Kathy D. Mill operator, MD Associate Professor and Sheila D. Ward Scholar Indiana University Melvin and Bren Simon Canc

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Kathy D. Mill operator, MD Partner Teacher and Sheila D. Ward Researcher Indiana College Melvin and Bren Simon Malignancy Center Indianapolis, IN. Clinical Upgrades. Propels in Focused Treatments for Bosom Growth A Report From SABCS 2009. Exchange Themes. HER2 positive malady

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Kathy D. Mill operator, MD Associate Professor and Sheila D. Ward Scholar Indiana University Melvin and Bren Simon Cancer Center Indianapolis, IN Clinical Updates Advances in Targeted Therapies for Breast Cancer A Report From SABCS 2009

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Discussion Topics HER2 positive malady Growing number of choices Angiogenesis Bevacizumab questions addressed and rethought Small particle achievement and dissatisfaction

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HER2: What We Knew Before SABCS Trastuzumab Active as single specialist and adds to chemo/HRT Effective with chemo past PD Adds to lapatinib monotherapy (ORR, PFS) Lapatinib Active as single operator and adds to chemo/HRT Effective with chemo after PD on trastuzumab MULTIPLE new specialists being developed

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Case 1 54 year old lady with recently analyzed stage II bosom growth s/p lumpectomy and axillary dismemberment Primary tumor 1.9 cm Involves 1 of 14 LN (1/2 SN, 0/12 extra LN) Grade III ER+ 15%, PR-HER2 2+ by IHC (serious recoloring in 20% of cells) FISH obscure with proportion 2.15 Do you prescribe adjuvant trastuzumab?

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Background In 2007, ASCO/CAP prescribed new rules to characterize HER2 energy by both IHC 3+* and FISH+** 3+ IHC: Uniform extraordinary film recoloring of > 30% of intrusive tumor cells FISH+: HER2/CEP17 proportion > 2.2 Original HER2 qualification criteria in the essential N9831 Phase III Adjuvant HER2 Trial 3+ IHC: Uniform exceptional layer recoloring of > 10% of obtrusive tumor cells FISH+: HER2/CEP 17 proportion ≥ 2.0 HerceptTest DAKO, Carpenteria, CA; FISH: PathVysion, Abbott Molecular; Masood S et al. Ann Clin Lab Sci 1998;28(4):215-223; Perez EA et al. SABCS 2009 #701

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N9831 DFS Based on Original Criteria: HER2 Non-positive* versus HER2+** * HER2 Non-positive (IHC ≤ 10 and FISH Ratio < 2.0) ** HER2+ (IHC > 10 or FISH Ratio ≥ 2.0) Perez EA et al. SABCS 2009 #701

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N9831 DFS Based on 2007 ASCO/CAP: HER2 Non-positive* versus HER2+** * HER2 Non-positive (IHC ≤ 30 and FISH Ratio ≤ 2.2) ** HER2+ (IHC >30 or FISH Ratio > 2.2) Perez EA et al. SABCS 2009 #701

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Conclusions A little rate (by IHC:3.7%, FISH 1.4%, both:1.7%) of N9831 pts did not meet ASCO/CAP 2007 HER2 energy rules when connected reflectively Trastuzumab impact seemed comparable for HER2+ pts paying little heed to ASCO/CAP or initially utilized FDA-affirmed rules Data bolster deciding qualification for trastuzumab in view of the first meaning of HER2 inspiration (IHC 3+, >10% recoloring; FISH ratio>2.0). Perez EA et al. SABCS 2009 #701

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Case 1 54 year old lady with recently analyzed stage II bosom growth s/p lumpectomy and axillary dismemberment Primary tumor 1.9 cm Involves 1 of 14 LN (1/2 SN, 0/12 extra LN) Grade III ER+ 15%, PR-HER2 2+ by IHC (extreme recoloring in 20% of cells) FISH ambiguous with proportion 2.15 Do you prescribe adjuvant trastuzumab? YES

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BCIRG 006 NCCTG N9831 IHC or FISH NSABP B-31 HERA Observation IHC or FISH IHC or FISH AC P D DCarbo Standard Trastuzumab 1 year Adjuvant Trastuzumab 1 v 2 years IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation

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BCIRG 006 DFS Events First/Second/Third Planned Efficacy Analyses (cutoff dates: 30June2005/01Nov2006/16Oct2009 ) Median follow-up time = 23/36/65 months 322/462/656 DFS occasions (42% extra occasions) Breast growth backslide Second essential harm Death 84/185/348 passings (88% extra passings)

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Current BCIRG 006 Disease-Free Survival – 3 rd Planned Analysis

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Current BCIRG 006 Overall Survival – 3 rd Planned Analysis

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Cardiac Deaths and CHF according to Independent Review Panel

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Therapeutic Index – Most Recent Data

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Efficacy Analysis *Patients qualified for hybrid edited Data solidified on 11/3/2009 Control (A)* versus Sequential (B)* AC → T → H AC → T Perez EA et al, SABCS 2009

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Alive and sickness free (%) 100 AC → T → H (164 occasions) 90 85.2% 80.1% 80 79.7% 70 71.9% AC → T (222 occasions) Log rank P =0.0005 60 50 735 675 624 586 513 1097 No. at hazard 728 643 581 529 1087 447 40 0 1 2 3 4 5 Years from randomization Control versus Sequential Perez EA et al, SABCS 2009

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Efficacy Analysis *Censoring in view of temp conclusion of C, and qualification for hybrid Data solidified on 11/3/2009 Sequential (B)* versus Concurrent (C) AC → T+H → H AC → T → H N9831 Perez EA et al, SABCS 2009

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Sequential versus Concurrent first Interim Analysis At half of arranged number of occasions (312 occasions) 1,903 pts, middle development: 5.3 yr 75% of pts took after for 5 yr DFS may contrast as for the planning of trastuzumab's expansion to AC → T Log rank P=0.019 (HR 0.77; 95% CI 0.61-0.96) Not crossing the limit for measurable criticalness, pre-set at 0.00116 Perez EA et al, SABCS 2009

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Alive and infection free (%) Sequential versus Concurrent AC →T+ H → H (138 occasions) 100 89.1% 90 84.2% 85.7% 80 79.8% AC → T → H (174 occasions) 70 Logrank p=0.0190 60 50 949 837 788 740 676 456 No. at hazard 830 766 705 954 641 418 40 0 1 2 3 4 5 Years from randomization Perez EA et al, SABCS 2009

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Conclusions DFS is fundamentally enhanced with the expansion of 52 wks of trastuzumab to AC  T There is a measurably huge 33% decrease in the danger of an occasion with the consecutive expansion of trastuzumab taking after AC  T 5 yr DFS: 72% versus 80% There is a solid pattern for a 25% lessening in the danger of an occasion with beginning trastuzumab simultaneously with taxane in respect to successively 5 yr DFS: 80% versus 84% Perez EA et al, SABCS 2009

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Median follow-up HERA 1 year Combined examination 2 years 2 years BCIRG 006 AC D H 2 years BCIRG 006 DCarboH 3 years FinHER VH/DH CEF Favors Trastuzumab Favors no Trastuzumab 0 1 2 HR Trastuzumab DFS Piccart-Gebhart et al 2005; Romond et al 2005;Slamon et al 2005; Joensuu et al 2005

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Adjuvant Trastuzumab Test everybody for HER2, ask about testing quality and take a gander at "ambiguous" results Most vital message - > Give Trastuzumab! Either TCH or AC>TH upheld by information Differences between regimens unassuming Slightly more repeat with TCH adjusted by expanded cardiovascular and long haul marrow poisonous quality with AC>TH Give simultaneously with chemo unless there is a convincing reason not to

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Case 2 74 year old presents with 5 cm essential bosom mass with related axillary adenopathy. ER-, PR-, HER2 3+ by IHC (FISH proportion 8.9) Staging finds a few liver injuries, biggest 2.2 cm Biopsy of liver sore affirms MBC, HER2+ LFTs ordinary LVEF 62% She rejects chemotherapy yet will consider different alternatives, family bolsters her desires What might you suggest?

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Lapatinib Trastuzumab Pathway Activation HER Ligands

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Lapatinib + Trastuzumab Lapatinib 1500 mg PO QD (n = 148) EGF104900 Primary endpoint: PFS Secondary endpoints: OS ORR CBR Optional hybrid to trastuzumab arm if PD after 4 wks (n = 77) Heavily pretreated patients with HER2-positive MBC and movement on trastuzumab (N = 296) Lapatinib 1000 mg PO QD + Trastuzumab 4 mg/kg stacking measurements, then 2 mg/kg IV wkly (n = 148) Stratified by instinctive sickness and hormone receptor status PO, orally; QD, once every day. Blackwell K, et al. SABCS 2009 # 61.

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Lapatinib + Trastuzumab 52% of patients traversed from single-specialist lapatinib to mix treatment on movement. Blackwell K, et al. SABCS 2009 # 61.

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Lapatinib + Trastuzumab Safety Update Most AEs announced in ≥ 10% of patients were review 1/2 Diarrhea was the main review 3/4 AE revealed in ≥ 5% of patients 8% of patients getting lapatinib in addition to trastuzumab versus 7% accepting lapatinib alone 1 lethal cardiovascular occasion in mix arm * Defined as review ≥ 3 LV brokenness, LVEF diminish ≥ 20% from pattern and underneath lower point of confinement of typical characterized by organization. Blackwell K, et al. SABCS 2009 # 61.

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Lapatinib + Trastuzumab Lapatinib + trastuzumab related with 26% change in OS versus lapatinib alone Significant survival advantage in spite of 52% hybrid Supports blend arm of ALTTO Lapatinib in addition to trastuzumab very much endured AEs equivalent to lapatinib alone Offers conceivable alternatives for vigorously pretreated patients who advance on trastuzumab Blackwell K, et al. SABCS 2009 # 61.

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T-DM1 T-DM1, a counter acting agent medicate conjugate, joins biologic impact of trastuzumab against HER2-communicating cells with very powerful antimicrotubule operator DM1 MOA likely includes receptor-intervened disguise of T-DM1 subsequent to authoritative to HER2, bringing about intracellular arrival of DM1 Austin CD et al. Mol Biol Cell. 2004;15:5268-5282.

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T-DM1 Monotherapy Multicenter, single arm (N=110) Primary endpoint – ORR by IRF at 24 weeks Eligibility Prior anthracycline, taxane, capecitabine, trastuzumab, lapatinib Active infection movement on last treatment LVEF half or better Krop I, et al. SABCS 2009.#5090.

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T-DM 1 Monotherapy ORR (by autonomous survey) 32.7% Clinical advantage rate (by free audit) 44.5% Median PFS 7.3 months T-DM1 all around endured Thrombocytopenia Offers an undeniable alternative for extra treatment for HER2+ patients Krop I, et al. SABCS 2009 #5090.

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P<0.0001 Response Rates for Novel HER2-Targeting Agents After Progression on Trastuzumab Modi et al, ASCO 2008; Gelmon et al, ASCO 2008; Swaby et al, ASCO 2009; Burris et al, ESMO 2009.

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Topics HER2 positive sickness Growing number of alternatives Angiogenesis Bevacizumab questions addressed and reworded Small atom achievement and frustration

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Angiogenesis is essential for tumor development Highly managed, different excess pathways VEGF among the most strong and much of the time overexpressed Bevacizumab M

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