Welcome and Introduction. Miguel Martin Spain

Transcription

1

2 Welcome and Introduction Miguel Martin Spain

3 Development of Adjuvant Chemotherapy 1970s 1980s 1990s Before anthracyclines CMF With anthracyclines Combinations: AC, FAC, AVCMF, FEC, CEF Dose intensity,dose density Standard treatment worldwide Taxanes Sequential: AC T Combinations: TA, TAC 2000s Non-anthracycline taxane regimens TC, TCH Biologics

4 BCIRG-main features Efficient Reliable Innovative

5 Agenda 18:15 BCIRG Beginnings John Mackey Changing the Adjuvant Standard for Node-Positive Early-Stage Breast Cancer Presenter: Charles Vogel and John Crown Optimizing Treatment of HER2+ Breast Cancer With Docetaxel-Non-Anthracycline Regimens Presenters: Dennis Slamon and John Forbes Translating BCIRG Trial Findings Into Clinical Practice Arlene Chan Panel Discussion 19:45 What s Next for the BCIRG? Dennis Slamon

6 BCIRG Beginnings John Mackey Canada

7 Where we are today A Worldwide Network of 2,000 Investigators in over 500 cancer centers in 45 countries spanning 5 continents Able to recruit quickly and generate high quality data Using state of the art systems Reporting groundbreaking trials in breast cancer systemic therapy Attracting the most exciting compounds and trial designs for our patients

8 How did this come about? If you would understand anything, observe its beginnings and its development. Aristotle

9 Although we may now be the flagship breast cancer research group To boldly go where no researchers have gone before»

10 Our beginnings were more modest

11 The Starting Place

12 A brief timeline 1997 BCIRG founded in collaboration with the Alberta Cancer Board Offices at the Cross Cancer Institute, Edmonton 1999 CIRG incorporated as not-for-profit corporation BCIRG is the first division of CIRG Moved to independent offices in Edmonton 2000 CIRG opens Paris office 2005 CIRG merges with TORI

13 What was the context in 1997? 20 year lag between introduction of doxorubicin in MBC and meta-analysis showing efficacy in the adjuvant setting Most large adjuvant studies were done through traditional Government sponsored cooperative groups Activation time up to two years, variable accrual, little intercontinental collaboration, non-registration quality data Large number of compounds warranting testing Credibility issues with Industry run trials

14 Why did BCIRG succeed? Good ideas Good people Good science Good technology

15 The ideas that launched our group Not-for profit organization specialized in running large Phase II and Phase III trials Academic Leadership Simple trial designs addressing important questions Focus on speed Global Investigator Network Independence from Government funding High quality Operational Teams Registration quality data

16 Why did BCIRG succeed? Good ideas Good people Good science Good technology

17 The people that lead to our success Our patients Agreed to participate in research Our investigators Contributed time, energy, and their resources in order to advance the science Our staff Dedicated, goal oriented, high standards Many were industry trained Our sponsors Collaborators in industry first sponsor RPR (aka Aventis, sanofi-aventis) and others including Amgen, Genentech, Astra Zeneca, Roche

18 BCIRG Investigator Sites

19 Why did BCIRG succeed? Good ideas Good people Good science Good technology

20 The Science Simple, clean study designs addressing important questions with good drugs Planned protocol analyses We will analyze no trial before its time Earned scientific credibility Transition from empiric to translational research

21 Why did BCIRG succeed? Good ideas Good people Good science Good technology

22 Our Technology Cutting edge Information Management Capabilities State of the art hardware State of the art software Shift from ERT to the industry standard, Oracle Clinical

23 Our Original Servers

24 Our New Servers (Disk Storage)

25 Our Technology Transition Dual Xeon 3.2 GHz CPUs Dual Pentium III Xeon 550MHz CPUs 1GIG RAM 8GIG RAM

26 BCIRG Beginnings An amazing success story Thank you to all the people who have brought us here! Our 12,000 patients Our more than 1000 investigators Our more than 80 staff Our industry collaborators

27 Changing the Adjuvant Standard for Node-Positive Early-Stage Breast Cancer

28 BCIRG001: TAC Charles Vogel APTIUM Oncology Boca Raton, FLA USA

29 BCIRG 001/TAX316: Study Design Stratification Nodes Centre N=1491 R F A C T A C 5-FU 500 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 Every 3 weeks x 6 cycles Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 Tamoxifen in all HR+ patients Martín M et al. N Engl J Med. 2005;352:

30 BCIRG 001: DFS and OS DFS OS Cumulative probability TAC FAC P= % 68% Cumulative probability P=.008 TAC FAC 87% 81% Time (months) Time (months) Martín M et al. N Engl J Med. 2005;352:

31 BCIRG 001: DFS Hazard Ratio and 95% CI for Subgroups TAC better FAC better DFS ITT (n=1491) Nodes: 1 3 (n=926) Nodes: 4+ (n=565) *HR+ (n=1132) *HR (n=359) *HER2+ (n=319) *HER2 (n=943) All interaction tests negative Premenop. (n=830) Postmen. (n=661) *Centrally confirmed Martín M et al. N Engl J Med. 2005;352:

32 BCIRG 001: Toxicity Grade 3/4 Toxicity, % Nausea Vomiting Diarrhea Stomatitis Asthenia CHF Premenopausal Amenorrhea Neutropenia Febrile neutropenia Infection Anemia Thrombocytopenia (Gr 3/4) Martín M et al. N Engl J Med. 2005;352: TAC n= * 7.1* 11.2* 1.6 n=420 62* 65.5* 24.7* * 2.0 FAC n= * 7.3* n= *p=0.05

33 BCIRG 001: Conclusions TAC significantly improved DFS and OS compared with FAC irrespective of nodal, HER2, menopausal, and hormonal status DFS: 28% relative reduction in the risk of relapse OS: 30% relative reduction in the risk of mortality Primary prophylaxis with G-CSF is recommended for TAC due to the risk of neutropenia The absolute benefit for DFS and OS with TAC is the highest reported for adjuvant treatment comparisons

34 CALGB Studies: ER Status and Outcome By Schedule and Paclitaxel vs Not Disease-free Survival Disease-free Survival ER-negative; Study 9741 q3wk q2wk ER-negative; Study 9344 ER-positive; Study 9344 Paclitaxel No paclitaxel RR=0.77 p= Years RR=0.75 p= Years ER-positive; Study 9741 q3wk Years No paclitaxel q2wk Paclitaxel RR=0.90 p=0.44 RR=0.88 p= Years Berry et al. JAMA 2006;295:

35 Docetaxel Efficacy in OS According to ER Expression Hazard ratio for death (95% CI) Ratio of events Docetaxel arm / no docetaxel arm ER- ER+ 5-year absolute benefit ER- ER+ Pooled 0.69 ( ) 0.70 ( ) 7% 4% BCIRG001 PACS ( ) 0.66 ( ) 0.78 ( ) 0.73 ( ) 9% 6% 6% 3% Ratio for docetaxel x ER interaction = 1.04 ( ); p=0.86 Andre et al. ASCO Abstract 537.

36 NSABP B-38: Study Design Operable breast cancer Histologically-proven node+ TAC x 6 (75, 50, 500) q3w Stratification Factors Number of nodes ER/PR status Type of surgery/rt R AC x 4 (60, 600) P x 4 (175) q2w AC x 4 (60, 600) PG x 4 (175, 2000) q2w PRIMARY PROPHYLAXIS WITH GROWTH FACTORS A = doxorubicin C = cyclophosphamide T = docetaxel P = paclitaxel G = gemcitabine

37 TAC: a Pivotal Regimen for Improving Outcome For High-risk EBC Patients Observation * 1 L-PAM * 1 CMF 2 AC, FAC or FEC 2 4 TAC year disease progression in N+ patients (%) *Patients aged =49 yrs Average value Courtesy of David Cameron 1. Fisher B et al. J Clin Oncol 1986;4:929 41; 2. Levine M et al. J Clin Oncol 1998;16: Bang S et al. Cancer 2000;89:2521 6; 4. Martin M et al. N Engl J Med 2005;352:

38 BCIRG005: Combination TAC or Sequential AC-T John Crown Ireland

39 Reported Clinical Trials Evaluating Sequential Taxanes Study N Regimen Outcome (5-year) DFS(%) OS(%) CALGB AC x AC + P x NSABP B AC x AC x 4? P x 4 GEICAM FEC x 6 FEC x 4? P x 8 PACS FEC x 6 FEC x 3? D x 3 BIG A x 4? CMF x 3 A x 3? D x 3? CMF x 3 AC x 4? CMF x 3 AD x 4? CMF x 3 Taxit E? CMF E? D? CMF E AC? P q3wk AC? P qwk AC? D q3wk AC? D qwk HR=0.79 p= HR=0.79 p= NR NR HR=0.72 p=

40 Event-free Survival: Sequential A-T vs Combination AT 1 Probabilityty Patients Events A-T (22%) AT (26%) HR = 0.83 [ ] p=0.047 A-T AT Time (months)

41 BCIRG 005: Background Optimal delivery of taxane regimens (sequential versus concurrent) is unknown NSABP B-30 comparing TAC to AC? T with 4 cycles of each BCIRG 005 evaluating 6 cycles of TAC, as iused in BCIRG 001 (TAC vs FAC) The first completed international adjuvant trial in HER2-negative early-stage breast cancer that compares sequential to combination approach of taxanes and anthracycline Accessed November Eiermann et al. Proc SABCS 2005: Abstract 1069.

42 BCIRG 005: Study Design Stage T1-3, N1 Node + HER2-negative (FISH) AC x 4 (60/600) T x 4 (100) q3w R Stratification Factors Center Number of nodes ER/PR status TAC 75 x 6 (75/50/500) q3w N=3298 Endpoints Primary: DFS Secondary: OS, safety, QoL, correlative studies

43 BCIRG 005: Current Status Enrollment complete; 594/688 events Expected analysis q Safety data Toxicity Grade 3/4 neutropenia Febrile neutropenia Gr 3/4 neutropenic infections Septic death 1º G-CSF TAC N = % 17.9% 8.9% 1 patient 16.4% AC T N = % 8.5% 8.1% 0 3.5% Eiermann et al. Proc SABCS 2005: Abstract 1069.

44 Optimizing Treatment of HER2- Positive Breast Cancer With Docetaxel-Non-Anthracycline Regimens

45 BCIRG006: TCH as Adjuvant Therapy Dennis Slamon USA

46 BCIRG 006 AC T 4 x AC 4 x Docetaxel 60/600 mg/m mg/m 2 Her 2+ (Central FISH) LN + High risk LN- AC TH 4 x AC 4 x Docetaxel 60/600 mg/m mg/m 2 1 Year Trastuzumab n=3,222 TCH Stratified by Nodes and Hormonal Receptor Status 6 x Docetaxel and Carboplatin 75 mg/m 2 AUC 6 1 Year Trastuzumab Slamon et al. SABCS Abstract 52.

47 First /SecondInterim Efficacy Analysis data to June 30, 2005 / November 01, 2006 Median follow-up time = 23 / 36 months 322 / 462 DFS Events Breast Cancer Relapse Second Primary Malignancy Death 84 / 185 Deaths Slamon et al. SABCS Abstract 52.

48 BCIRG 006: Disease-Free Survival 2 nd Interim Analysis % Disease Free Patients Events AC->T AC->TH TCH 93% 92% 87% 87% 86% 81% 83% 82% 77% HR (AC->TH vs AC->T) = 0.61 [0.48;0.76] p< HR (TCH vs AC->T) = 0.67 [0.54;0.83] p= Year from randomization AC-TH v AC-T 6% TCH v AC-T 5% Slamon et al. SABCS Abstract 52.

49 BCIRG 006: P-values at Interim DFS Analysis Patients with event at 1 st interim analysis at 2 nd interim analysis HR at 1 st interim analysis AC-T n=1, / / / 142 p= AC-TH n=1,074 / p= TCH n=1,075 / HR at 2 nd interim analysis p=0.16 / 0.42 TCH 0.61 TCH 0.67 AC-TH 0.49 AC-TH Metastatic events 113 / / / 98 Slamon et al. SABCS Abstract 52.

50 BCIRG 006: Overall Survival 2 nd Interim Analysis % Survival Patients Events AC->T AC->TH TCH 99% 98% 97% 97% 95% 92% 93% 91% 86% HR (AC->TH vs AC->T) = 0.59 [0.42;0.85] p=0.004 HR (TCH vs AC->T) = 0.66 [0.47;0.93] p= Year from randomization Absolute benefit 5 6 % Slamon et al. SABCS Abstract 52.

51 BCIRG 006: DFS Subpopulations Subgroup Node neg Node pos AC-TH vs AC-T Subgroup Node neg Node pos TCH vs AC-T HR - HR + HR - HR + Tsize<2cm Tsize=2cm Tsize<2cm Tsize=2cm AC-TH better AC-T better TCH better AC-T better Slamon et al. SABCS Abstract 52.

52 BCIRG 006: OS Subpopulations Subgroup Node neg Node pos AC-TH vs AC-T Subgroup Node neg Node pos TCH vs AC-T HR - HR + HR - HR + Tsize<2cm Tsize=2cm Tsize<2cm Tsize=2cm AC-TH better AC-T better TCH better AC-T better Slamon et al. SABCS Abstract 52.

53 BCIRG 006: Grade 3/4 Non- Hematologic Toxicity AC-T n=1,050 (%) AC-TH n=1,068 (%) TCH n=1,056 (%) Arthralgia * Myalgia * Fatigue Hand-foot syndrome * Stomatitis * Diarrhea Nausea Vomiting * Irregular menses Numerically less events for AC-TH or TCH; *Statistically significant for AC-TH or TCH Slamon et al. SABCS Abstract 52.

54 BCIRG 006: Grade 3/4 Hematologic Toxicity AC-T n=1,050 (%) AC-TH n=1,068 (%) TCH n=1,056 (%) Neutropenia * Leucopenia * Febrile neutropenia Neutropenic infection Anemia * 5.8 Thrombocytopenia * 5.4 Leukemia (%) 0.3 (n=3) 0.1 (n=1) 0 Yellow = numerically less events AC-TH or TCH *Statistically significant AC-TH or TCH Slamon et al. SABCS Abstract 52.

55 BCIRG 006: CVS Risk Factors Randomized AC-T AC-TH TCH (n=3,222) n=1,073 n=1,074 n=1,075 Age Median 49 y 49 y 49 y Range (23-74 y) (22-74 y) (23-73 y) Risk factors (# of Pts) Diabetes Hypercholesterolemia Hyperlipidemia Obesity (BMI > 30) Hypertension Radiotherapy (# of Pts) After chemotherapy To left chest

56 Cardiac Deaths and CHF per Independent Review Panel Cardiac related death Cardiac dysfunction (CHF) Grade 3/4 3 AC-T AC-TH TCH n=1,050 n=1,068 n=1,056 / 0 / 0 / / 4 / 20 / 4 first interim analysis second interim analysis p = Slamon et al. SABCS Abstract 52.

57 BCIRG 006: Patients with >10% Relative LVEF Decline n = 1012 AC-T AC-TH TCH n = 1040 n = 1029 / 1014 / 1042 / 1030 Patients % / 102 / 189 / 89 / 10 / 18 / p = / p < p < / p < first interim analysis second interim analysis p = 0.5 / p = 0.5 Slamon et al. SABCS Abstract 52.

58 Mean LVEF - All Observations 2 nd Analysis TCH LVEF points % AC->T AC->TH AC->T (N=1014) AC->TH (N=1042) TCH (N=1030) Time since randomization (days)

59 BCIRG 006: HER2 and TOPO II 2990 of 3222 (93%) patients analyzed 17 q q q 21.2 HER2 Core region TOPO II region Non Co-Amplified 1788 pts (60%) 145 pts (5%) Co-Amplified 1057 pts (35%) Normal Amplified Deletion Slamon et al. SABCS Abstract 52.

60 DFS Topo II Co-Amplified vs Non Co-Amplified All Patients (2 nd interim analysis) % Disease Free PatientsEvents Topo II % 88% Co-Amplified Non Co-amplified 88% 82% 84% 78% Co-Amplified Year from randomization Non Co-amplified HR (Co-Amp vs Non Co-Amp) = 1.44 [1.16;1.78] p<0.001 Slamon et al. SABCS Abstract 52.

61 DFS Non Co-Amplified Topo II by Arm (2 nd Interim Analysis) % Disease Free Patients Events AC->T AC->TH TCH 91% 90% 83% P<0.001 P< % 84% 78% 83% 81% 71% AC->TH TCH AC->T Year from randomization Slamon et al. SABCS Abstract 52.

62 DFS Co-Amplified Topo II by Arm (2 nd Interim Analysis) % Disease Free % 94% 92% PatientsEvents AC->T AC->TH P= TCH P= % 87% 87% 85% 83% 83% TCH AC->TH AC->T Year from randomization Slamon et al. SABCS Abstract 52.

63 BCIRG 006: Conclusions Benefits of AC-TH & TCH maintained at 36-month follow-up for DFS (primary endpoint) Overall survival Breast cancer deaths Adverse event profile favors TCH Cardiac dysfunction, leukemia GIT, arthralgias, neuropathy Myelosuppression

64 Therapeutic Index Most Recent 006 Data BrCa Recurrence BrCa Deaths Grade 3 / 4 CHF Leukemia Total * in both anthracycline-based arms. AC-TH * 161 TCH In addition, 23 pts with bona fide HER2 amplification who were randomized to the AC-TH arm never got trastuzumab due to unacceptable declines in LVEF before receiving the antibody

65 BCIRG 006: Clinical Implications Superior efficacy benefits for anthracyclines (when present) based on effects on topo IIa amplification and/or overexpression Topo IIa amplification occurs ONLY in 35% of patients with HER2 amplification (tested in >4,500 patients) What data supports preferential use of anthracyclines in a HER2-negative breast cancer population (~ 75% of breasts cancers)? For HER2-positive breast cancers trastuzumab and lapatinib will more than replace the gained efficacy of anthracyclines in the 1/3 of patients with co-amplification of HER2 and Topo IIa without risking their known and well established toxicities

66 BCIRG007: TH vs TCH for MBC John Forbes ANZ BCTG Australia

67 BCIRG 007 First Line Metastatic Breast Cancer 8 TH Docetaxel 100 mg/m 2 q3w HER2 + by FISH N=263 8 TCH Trastuzumab Docetaxel 75 mg/m 2 q3w Carboplatin AUC: 6mg/ml/min Stratification: - Prior CT: adjuvant and/or neoadjuvant - Center Trastuzumab Pegram et al. ASCO Abstract LBA 1008 Forbes JF et al. ASCO Abstract LBA 1008

68 BCIRG 007: Tumor and Patient Characteristics Randomized (n=263) TH (n=131) TCH (n=132) Median age, years KPS ER and/or PgR+ 95 (72.5%) 86 (65.2%) Extent of Disease 1 or 2 sites 70 (53.4%) 72 (54.5%) > 2 sites 61 (46.6%) 60 (45.5%) Disease Involvement Visceral involvement 87 (66.4%) 77 (58.3%) Liver involvement 67 (51.1%) 65 (49.2%) Bone involvement 55 (41.9%) 44 (33.3%) Disease status at study entry Locally Advanced Metastatic 3 (2.3%) 128 (97.7%) 2 (1.5%) 130 (98.5)

69 BCIRG 007: ORR and TTP (ITT) % Patients without Progression TCH = mo TH = mo Years from randomization Treatment Patients Events TH TCH Log-rank P = 0.57 ORR: TH:72.5% v TCH: 72.7% Pegram et al. ASCO Abstract LBA 1008.

70 BCIRG 007: Overall Survival (ITT) Treatment Patients Events TH TCH Total % Survival TCH: mo TH: mo Log-rank P = Years from randomization Pegram et al. ASCO Abstract LBA 1008.

71 BCIRG 007: Toxicity Number of Patients TH (N=131) TCH (N=131) P-value Grade 3/4 Hematologic Febrile neutropenia 16 (12.2%) 17 (13%) NR Neutropenic infection 22 (16.8%) 12 (9.2%) Thrombocytopenia 3 (2.3%) 20 (15.3%) <0.001 Non-Hematologic Toxicities Nausea 70 (53.4%) 96 (73.3%) NR Vomiting 37 (28.2%) 58 (44.3%) NR Nail changes 72 (55%) 43 (32.8%) <.001 Neuropathy 4 (3%) 1 (0.8%).048 Rash 42 (32.1%) 20 (15.3%).002 Myalgia 58 (44.3%) 41 (31.3%).041 Grade 3 change in LVF 1 (1.6%) 0 NR

72 Progression free survival Overall survival Median PFS TPC 10.7m TP 7.1m TP: TPC: Trastuzumab, Paclitaxel Trastuzumab, Pacitaxel, Carboplatin Robert et al JCO 2006, 24:

73 BCIRG 007/ US Oncology Study Feature: BCIRG 007 USO Randomised: HER2 testing: FISH IHC 2+/3+ Taxane: docetaxel paclitaxel 8 x TH 100 q 3w 6 x TP 175 q 3w 8 x TCH 75 q 3w 6 x TPC 175 q 3w TH: TCH: TP: TPC: Taxotere, Herceptin Taxotere, Carboplatin, Herceptin Trastuzumab, Paclitaxel Trastuzumab, Pacitaxel, Carboplatin Robert et al JCO 2006, 24:

74 BCIRG 007: Conclusions TH (T 100) and TCH (T 75) are effective therapies for HER2+ MBC Carboplatin did not enhance efficacy of TH TCH and TH were generally well tolerated, but with different toxicity profiles - TH: more neuropathy, myalgia, skin/nail changes, and neutropenic infection - TCH: more thrombocytopenia, nausea and emesis No serious cardiac toxicity with either treatment

75 Translating BCIRG Findings Into Clinical Practice Arlene Chan Australia ANZ BCTG

76 Factors for Treatment Selection Patient selection Individualised risk vs benefits Node positive ER/PR positive / negative Her2 positive / Topo IIa positive Specific treatment-related adverse effects Particular to Taxotere Incidence Management

77 Managing Key Adverse Events Neutropenic complications Epiphora Cardiac toxicity: Herceptin/anthracyclines

78 Hematological Adverse Events Grade 3/4 100% 80% Neutropenia FN Anaemia Thrombocytopenia 60% 40% 20% 0% TAC* TAC* AC-T** AC_T** AC-TH** TCH* TH** TCH* BCIRG001 BCIRG005 BCIRG006 BCIRG007 *Docetaxel 75mg **Docetaxel 100mg

79 Neutropenic Complications: Pre/Post Primary G-CSF TAC-pre TAC-post FAC P (n=116) (n=423) (n=520) Completed 6 cycles 90.4% 95.7% 97.3% FN 24.6% 6.5% 2.3% Gd 2-4 Anaemia 47.4% 27.5% 7.5% < Transfusion 7% 2% 0.8% ns Martin, et al. Ann Oncol. 2006;GEICAM FAC v TAC in High risk node negative 25% FN.

80 Febrile Neutropenia G-CSF primary vs Nil / Placebo n = 3493 from 17 randomised trial 65% pts with solid tumours Kuderer N, et al. JCO 2007.

81 Infection-Related Mortality

82 Early Mortality

83 Predictive Model for Secondary Prophylaxis Probability of subsequent event Chemo only Event prediction: ANC 250/ul Dose reduction = 15% Delay = 7 days N = 95 Adjuvant Breast Cancer Chemo + radiation First cycle nadir ANC Silber et al. J Clin Oncol. 1998;16:

84 Non-Hematological Adverse Events Grade 3/4 100% 80% Taxotere 100mg Taxotere 75mg 60% 40% 20% 0% Asthenia Nausea Stomatitis Vomiting Diarrhea Oedema Neurosensory Arthralgia Myalgia Nails

85 Non-Hematological Adverse Events All Grades 100% 80% Taxotere 100mg Taxotere 75mg 60% 40% 20% 0% Asthenia Neurosensory Arthralgia Myalgia Nails

86 Epiphora Excessive tearing due to secretion or? elimination from ocular surface and sac Due to: Canalicular inflammation Sclerosing canaliculitis

87 9.0% nr Weekly IV 12 Meden 52.0% 720 Weekly IV 29 Burstein 93.0% 630 Weekly IV 30 Esteva 76.0% 350 Weekly IV 30 Maisano 11% - 18% Weekly IV 35 Ramos 13.0% 560 Weekly IV 37 Aihara 6.0% 351 Weekly IV 37 Stemmler 11.0% 540 Weekly IV 57 Konek 17.0% 600 Weekly IV 57 Kuroi 34% 69% weekly Weekly % 620 Weekly IV 41 Tabernero 76.0% 315 Weekly III 17 Dang 48.0% 480 Weekly II/III 56 Estevez 39.0% weekly IV 42 Tabernero 11.0% weekly III 18 Esmaeli Incidence Dose (mean) Schedule Stage Pt Nos Study Incidence With Docetaxel Esmaeli IV

88 Management of Epiphora Ocular moisturizers Topical steroid ± antibiotics? Role of steroid pre-medication Ophthalmologic review Surgical intervention Surgical intubation Punctoplasty Dacryocystorhinostomy

89 Prevalence of Epiphora in Women with Early Breast Cancer Receiving Adjuvant Docetaxel- Based Chemotherapy: A Multicentre Study Goal to recruit 100 patients receiving adjuvant Taxotere-based chemotherapy Ophthalmological assessment Baseline, mid-chemotherapy, 12 weeks post-chemotherapy Slit lamp, CT-DCG, Eye questionnaire Conservative treatment of epiphora Chan, et al.

90 Cardiac Assessment and Management Radiation exposure with MUGA Reproducibility of repeated evaluations Bellenger, et al. Eur Heart J n=52 Compared Echocardiogram, MUGA, Cardiovascular MRI Prevention

91 Cardiac Assessment and Management (cont.) Cardinale D, et al. Circulation n=473 ACE inhibitor vs Nil after high-dose chemotherapy Ejection fraction decline EF>10%? to <LLN 0% v 43% p<0.001

92 Conclusions Efficacy of docetaxel is established Short- and long- term adverse effects Awareness Monitoring Prevention/early intervention Other areas: Aesthenia Erythropoetin Myalgia Nails

93 What s Next for the BCIRG? Dennis Slamon USA

94 CIRG / NSABP TCH 6 x Docetaxel and Carboplatin Her2+ (Central FISH) N+ or high risk N- 1 Year Trastuzumab 6 x Docetaxel and Carboplatin N=2875 Stratified by Nodes and Hormonal Receptor Status TCHB 1 Year Trastuzumab 1 Year Bevacizumab

95 A a b c d e f g h i j k l m n o Tissue MicroArrays (TMAs) a b c d e f g h i j k l m n o H&E Histopathology B C a b c d e f g h i j red= randomized BCIRG 005 patient red= randomized BCIRG 006 patient BCIRG ARRAY #2 Computerized Specimen Key a b c d e f g h i j D Immunohistochemistry Breast Cancers Screened: 10,948 Total in TMAs: 7,755 Cases as sections: 3,193 Total BCIRG 006 cases: 3,222 BCIRG006 in TMAs: 2,204 Cases as sections: 1,018

96 Please complete the evaluation form and turn into the hostess as you leave

97