely inhibits EGFRTK signaling regardless of the triggering event Inhibition of apoptosis Proliferation Invasion Metastasis Angiogenesis 1. Leserer M et al. IUBMB Life. 2000;49:405-409. 2. Raymond E et al. Drugs. 2000;60(suppl 1):15-23. 3. Prenzel N et al. Endocr Relat Cancer. 2001;8:11-31.
Drugs • • • • Lapatinib Sorafenib Sunitinib Motesanib (pan VEGF inhibitor)
Tykerb (lapatinib)—A Dual Receptor Tyrosine Kinase Inhibitor • Potent, oral, reversible dual tyrosine kinase inhibitor • Binds to ATP site of erbB-1 and erbB-2 receptor kinases, blocking kinase activity and downstream signaling
Lapatinib • Phase 3 RCT 392 pts HER2+ve, progressed following herceptin N Engl J Med. 2006 355(26): 2733-43 – Capecitabine vs Capecitabine + Lapatinib 1250mg daily continuously – PFS 4.4 vs 8.4 months • Lapatinib is effective in patients who have been previously treated with Anthracyclines , Taxanes and Herceptin.
Lapatinib Monotherapy in Inflammatory Breast Cancer Cohort A: erbB2+ (n = 24) Partial response Cohort B: erbB1+/erbB2(n = 12) 62% 8.3% erbB2 overexpression, but not erbB1 expression alone, predicts for sensitivity to lapatinib in inflammatory breast cancer Spector NL, et al. 42nd ASCO; June 2-6, 2006. Abstract 502
Lapatinib in ER positive disease • Cross talk between EGFR and ER responsible for endocrine Rx resistance, • Lapatinib upregulates ER • EGF 30008 RCT Phase III • Lapatinib + Letrozole vs Letrozole – PFS 11.9 vs 10.9 – PFS 8.2 vs 3.0 for HER2 positive
Sorafenib (in advanced metastatic Her 2 negative breast cancer) • SOLTI 0701 – Capeciabine vs Capecitabine + Sorafenib – PFS 4.1 vs 6.4 months – Response better when patients who had recd prior chemo were excluded • TIES – – – – company funded trials Paclitaxel vs Paclitaxel +Sorafenib PFS 5.6 vs 6.9 months Deaths in indian arm skewed results TTP 5.6 vs 8.1 months (p 0.017)
Motesanib • CIRG/TORI 010 trial PFS Response rate Paclitaxel 9 41.49 Pacli + Motesanib 9.49 49.45 Pacli + Bevacizumab 11.5* 51.55 • High GI and Hepatobiliary toxicity * Better response than ECOG 2100
PARP Inhibitors
Poly ADP ribose Polymerase • Enzyme central to DNA repair (base excision repair pathway) of single stand breaks • 17 iso enzymes detected so far of which PARP1 and 2 are located in the nucleus • Enhances the effect of cytotoxic drugs and RT • PARP 1 levels are elevated in TNBC • It is a valuable approach to BRCA 1 and 2 associated breast cancers and ‘Basal type’ TNBC
Mechanism of action
Caspase Cascade
mTOR • It acts as a central regulator of cell proliferation, angiogenesis, and cell metabolism • It is a key intracellular point of convergence for a number of signaling pathways that are abnormally activated in many types of cancer • It appears to be a stable target that does not mutate • Inhibiting mTOR: – May inhibit abnormal cell proliferation, tumor angiogenesis, and abnormal cell metabolism – May potentially enhance the efficacy of other cancer treatments
Temsolimus, Everolimus • The efficacy of the drug in combination with AI depends on cell proliferation dependance on the PI3K/Akt/mTOR pathway • High levels of a downstream molecule (pS6240 kinase) suggests response to the combination
Denosumab—Mechanism of Action RANKL – A key mediator of osteoclast formation, function, and survival, thus, a pivotal factor in much of the pathologic bone destruction associated with bone metastases Denosumab – Binds to and inhibits RANKL, potentially reducing bone destruction in patients with breast cancer RANKL = receptor activator of NFKappa B ligand. Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.
New drugs
NCI Phase II Clinical Trials for Breast Cancer • BMS-247550 – Epothilone B analog – Microtubule stabilizer – Active in taxane resistant tumors • Phase II trial – Measurable disease – Metastatic or locally advanced patients for whom you would consider taxane therapy • Tamoxifen/ Zarnestra – Oral farnesyl transferase inhibitor, (inhibits ras oncogene pathway) – May reverse tamoxifen resistance • Phase II trial – Measurable disease – Hormone receptor positive • T cell depleted allogeneic stem cell transplant – Immunotherapy to induce a graft vs tumor effect • Phase II trial – Measurable disease – HLA matched sibling donor – Prior chemotherapy
Each breast cancer has unique features New Breast Cancer Taxonomy Basal-like HER-2 “Normal” Luminal B Luminal A Sorlie T et al, PNAS 2001
Conclusions • Targeted therapies which improve the therapeutic index are the future of anti-cancer therapy • Advances in molecular pathology will provide the means to identify the targets and will be used to subtype tumours and will provide predict response to therapy and provide prognostic information
Future therapy Breast Ca Target Identifying and Matching Integrated Device (TIMID) Customized prescription Rx: ……mab …….cin …….erb ……ib ……ane ……..rib

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Targeted therapy in breast cancer

  • 1.
  • 2.
    Turnaround: decline in mortalityrates 35 30 20 15 UK Netherlands Sweden Italy France 10 5 0 19 51 19 54 19 57 19 60 19 63 19 66 19 69 19 72 19 75 19 78 19 81 19 84 19 87 19 90 19 93 19 96 19 99 20 02 Mortality rate 25 Year Veronesi et al 2005
  • 4.
    Cancer is amultistep process Cures need to attack many features of tumors Creating own instructions to grow Ignoring body’s own orders to stop growing  Avoiding cell death Growing new blood supply Tissue invasion & metastasis ∞ Endless potential to replicate Adapted from Hanahan and Weinberg, Cell 2000
  • 5.
    Six Essential Alterations inCell Physiology in Malignancy Self-sufficiency in growth signals Evading apoptosis Hanahan & Weinberg, Cell 100:57 (2000) Insensitivity to anti-growth signals Targets for classical drugs? Targets for novel drugs? Sustained angiogenesis Tissue invasion & metastasis Limitless replicative potential
  • 6.
    Molecular alterations inbreast cancer progression p53 BRCA1 BRCA2 Normal Growth factor, hormone, ER deregulation? Hyperplasia Dysplasia - p53 - BRCA 1, 2 +HER-2 +Cyclin-D +myc In Situ Carcinoma - p53 - BRCA 1, 2 +HER-2 +Cyclin-D +myc Invasive Carcinoma
  • 7.
    Targeted Therapy: Adefinition • Drugs targeted at pathways, processes and physiology which are uniquely disrupted in cancer cells: – – – – Receptors Genes Angiogenesis Tumor pH • these pathways etc. are not so distinct or unique • Smart bombs can cause collateral damage
  • 8.
    New cancer treatmentspresent a complex picture… Metastases Inhibitors AntiAngiogenesis EGFR inhibitors mTOR inhibitors HIF inhibitor Proteasome inhibitor Tubulininteracting agents MUC-1 Directed antibodies Src inhibitor MEK inhibitors Raf inhibitor Death Receptors IGF-1R inhibitors HER2-R inhibitors Cell Cycle inhibitors HSP90 inhibitors Mdm2 inhibitor Pro-apoptotic drugs HDAC Inhibitors Farnesyl Transferase Inhibitors Aurora Kinase inhibitor Kinesins
  • 9.
    The Homing Pigeons • • • • • Hormonalreceptor HER2 inhibitors Tyrosine Kinase Inhibitors VEGF inhibitors PARP inhibitors
  • 10.
  • 12.
    Rationale for HormonalTreatment of Breast Cancer • Endocrine manipulation can: – Decrease levels of estrogen that stimulate tumor growth – Block estrogen interaction with estrogen receptors • Less toxicity • Response rates in metastatic disease: – 30% of unselected patients – ≥50% of ER-positive patients
  • 13.
    Hormonal Therapies (FDA indications) •1st line therapy: – Tamoxifen, anastrozole (Arimidex), letrozole (Femara) • 2nd line therapy: – Fulvestrant (Faslodex), toremifene (Fareston), exemestane (Aromasin) • “Palliative” – Goserelin (LHRH analog, Zoladex)
  • 14.
    Hormonal Therapies forPostmenopausal Metastatic • Tamoxifen 20 mg po daily • Aromatase inhibitors: • anastrozole 1 mg po daily, • letrozole 2.5 mg po daily • exemestane 25 mg po daily • Fulvestrant 250 mg IM q month • Megace 40 mg po QID • Aminoglutethimide 250 mg po QID with hydrocortisone
  • 15.
    Hormonal therapy forPremenopausal Metastatic • LHRH analog 7.5 mg depot every 28 days • Tamoxifen 20 mg po daily • May be considered with LHRH analog: • anastrozole 1 mg po daily, • letrozole 2.5 mg po daily • exemestane 25 mg po daily • Fulvestrant 250 mg IM q month ?? • Premenopausal dose may be higher? • Megace 40 mg po QID
  • 16.
    Treatment Sequence forPostmenopausal Women With Metastatic Breast Cancer First line Second line Antiestrogen or Nonsteroidal Aromatase Inhibitor (AI) Nonsteroidal AI or Antiestrogen if response Third line Steroidal AI if response Fourth line Progestin if response Fifth line Androgen No Response Chemotherapy
  • 17.
    Proportion of patients Breastcancer events in ER+/PgR+ subgroup (n=5704) (ATAC) 1.0 0.95 0.9 0.85 HR (95% CI) 0.8 A vs T 0 6 P-value 0.82 (0.65–1.03) 0.091 12 18 24 30 36 - Anastrozole - Tamoxifen - Combination 42 Time to event (months) 48 54
  • 18.
    Proportion of patients Breastcancer events in ER+/PgRsubgroup (ATAC) 1.0 0.95 0.9 0.85 0.8 0.75 HR (95% CI) 0.7 A vs T 0 6 0.48 (0.33–0.71) - Anastrozole - Tamoxifen - Combination P-value <0.001 12 18 24 30 36 42 Time to event (months) 48 54
  • 21.
    FIRST (Fulvestrant fIRst-lineStudy Comparing Endocrine Treatments) Phase II, randomized, open-labeled, multi-center Advanced breast cancer ER positive First line Ellis et al SABCS 2008, Abst 6126 Fulvestrant HD (500 mg/mos plus 500 mg D14) Anastrozole 1 mg/d
  • 22.
    Kaplain Meier Plotfor Time to Progression (TTP)
  • 23.
    TEAM Trial DFS:5 Yrs (ITT) no difference on OS, DFS 1.0 Probability 0.8 HR: 0.97 (95% CI: 0.88-1.08; P = .604) 0.6 0.4 0.2 0 T→E E 1 0 Patients at Risk, n T → E: 4868 E: 4898 5 yrs T → E = 85.4% 5 yrs E = 85.7% 4 3 2 Yrs Since Randomization 111/4660 109/4716 Rea D, et al. SABCS 2009. Abstract 11. 160/4436 117/4533 5 155/4140 108/3377 100/2529 166/4272 133/3575 107/2564
  • 24.
    IES Trial ER+/Unknown DFS 100 Exemestane Tamoxifen E= 530/2294 80 70 Absolute difference at 5 yrs = 3.0% (95% CI: 1.3-4.6) 60 50 T = 622/2305 40 30 20 10 0 0 1 Events/Patients at Risk, n E 0/2294 55/2193 81/2193 T 0/2305 2 t ne maert f o dn E t Women Surviving , Alive and Disease Free (%) 90 59/2124 101/2077 Bliss JM, et al. SABCS 2009. Abstract 12. Absolute difference at 8 yrs = 4.4% (95% CI: 1.8-7.2) HR: 0.82 (95% CI: 0.73-0.92; P = .0009) 3 80/2017 98/1948 4 5 Yr From Randomization 70/1915 69/1847 67/1810 65/1745 6 7 8 9 61/1662 70/1596 51/1333 65/1244 53/758 44/676 27+7*/267 22+7*/255
  • 27.
    Estrogen signaling interactswith EGFR/HER pathways EGFR/HER estrogen shc ER Src MNAR ER ARO cytoplasm ER ER MAPK/AKT Ligand-independent Ligand-dependent SRC-3 ER nucleus ER ER P TF Growth Survival Angiogenesis
  • 28.
    The importance ofEGFR as a target EGFR activation Survival/protection from apoptosis Dedifferentiation Signalling cascade Angiogenesis • • • • • • • • Gene activation M G2 G1 S Cell proliferation Metastasis: cell migration and invasion
  • 29.
    EGFR Expression associatedwith poorer prognosis Colon Head and Neck Pancreatic NSCLC Renal cell carcinoma Breast Ovarian Glioma Bladder 25-77% 95-100% 30-89% 40-80% 50-90% 14-91% (45%) 35-70% 40-63% 31-48%
  • 30.
    The erB Family •4 tyrosine kinase receptors • act as signal transductors for cell proliferation and differentiation via the MAPK path – erB-1: aka EGFR and HER1 – erB-2: aka HER2 (no ligands; potent signal) – erB-3: aka HER3 (no TK; uses PI3K/AKT) – erb-4: aka HER4
  • 31.
    Multiple Activation Mechanismsfor EGFRTK1-4 1. Overexpression of EGFR protein 2. Increased ligand expression/autocrine loop 3. Heterodimerization 4. Lateral signal propagation, cross talk (G-protein coupled receptors, cytokine receptors, cell stress) 5. Mutant EGFR – constitutive activation 6. Decreased phosphatase 7. Altered downstream signal function 1. Raymond E et al. Drugs. 2000;60(suppl 1):15-23. 2. Velu TJ. Mol Cell Endocrinol. 1990;70:205-216. 3. Wells A. Int J Drugs. Endocrinol. Biochem Cell Biol. 1999;31:637-643. 4. Moghal N et al. Curr Opin Cell Biol. 1999;11:190-196. Biol. Biol.
  • 32.
    HER2 • HER2 gene(neu, c-erb-2) ecodes a transmembrane gycoprotein receptor • HER 2 is over expressed by 1/4 human breast cancer and correlates with poorer outcome • MoAb against the receptor inhibits the growth of overexpressing cells • 15% chance of PR and 4% Cr as single therapy
  • 34.
  • 36.
    Unanswered ? • • • • Duration oftrastuzumab Ideal chemotherapy combination Role in equivocal HER2 by FISH Can Anthracyclines be omitted to reduce cardiotoxicity
  • 38.
    Trastuzumab Resistance Virtually allHER2+ metastatic breast cancers develop resistance Adjuvant trastuzumab reduces the annual hazard rate by 1/2, ie, 1/2 of recurrences are not prevented Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.
  • 40.
    Possible Causes ofTrastuzumab Resistance  Suboptimal drug delivery  Altered target expression persistant signaling by full length or trunkated C terminal end  Activation of other receptors EGFR and IGFR  Modified target-regulating proteins PTEN mutation leading to uncoupling of PI 3 kinase pathaway  Alternative pathway signaling Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.
  • 41.
    Phase I/II trialof trastuzumab + bevacizumab in relapsed/MBC Phase I COHORT 1 (N=3) Trastuzumab qw + bevacizumab 3 mg/kg day 7 then q2w HER2+ (FISH+) N=9 COHORT 2 (N=3) Trastuzumab qw + bevacizumab 5 mg/kg day 7 then q2w COHORT 3 (N=3) Trastuzumab qw + bevacizumab 10 mg/kg day 7 then q2w • • • Investigator-initiated, investigator held IND First report of 2 humanized MAbs in human subjects Primary endpoints: PK – no evidence for a PK interaction between these humanized MAbs Safety – generally well tolerated, one pt with ↓LVEF Pegram et al. Breast Cancer Res Treat. 2004;88(suppl 1):S124. Abstract 3039.
  • 42.
    Phase I trastuzumab+ bevacizumab clinical efficacy: 2CR, 3PR, 2SD (>6months) Day 0 9 months Pre-treatment Post-treatment Pegram, et al., SABCS (2004) #3039
  • 43.
    Updated Analysis: PhaseIII Trial of Lapatinib ± Trastuzumab in HER2+ MBC EGF104900 Lapatinib 1500 mg PO QD (n = 148) Heavily pretreated patients with HER2-positive metastatic breast cancer and progression on trastuzumab (N = 296) Optional crossover to trastuzumab arm if PD after 4 wks (n = 77) Lapatinib 1000 mg PO QD + Trastuzumab 4 mg/kg loading dose, then 2 mg/kg IV wkly (n = 148) Stratified by visceral disease and hormone receptor status Blackwell K, et al. SABCS 2009. Abstract 61. Primary endpoint: PFS Secondary endpoints: OS ORR CBR
  • 44.
    Updated Analysis: PhaseIII Trial of Lapatinib ± Trastuzumab in HER2+ MBC • Lapatinib + trastuzumab associated with 26% improvement in OS vs lapatinib alone – Significant survival benefit despite 52% crossover to combination therapy at disease progression • Lapatinib + trastuzumab well tolerated – AEs comparable to lapatinib alone – Higher incidence of serious cardiac AEs with combination vs lapatinib alone • Findings support continued use of trastuzumab • Offers possible options for heavily pretreated patients who progress on trastuzumab
  • 45.
    A Phase IIStudy of Trastuzumab-DM1 (T-DM1), a HER2 Antibody-Drug Conjugate, in Patients with HER2Positive Metastatic Breast Cancer (MBC): Interim Results • DM1 Mertansine is conjugated to trastuzumab via a nonreducible thioether bond to a linker molecule (MCC).1 Average number DM1 molecules/monoclonal antibody=3.5 1. Beeram M., et al. J Clin Oncol. 2008; 26 (May 20 suppl; abstr 1028).
  • 46.
    Trastuzumab-DM1 in Heavily PretreatedHER2+ MBC • T-DM1 demonstrated significant clinical benefit in heavily pretreated HER2+ metastatic breast cancer patients – ORR (by independent review): 32.7% – CR + PR + SD ≥ 6 mos (by independent review): 44.5% – Median PFS: 7.3 mos • T-DM1 well tolerated with manageable adverse effects • Offers therapeutic option for heavily pretreated HER2+ patients – Possible utility in earlier therapeutic strategies
  • 47.
    Trastuzumab + HeatShock Protein (HSP) Inhibitor: Tanespimycin  Inhibition of HSP90 chaperone function induces degradation of client protein like HER2  Phase I trial of KOS-953, an HSP90 inhibitor, plus trastuzumab: 17 HER2+ patients with trastuzumab-resistant metastatic breast cancer – 1 partial response, 3 minimal response, 5 prolonged (>4 mo) stable disease  Phase II trial under way Modi S, et al. 42nd ASCO; June 2-6, 2006. Abstract 501.
  • 48.
    Change in SerumHER2 and Outcome Change in HER2 Serum Levels DR (median/d) TTP (median/d) OS from Baseline ORR (median/d) <20% decrease 28.4% 230 182 593 >20% decrease 56.5% 369 320 898 P value <.001 .008 <.001 .018 Patients with <20% decrease in serum HER2 have decreased benefit from trastuzumab and should be considered for additional HER2-targeted therapies ORR = objective response rate; DR = duration of response; TTP = time to tumor progression; OS = overall survival. Ali SM, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 500. Reprinted with permission from the American Society of Clinical Oncology.
  • 49.
    ER+/PR- Status Compared withER+/PR+ disease, ER+/PRbreast cancer has – Lower response rate to estrogen deprivation – Worse prognosis – May be dependent on other signaling pathways ER = estrogen receptor; PR = progesterone receptor. Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.
  • 50.
    ER+/PR- Breast Cancerand EGFR Inhibition  Presurgical exposure to short-term gefitinib, an EGFR inhibitor, in 43 patients with operable breast cancer  Tissue obtained at surgery – ER+/PR- tumors more likely to show molecular growth inhibition – ER+/PR+ tumors more likely to show molecular growth proliferation  Conclusions – ER+/PR- breast cancer is growth factor dependent – ER+/PR- patients may be more likely to benefit from EGFR inhibition ER = estrogen receptor; PR = progesterone receptor; EGFR = epidermal growth factor receptor. Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.
  • 51.
  • 52.
    Vascularization is requiredto convert an in-situ carcinoma into a rapidly growing malignancy Premalignant stage Malignant tumor (Avascular tumor) (Angiogenic switch) Tumor growth (Vascularized tumor) Vascular invasion Dormant micrometastasis Overt metastasis (Tumor cell intravasation) (Seeding in distant organs) (Secondary angiogenesis) Stages at which angiogenesis plays a role in tumor progression Adapted from Poon RT, et al. J Clin Oncol. 2001;19:1207–25
  • 53.
    Tumor characteristics andenvironment promote VEGF expression Hypoxia EGF PDGF IGF-1 IL-8 bFGF Binding and activation of VEGFR VEGF release COX-2 NO Oncogenes Increased expression (MMP, tPA, uPA, uPAr, eNOS, etc.) P– P– –P –P Survival Proliferation Migration ANGIOGENESIS PDGF = platelet-derived growth factor; IGF-1 = insulin-like growth factor 1 IL-8 = insulin-like growth factor 8 Permeability
  • 54.
    Bevacizumab (Avastin)- first effectiveanti-VEGF targeted agent • Bevacizumab (Avastin) - a major breakthrough in cancer treatment – Monoclonal antibody – Mode of action that differs fundamentally from chemotherapy – Novel target – antiVEGF/angiogenesis – First agent to specifically target VEGF and show improved survival
  • 55.
    Progression-free survival proportion E2100MBC: progression-free survival 1.0 0.9 0.8 Paclitaxel + Avastin: 10.97 months 0.7 Paclitaxel: 6.11 months 0.6 0.5 0.4 HR=0.49 p=<0.001 0.3 0.2 0.1 0 6.11 0 10.97 10 20 Months 30
  • 56.
    AVADO: Bevacizumab +Docetaxel in First-line Treatment of Advanced Breast Cancer • Adding bevacizumab to docetaxel in first-line treatment of advanced breast cancer improves PFS but not OS[1] – Previous analysis: addition of bevacizumab to docetaxel significantly improved PFS in locally recurrent or metastatic breast cancer with both 7.5-mg/kg and 15.0mg/kg doses[2] • Updated results confirmed preliminary findings: addition of bevacizumab 15 mg/kg to docetaxel – Significantly increased ORR – Prolonged PFS – Toxicity profile similar among treatment arms 1. Miles DW, et al. SABCS 2009. Abstract 41. 2. Miles D, et al. ASCO 2008. Abstract LBA1011.
  • 59.
    RIBBON-2: Phase IIITrial of SecondLine Bevacizumab + Chemotherapy: PFS Primary Endpoint of PFS, ITT Population Proportion of Progression Free 1.0 Chemo/placebo (n = 225) Chemo/bevacizumab (n = 459) 0.8 0.6 Median PFS: 7.2 vs. 5.1 mos HR: 0.78 (P = .0072) 0.4 0.2 0 0 2 4 6 8 10 12 Patients at Risk, n Chemo/placebo 225 165 129 93 77 44 Chemo/bev 459 381 334 254 190 130 33 87 Brufsky A, et al. SABCS 2009. Abstract 42. 14 16 18 20 22 Duration of PFS (Mos) 19 47 12 27 8 18 5 9 4 5 24 26 28 30 32 34 3 2 1 1 1 1 0 0 0 0 0 0
  • 60.
    RIBBON-2: Phase IIITrial of SecondLine Bevacizumab + Chemotherapy: ORR* 45 40 Response (%) 35 CR PR 30 ORR = 29.6% 1.1% 25 P = .0193† ORR = 39.5% 2.2% 28.5% 37.3% 20 15 10 5 0 Chemo/Placebo Chemo/Bevacizumab *Includes only patients with measurable disease at baseline. † Not significant at pre-specified α = 0.01 Duration of response: 7.3 mos in chemo/bevacizumab vs 7.5 mos in chemo/placebo Brufsky A, et al. SABCS 2009. Abstract 42.
  • 61.
    RIBBON-2: Phase IIITrial of SecondLine Bevacizumab + Chemotherapy in MBC • Study met primary endpoint – Improved PFS with combination bevacizumab + standard chemotherapy vs chemotherapy alone for second-line treatment of HER2-negative MBC • Observed improvement in PFS supported by secondary endpoint of ORR – OS data immature • Bevacizumab combination chemotherapy regimens well tolerated with no unexpected adverse events • Feasible to consider bevacizumab in second-line setting Brufsky A, et al. SABCS 2009. Abstract 42.
  • 62.
    RIBBON-2: Phase IIITrial of SecondLine Bevacizumab + Chemotherapy in MBC • Study met primary endpoint – Improved PFS with combination bevacizumab + standard chemotherapy vs chemotherapy alone for second-line treatment of HER2-negative MBC • Observed improvement in PFS supported by secondary endpoint of ORR – OS data immature • Bevacizumab combination chemotherapy regimens well tolerated with no unexpected adverse events • Feasible to consider bevacizumab in second-line setting Brufsky A, et al. SABCS 2009. Abstract 42.
  • 63.
  • 64.
    Turning Off theEGFR-TK Signal At the Source1-3  Inhibition of the EGFR-TK itself—inside the cell— completely inhibits EGFRTK signaling regardless of the triggering event Inhibition of apoptosis Proliferation Invasion Metastasis Angiogenesis 1. Leserer M et al. IUBMB Life. 2000;49:405-409. 2. Raymond E et al. Drugs. 2000;60(suppl 1):15-23. 3. Prenzel N et al. Endocr Relat Cancer. 2001;8:11-31.
  • 65.
  • 66.
    Tykerb (lapatinib)—A DualReceptor Tyrosine Kinase Inhibitor • Potent, oral, reversible dual tyrosine kinase inhibitor • Binds to ATP site of erbB-1 and erbB-2 receptor kinases, blocking kinase activity and downstream signaling
  • 67.
    Lapatinib • Phase 3RCT 392 pts HER2+ve, progressed following herceptin N Engl J Med. 2006 355(26): 2733-43 – Capecitabine vs Capecitabine + Lapatinib 1250mg daily continuously – PFS 4.4 vs 8.4 months • Lapatinib is effective in patients who have been previously treated with Anthracyclines , Taxanes and Herceptin.
  • 69.
    Lapatinib Monotherapy in InflammatoryBreast Cancer Cohort A: erbB2+ (n = 24) Partial response Cohort B: erbB1+/erbB2(n = 12) 62% 8.3% erbB2 overexpression, but not erbB1 expression alone, predicts for sensitivity to lapatinib in inflammatory breast cancer Spector NL, et al. 42nd ASCO; June 2-6, 2006. Abstract 502
  • 70.
    Lapatinib in ERpositive disease • Cross talk between EGFR and ER responsible for endocrine Rx resistance, • Lapatinib upregulates ER • EGF 30008 RCT Phase III • Lapatinib + Letrozole vs Letrozole – PFS 11.9 vs 10.9 – PFS 8.2 vs 3.0 for HER2 positive
  • 71.
    Sorafenib (in advanced metastaticHer 2 negative breast cancer) • SOLTI 0701 – Capeciabine vs Capecitabine + Sorafenib – PFS 4.1 vs 6.4 months – Response better when patients who had recd prior chemo were excluded • TIES – – – – company funded trials Paclitaxel vs Paclitaxel +Sorafenib PFS 5.6 vs 6.9 months Deaths in indian arm skewed results TTP 5.6 vs 8.1 months (p 0.017)
  • 72.
    Motesanib • CIRG/TORI 010trial PFS Response rate Paclitaxel 9 41.49 Pacli + Motesanib 9.49 49.45 Pacli + Bevacizumab 11.5* 51.55 • High GI and Hepatobiliary toxicity * Better response than ECOG 2100
  • 73.
  • 74.
    Poly ADP ribosePolymerase • Enzyme central to DNA repair (base excision repair pathway) of single stand breaks • 17 iso enzymes detected so far of which PARP1 and 2 are located in the nucleus • Enhances the effect of cytotoxic drugs and RT • PARP 1 levels are elevated in TNBC • It is a valuable approach to BRCA 1 and 2 associated breast cancers and ‘Basal type’ TNBC
  • 75.
  • 79.
  • 80.
    mTOR • It actsas a central regulator of cell proliferation, angiogenesis, and cell metabolism • It is a key intracellular point of convergence for a number of signaling pathways that are abnormally activated in many types of cancer • It appears to be a stable target that does not mutate • Inhibiting mTOR: – May inhibit abnormal cell proliferation, tumor angiogenesis, and abnormal cell metabolism – May potentially enhance the efficacy of other cancer treatments
  • 82.
    Temsolimus, Everolimus • Theefficacy of the drug in combination with AI depends on cell proliferation dependance on the PI3K/Akt/mTOR pathway • High levels of a downstream molecule (pS6240 kinase) suggests response to the combination
  • 83.
    Denosumab—Mechanism of Action RANKL –A key mediator of osteoclast formation, function, and survival, thus, a pivotal factor in much of the pathologic bone destruction associated with bone metastases Denosumab – Binds to and inhibits RANKL, potentially reducing bone destruction in patients with breast cancer RANKL = receptor activator of NFKappa B ligand. Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.
  • 85.
  • 86.
    NCI Phase IIClinical Trials for Breast Cancer • BMS-247550 – Epothilone B analog – Microtubule stabilizer – Active in taxane resistant tumors • Phase II trial – Measurable disease – Metastatic or locally advanced patients for whom you would consider taxane therapy • Tamoxifen/ Zarnestra – Oral farnesyl transferase inhibitor, (inhibits ras oncogene pathway) – May reverse tamoxifen resistance • Phase II trial – Measurable disease – Hormone receptor positive • T cell depleted allogeneic stem cell transplant – Immunotherapy to induce a graft vs tumor effect • Phase II trial – Measurable disease – HLA matched sibling donor – Prior chemotherapy
  • 87.
    Each breast cancerhas unique features New Breast Cancer Taxonomy Basal-like HER-2 “Normal” Luminal B Luminal A Sorlie T et al, PNAS 2001
  • 88.
    Conclusions • Targeted therapieswhich improve the therapeutic index are the future of anti-cancer therapy • Advances in molecular pathology will provide the means to identify the targets and will be used to subtype tumours and will provide predict response to therapy and provide prognostic information
  • 89.

Editor's Notes

  • #29 The EGFR intracellular signaling cascade stimulates not only cell proliferation but also protection from apoptosis, loss of differentiation, angiogenesis, cell migration and metastasis formation (ie all the key processes involved in tumorigenesis) [1]. EGFR is expressed in a high proportion of solid tumors, in particular head and neck, lung and colorectal cancer [2]. Expression has been correlated with disease progression [3]. Many studies have shown that EGFR expression can be an adverse prognostic factor for cancer treatment outcome [2]. ‘Evidence for a role for the EGFR in the inhibition and pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor,’ Baselga 2002 [3]. Baselga J. Eur J Cancer 2001; 37 Suppl 4:S16–S22. Nicholson RI, Gee JMW, Harper ME. Eur J Cancer 2001; 37 Suppl 4:S9–S15. Baselga J. The Oncologist 2002; 7 Suppl 4:2–8.
  • #46 The trastuzumab-MCC-mertansine drug conjugate efficiently delivers a chemotherapeutic drug to HER2 positive breast cancer cells by encompassing three components (drug, linker, and antibody). The unique chemical linker, MCC, is conjugated via lysine side chains to the cytotoxic agent, mertansine, and is designed to provide a stable antibody-drug bond that preserves the binding activity of trastuzumab to the extracellular domain of HER2. Conjugation of the highly cytotoxic mertansine to a HER2 specific monoclonal antibody is an important approach to confer selectivity to mertansine and potentially increases the therapeutic index.
  • #48 See slide 0653 for efficacy data
  • #54 Several mechanisms have been shown to participate in the regulation of VEGF gene expression. Among these, hypoxia plays a major role, both in vitro and in vivo. VEGF mRNA expression is rapidly and reversibly induced by exposure to low pO2 in a variety of normal and transformed cultured cell types. Several cytokines or growth factors up-regulate VEGF mRNA expression and/or induce release of VEGF protein. For example, exposure of quiescent human keratinocytes to serum, epidermal growth factor (EGF), TGF-β or keratinocyte growth factor results in a marked induction of VEGF mRNA expression.(Ferrara &amp; Davis 1997) A number of oncogenes have also been identified that promote VEGF expression. For example kRAS, HRAS and erbB-2 up-regulate VEGF and HPV-16 stimulates secretion of VEGF. Mutated p53 protein has reduced ability to down-regulate VEGF transcription, a property that wild-type p53 possesses, and in this case the response of tumor cells to anti-angiogenic agents can be reduced (Kerbel &amp; Folkman 2002).
  • #67 Tykerb is a potent, oral, reversible dual tyrosine kinase inhibitor that competitively binds to the ATP binding sites of both erbB-1 and erbB-2 receptor tyrosine kinases. It inhibits ATP binding to the kinase, thereby blocking the ability of the enzyme to phosphorylate receptor tyrosine residues. By this mechanism it may inhibit downstream cell signaling pathways, inducing growth arrest and apoptosis. It also may partially reverse tumor resistance to chemotherapy, radiation, and hormonal therapies. Unlike monoclonal antibodies, it has been shown to inhibit the enzymatic activity of truncated erbB-2, and it is not inhibited by the presence of high levels of ligand. (Blackwell et al, 2004; Burris, 2004; Rusnak et al, 2001; Wood et al, 2004; Xia et al, 2002; Xia et al, 2004; Zhou et al, 2004)
  • #70 [Note: Data above taken from Spector’s slide 0674, which differs considerably from the abstract.]
  • #84 Eric: The denosumab portion of the original audio for the previous slide should go here.