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Vice-chair of the MD Anderson’s Institutional Review Board

Marjorie Green Assistant Professor and Associate Medical Director of the Nellie B. Connally Breast Center at the MD Anderson Cancer Center, Houston, Texas, USA. Vice-chair of the MD Anderson’s Institutional Review Board

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Vice-chair of the MD Anderson’s Institutional Review Board

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  1. Marjorie GreenAssistant Professor and Associate Medical Director of the Nellie B. Connally Breast Center at the MD Anderson Cancer Center, Houston, Texas, USA • Vice-chair of the MD Anderson’s Institutional Review Board • Completed fellowships in medical oncology and haematology at the MD Anderson Cancer Center • Past and current co-chair for two phase III prospective, preoperative chemotherapy clinical trials • Authored numerous manuscripts and book chapters on preoperative chemotherapy • Chair of several studies evaluating the treatment and prevention of bone metastasis MD Anderson Cancer Center

  2. Treatment advances for earlybreast cancer: selecting patientsfor optimal outcome Marjorie Green MD Anderson Cancer CenterHouston, Texas, USA

  3. Issues for considerationin the adjuvant setting • Modality of trastuzumab administration • Concurrent versus sequential administration • Optimal treatment duration • Optimal timing of trastuzumab initiation in patients who have completed adjuvant chemotherapy • Long-term efficacy • Trastuzumab resistance

  4. Trastuzumab in early breast cancer Observation T q3w x 12 months T q3w x 24 months HERA (ex-USA)(n=5,090) Any CT ± RT NSABP B-31 (USA)(n=2,030) AC x 4 AC x 4 P q3w x 4 or qw x 12 P q3w x 4 or qw x 12 + T qw x 52 AC x 4 AC x 4 AC x 4 P qw x 12 P qw x 12 P qw x 12 + T qw x 52 NCCTG N9831 (USA)(n=3,505) T qw x 52 AC x 4 Dq3wx 4 BCIRG 006 (global)(n=3,222) T q3w x 13 Dq3wx 4 + T qw x 12 AC x 4 T q3w x 11 D + Carbo q3w x 6 + T qw x 18 CEF q3w x 3 D q3w x 3 or V qw x 8 D q3w x 3 or V qw x 8 + T qw x 9 FinHer (Finland)(n=232*) CEF q3w x 3 *HER2-positive subgroupCT = chemotherapy; RT = radiotherapy; qw = every week; q3w = every 3 weeksT = trastuzumab; A = doxorubicin; C = cyclophosphamide; P = paclitaxelD = docetaxel; Carbo = carboplatin; V = vinorelbine; E = epirubicin; F = 5-fluorouracil Baselga J, et al. Oncologist2006;11(Suppl. 1):4–12

  5. NSABP B-31/NCCTG N9831combined analysis: trial design Control NSABP B-31 arm 1 NCCTG N9831 arm A Trastuzumab NSABP B-31 arm 2 NCCTG N9831 arm C = AC 60/600mg/m2 q3w x 4 = paclitaxel 175mg/m2 q3w x 4 = paclitaxel 80mg/m2 qw x 12 = trastuzumab 4mg/kg loading dose  2mg/kg qw x 51 Perez EA, et al. J Clin Oncol 2007;512:185 (Abstract 512)

  6. NSABP B-31/NCCTG N9831 combined analysis: disease-free survival (DFS) Updated N9831/B-31 Joint AnalysisDFS* 100 80 60 40 20 0 ACP+T(n=1,989; 222 events) 92.3% 89.9% 85.9% 86.4% 77.6% 73.1% ACP(n=1,979; 397 events) Alive and disease-free (%) n=619 eventsHR* adjuvant = 0.48 (95% CI: 0.41–0.57) *Nodes, receptor status, paclitaxel schedule, protocolp<0.00001 1,854 1,347 868 522 202 4 1,800 1,235 753 460 168 8 No.at risk 0 1 2 3 4 5 6 7 Follow-up (years) *Intent-to-treat events: recurrent disease, contralateral bc, second primary, deathHR = hazard ratioCI = confidence interval Perez EA, et al. J Clin Oncol 2007;512:185 (Abstract 512)

  7. NSABP B-31/NCCTG N9831 combined analysis: cumulative incidence of cardiac events Cardiac tolerability – N9831Cumulative incidence of cardiac events *Patients randomised to ACP who received H were censored at the date that H was first administered CHF = congestive heart failure Perez EA, et al. J Clin Oncol 2007;512:185 (Abstract 512)

  8. NSABP B-31/NCCTG N9831 combined analysis: conclusions • Benefit of adding concurrent trastuzumab to paclitaxel after AC is maintained with longer follow-up • hazard of disease recurrence decreased by 52% • hazard of death decreased by 35% • Hazard of disease recurrence • increased in patients with greater number of positive nodes, ER-negative tumours, and large tumours • appears to peak at year 2, but tumour recurrences continue to occur with longer follow-up • ACP+T, with nine additional months of trastuzumab, continues to demonstrate significant clinical benefit Perez EA, et al. J Clin Oncol 2007;512:185 (Abstract 512)

  9. Randomisation After ASCO 2005, option of switch to trastuzumab Observation HERA trial design Women with locally determined HER2-positive invasive early breast cancer Surgery + (neo)adjuvant chemotherapy ± radiotherapy Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55% X 2 years trastuzumab 8mg/kg →6mg/kg 3 weekly schedule 1-year trastuzumab 8mg/kg → 6mg/kg 3 weekly schedule • Primary endpoint: DFS • Secondary endpoints: overall survival (OS), time to recurrence (TTR), time to distant recurrence (TTDR),safety (three interim analyses of cardiac endpoints) IHC = immunohistochemistry; FISH = fluorescent in situ hybridisationLVEF = left ventricular ejection fraction

  10. HERA: DFS (intent-to-treat) Median follow-up = 2 years 1-yeartrastuzumab 100 80 60 40 20 0 6.3% Observation Patients (%) 3-yearDFS Events HR 95% CI p value 80.6 218 0.54, 0.76 <0.0001 0.64 74.3 321 0 6 12 18 24 30 36 Months from randomisation No. at risk 1,703 1,591 1,434 1,127 742 383 140 1,698 1,535 1,330 984 639 334 127 Smith I, et al. Scientific special session, ASCO 2006

  11. HERA: OS (intent-to-treat) Median follow-up = 2 years 1-yeartrastuzumab 100 80 60 40 20 0 2.7% Observation Patients (%) 3-yearDFS Events HR 95% CI p value 92.4 0.47, 0.91 0.0115 0.66 59 89.7 90 0 6 12 18 24 30 36 Months from randomisation No. at risk 1,703 1,627 1,498 1,190 794 407 146 1,698 1,608 1,453 1,097 711 366 139 Smith I, et al. Scientific special session, ASCO 2006

  12. HERA: adverse events *Cardiac failure, suicide, unknown †Cerebral haemorrhage, cerebrovascular accident, sudden death, appendicitis, intestinal obstruction, unknown following a road accident, carcinomatous lymphangitis, two unknown. The intestinal obstruction occurred after a second non-breast malignancy‡Safety in 6.8%, refusal in 2.5%, other in 0.8% AE = adverse event Smith I, et al. Scientific special session, ASCO 2006

  13. HERA: cardiac safety NYHA = New York Heart Association Smith I, et al. Scientific special session, ASCO 2006

  14. Case presentation 1

  15. Patient TK:history • TK is a 57-year-old woman diagnosedwith stage II breast cancer • She underwent • segmental mastectomy • axillary lymph node dissection • T2 (3.7cm IDC), N1 (3 LN+), M0 • ER-positive 30%, PR-negative • HER2 FISH+ (ratio 12.3) • Initial evaluation • no metastases • EF 65% IDC = invasive ductal carcinoma; LN = lymph nodePR = partial response; EF = ejection fraction

  16. Patient TK: treatment recommendation • AC x four cycles • Followed by paclitaxel concurrent with trastuzumab weekly • 12 weeks • followed by additional 9 months of single-agent trastuzumab • Adjuvant radiation • Anti-oestrogen therapy

  17. Patient TK: cardiac safety • Evaluation after AC: slight decrease in EF (60%) • After 12 doses of paclitaxel plus trastuzumab: another slight decrease in EF (55%) • Repeat echocardiogram after 3 months of single-agent trastuzumab: additional drop in EF (50%) • she was asymptomatic • Trastuzumab interrupted and patient referred to cardiology • Started on low-dose beta blocker plus low-dose ACE inhibitor • Repeat echocardiogram 1 month after stopping trastuzumab: improvement in EF to 60% • Trastuzumab restarted with EF monitored every 3 months: no further decline in EF ACE = angiotensin-converting enzyme

  18. Patient TK: cardiac safety guidelines • Patients may have a transient EF decrease with trastuzumab • Guidelines recommend trastuzumab be interrupted for • a drop in EF >10% when EF falls below normal • a drop in EF ≥16% regardless of overall EF • Repeat echocardiogram should be conducted within 1 month after interruption of trastuzumab • If EF returns to within normal limits or there is <15% drop when the EF is within normal limits, restart trastuzumab • If EF has not returned to normal, recheck in a further 4 weeks, if EF is still below acceptable limits, discontinue trastuzumab

  19. BCIRG 006: trial design 4 x AC60/600mg/m2 4 x docetaxel100mg/m2 Node-positiveand high-risk node-negative EBC AC  D AC  DT HER2-positiveby FISH 1-year trastuzumab DCarboT 6 x docetaxel and carboplatin n=3,222 75mg/m2 AUC 6 1-year trastuzumab Slamon D, et al. Breast Cancer Res Treat 2005;94(Suppl. 1) (Abstract 1) EBC = early breast cancer

  20. BCIRG 006: DFS Median follow-up = 23 months First interim efficacy analysis(cut-off date 30 June 2005) 100 90 80 70 60 50 93% 86% 91% 84% 80% 86% 80% HR=0.49 HR=0.61 Patients (%) 77% 73% n 1,074 1,075 1,073 Events 77 98 147 ACDT DCarboT ACD 0 1 2 3 4 5 Years from randomisation Slamon D, et al. Breast Cancer Res Treat 2005;94(Suppl. 1) (Abstract 1)

  21. BCIRG 006: interim cardiac safety analysis –clinically significant events *5/20 arrhythmias not yet adjudicated by independent review panel(two in ACD, one in ACDT, two in DCarboT) Slamon D, et al. Breast Cancer Res Treat 2005;94(Suppl. 1) (Abstract 1)

  22. FinHer: trial design • Primary endpoint = recurrence-free survival • Secondary endpoints = adverse events, effect of treatment on LVEF, TTDR, OS Docetaxel q3w x 3 OR vinorelbine qw x 8 Fluorouracil, epirubicin, cyclophosphamide q3w x 3 HER2-positive breast cancer (n=232) Docetaxel q3w x 3 OR vinorelbine qw x 8 + trastuzumab qw x 9 Fluorouracil, epirubicin, cyclophosphamide q3w x 3 Joensuu H, et al. N Engl J Med 2006;354:809–20

  23. FinHer: recurrence-free survival 97.4 • Recurrence-free survival significantly improved in the trastuzumab group 100 80 60 40 20 0 91.3 Trastuzumab 89.3 94.0 83.6 77.6 No trastuzumab Patients (%) Median follow-up = 3 years HR=0.42 (95% CI: 0.21–0.83) p=0.01 0 1 2 3 4 Years No. at risk Trastuzumab 115 112 97 64 21 No trastuzumab 116 109 91 51 18 Joensuu H, et al. N Engl J Med 2006;354:809–20

  24. Summary of trastuzumab efficacy in early breast cancer: DFS Median follow-up HERA (n=3,387) 1 year Combined analysis(n=3,351) 2 years BCIRG 006 AC DH(n=2,147) 2 years BCIRG 006 DCarboH(n=2,148) 2 years FinHer VH/DH*(n=231) 3 years 0 1 2 Favours trastuzumab Favours no trastuzumab HR Baselga J, et al. Oncologist 2006;11(Suppl. 1):4–12 *Recurrence-free survival

  25. Case presentation

  26. Patient SG  history • SG is a 36-year-old mother of three • She is s/p right MRM with axillary LND • Pathology • T3 (5.4cm), N1 (3+ LN) • HER2 FISH+ (ratio 8.8) • ER and PR-negative • No evidence of MBC • EF >65% MRM = modified radical mastectomy; LND = lymph node density MBC = metastatic breast cancer

  27. Patient SG: adjuvant treatment recommendations • AC x four cycles • Followed by paclitaxel concurrent with trastuzumab weekly • 12 weeks • followed by additional 9 months of single-agent trastuzumab

  28. Patient SG: duration of therapy • After completion of AC, paclitaxel plus trastuzumab • SG returns to clinic with FinHer study results • asks to discontinue trastuzumab • She is asymptomatic • EF has remained WNL (>60%) • My recommendation • at this time, there are insufficient data to advocate abbreviated duration of treatment with trastuzumab • One year of trastuzumab is re-recommended, patient agrees • Consider use of q3w trastuzumab once chemotherapy is completed WNL = within normal limits

  29. Retreatment with adjuvanttrastuzumab (RHEA): trial design Cohort A Trastuzumab 4mg/kg loading dose then 2mg/kg qw • Primary endpoint = overall response rate • Secondary endpoints = clinical benefit rate, survival, safety • Planned cohort size = 40 patients in each HER2-positive breast cancer IHC 3+/FISH+ Baseline LVEF 50% Relapsed 12 months after 10 months of adjuvant trastuzumab-based therapy Cohort B Trastuzumab +docetaxel 100mg/m2q3w x 6 orpaclitaxel 175mg/m2 q3w x 6 or75mg/m2 qw x 18 RHEA = Retreatment after HErceptin Adjuvant trial Bell R, et al.ASCO Breast Cancer Symposium 2007 (Abstract 245)

  30. RHEA: trastuzumab is effective after recurrenceof disease following adjuvant trastuzumab • 10 patients enrolled into cohort B to date • Recruitment into both cohorts ongoing Bell R, et al. ASCO Breast Cancer Symposium 2007 (Abstract 245)

  31. HER2 targeting consensus polling

  32. HER2 targeting consensus polling (cont’d)

  33. Neoadjuvant trastuzumab in LABC (NOAH): trial design HER2-positive LABC(IHC 3+ or FISH+) HER2-negative LABC(IHC 0/1+) n=115 n=113 n=99 APq3w x 3 cycles T + APq3w x 3 cycles APq3w x 3 cycles T + P q3w x 4 cycles Pq3w x 4 cycles Pq3w x 4 cycles T q3w x 4 cycles+ CMF q4w x 3 cycles CMFq4w x 3 cycles CMFq4w x 3 cycles Surgery followed byradiotherapy* Surgery followed byradiotherapy* Surgery followed byradiotherapy* T continued q3wto week 52 Primary endpoint: event-free survival AP = doxorubicin (60mg/m2), paclitaxel (150mg/m2); T = trastuzumab (8mg/kg loading dose then 6mg/kg); P = paclitaxel (175mg/m2); *Hormone receptor-positive patients will receive adjuvant tamoxifenNOAH = neoadjuvant trastuzumab plus doxorubicin, paclitaxel and CMF in locally advanced breast cancer; LABC = locally advanced breast cancer; CMF = cyclophosphamide, methotrexate and fluorouracil Gianni L, et al. J Clin Oncol2007;25:18s (Abstract 532)

  34. Neoadjuvant trastuzumab doubles the pathological response rates p=0.002 50 40 30 20 10 0 p=0.003 p=0.29 p=0.43 Patients (%) With T Without T HER2- negative With T Without T HER2- negative HER2-positive HER2-positive pCR tpCR pCR = pathological complete responsetpCR = total pCR in breast and nodes Gianni L, et al. J Clin Oncol 2007;25:18s (Abstract 532)

  35. NOAH: serious adverse events *Lung artery embolism <24 hours from surgery Gianni L, et al. J Clin Oncol 2007;25:18s (Abstract 532)

  36. NOAH: conclusions • In patients with LABC, neoadjuvant trastuzumab in combination with APPCMF chemotherapy • significantly improved the rate of invasive cancer eradication in the breast (pCR rates) and in breast plus axillary nodes (tpCR rates) • was well tolerated with an acceptable level of cardiac dysfunction • Final analysis is expected after 106 patients with HER2-positive tumours have had an event, defined as progression during neoadjuvant therapy or breast cancer relapse after surgery Gianni L, et al. J Clin Oncol 2007;25:18s (Abstract 532)

  37. MD Anderson phase III trial of neoadjuvant trastuzumab/chemotherapy • Accrual: 42 patients Paclitaxel q3w x 4 FEC x 4 T1–3, N0–1, M0 breast cancer HER2-positive (IHC 3+/FISH+) Paclitaxel q3w x 4+trastuzumab x 124mg/kg loading dosethen 2mg/kg qw FEC x 4+trastuzumab x 124mg/kg loading dosethen 2mg/kg qw Buzdar AU, et al. J Clin Oncol 2005;23:3676–85

  38. MD Anderson study: highest reported pCR rate in this patient population • Early closure by Data Monitoring Committee due to superiority of trastuzumab arm • Follow-up to this study is ongoing: NSABP B-41 • arm 1: paclitaxel + trastuzumab  FEC • arm 2: FEC  paclitaxel + trastuzumab Buzdar AU, et al. J Clin Oncol 2005;23:3676–85

  39. Conclusions: duration and modalityof trastuzumab therapy • Current data support 1 year of therapy • Current data support initiation of trastuzumab concurrently with paclitaxel (combined analysis) • Current data support initiation of trastuzumab after adjuvant therapy (HERA) • A benefit to patients cannot be excluded even when trastuzumab is started >6 months after adjuvant therapy

  40. HER2-negative disease

  41. High efficacy and well-tolerated • monotherapy in MBC • X improves OS vs CMF (p=0.02)1 • High efficacy and well tolerated • in combination with taxanes • in MBC • XT extends OS by 3 months vs T alone (p<0.01)2,3 A logical partner to further improve outcomes ± taxanes in EBC Rationale for evaluatingcapecitabine in HER2-negative EBC Capecitabine 1Stockler M, et al. Breast Cancer Res Treat 2006;100 (Abstract 6066) 2O’Shaughnessy J, et al. J Clin Oncol 2002;20:2812–233Miles D, et al. Clin Breast Cancer 2004;5:273–8 X = capecitabine; T = docetaxel

  42. US Oncology adjuvant phase III trial:ACXT • Primary endpoint: 5-year DFS • Interim data analysis planned for 2008 RANDO MIS ATION AC (4 cycles) A: 60mg/m2 C: 600mg/m2 q21d Docetaxel (4 cycles) T: 100mg/m2 d1 q21d N0, tumour > 2cm N0, ER/PR-negative N1–2 HER2-positive or -negative n=2, 610 (complete) AC (4 cycles) A: 60mg/m2 C: 600mg/m2 q21d XT (4 cycles) X: 825mg/m2 b.i.d. d1–14 T: 75mg/m2 d1 q21d 5 years’ tamoxifen or aromatase inhibitor for ER/PR-positive; Herceptin for 1 year in HER2-positive disease

  43. FinXX adjuvant phase III trial:sequential Xeloda-based combinations • Primary endpoint: relapse-free survival RANDO MIS ATION FEC (3 cycles) F: 500mg/m2 d1 E: 75mg/m2 d1 C: 600mg/m2 d1 q21d Docetaxel (3 cycles) T: 80mg/m2 d1 q21d >25% 5-year risk of recurrencenode-positive or -negative with tumour >2cmPR-negative n=1,500 (complete) CEX (3 cycles) C: 600mg/m2 d1 E: 75mg/m2 d1 X: 900mg/m2 b.i.d. d1–15 q21d XT (3 cycles) X: 900mg/m2b.i.d. d1–15 T: 60mg/m2 d1 q21d 5 years’ tamoxifen or anastrozolefor ER-positive or PR-positive Joensuu H, et al. J Clin Oncol 2007;25:18s (Abstract 11035)

  44. T FEC XT CEX Capecitabine improves tolerability: FinXX Grade 3/4 AEs: interim safety results (n=600) 14 12 10 8 6 4 2 0 Patients (%) HFS Nail changes Fatigue Myalgia Diarrhoea Neutropenic fever Infection + neutropenia HFS = hand foot syndrome Joensuu H, et al. J Clin Oncol 2007;25:18s (Abstract 11035)

  45. GAIN adjuvant trial design (node-positive, dose dense, dose intensified) • Randomisation after chemotherapy to oral ibandronate 50mg/day for 2 years or observation • Primary endpoint: event-free survival RANDO MIS ATION P (q14d x 3) 225mg/m2 d1 C (q14d x 3) 2,000mg/m2 d1 E (q14d x 3) 150mg/m2 d1 Histological complete resection 10 axillary nodes (n=2,143/3,000) Primary prophylaxis: pegfilgrastim + oral ciprofloxacin + epoetin beta or darbepoetin alfa XP X: 1,000mg/m2 b.i.d. d1–14 q21d x 4 P: 67.5mg/m2 d1 q7d x 10 EC (q14d x 4) E: 112.5mg/m2 d1 C: 600mg/m2 d1 Radiotherapy and endocrine therapy: current AGO recommendations

  46. ER-positive: aromatase inhibitor for 5 years ICE trial: adjuvant capecitabineplus ibandronate (B) • Among the first 100 patients receiving capecitabine plus ibandronate • no grade 3/4 haematological AEs • no grade 4 non-haematological AEs • grade 3 AEs: HFS (15%), diarrhoea (4%), nausea/vomiting (3%) X + B X: 1,000mg/m2 b.i.d. d1–14 q21d x 6 B: 50mg/day p.o. or 6mg i.v. q28d for 2 years* R Age 65 years(n=1,058/1,400) B alone B: 50mg/day p.o. or 6mg i.v. q28d for 2 years* Reimer T, et al. Breast Cancer Res Treat2006;100(Suppl. 1) (Abstract 2094) *Patient’s choice

  47. The mechanism of action of bevacizumab suggests that it has utility in early breast cancer EARLY EFFECTS CONTINUED EFFECTS Regression of existing tumour microvasculature1–7 Inhibition of new tumour vasculature1,2,9,10 1 3 Normalisation of remaining tumour vasculature5–8 2 Reduces tumour mass Enhances activity of concomitant therapies Prevents growth of micrometastases Efficacy in the neoadjuvant and adjuvant, as well as metastatic, settings 1Baluk P, et al. Curr Opin Genet Dev 2005;15:102–11; 2Inai T, et al. Am J Pathol 2004;165:35–52 3Erber R, et al. FASEB J 2004; 4Tong R, et al. Cancer Res 2004;64:3731–6; 5Jain R. Nat Med 2001;7:987–9 6Jain R. Science 2005;307:58–62; 7Lee C-G, et al. Cancer Res 2000;60:5565–70; 8Willett C, et al. Nat Med 2004;10:145–7 9Gerber H-P, et al. Cancer Res 2005;65:671–81; 10Warren R, et al. J Clin Invest 1995;95:1789–97

  48. Pilot study of bevacizumab plus adjuvant chemotherapy in breast cancer (E2104) Dose and schedule doxorubicin (A): 60mg/m2 q2w cyclophosphamide (C): 600mg/m2 q2w bevacizumab (B): 10mg/kg q2w paclitaxel (P): 175mg/m2 q2w First 106 patients AC + Bx 4 P + B x 4 B x 18 Resected, treatment-naïve, lymph node-positive breast cancer ECOG PS 0–2 Surgery 28–84 days prior to treatment Next 106 patients ACx 4 P + B x 4 B x 22 • Investigator-reported CHF occurred in four patients in arm A after four (n=2), six (n=1) and 17 (n=1) cycles • The incorporation of bevacizumab into anthracycline-containing adjuvant therapy is feasible based on these pilot data Miller KD, et al. Breast Cancer Res Treat 2007;106(Suppl. 1) (Abstract 3063)

  49. Phase III trial of bevacizumab plus adjuvant chemotherapy in breast cancer (E5103) AC x 4(n~1,000) RANDO MIS ATION Endpoints • Primary: DFS • Secondary: OS, toxicity, short versus long-term bevacizumab use • doxorubicin (A): 60mg/m2 q3w • cyclophosphamide (C): 600mg/m2 q3w • bevacizumab (B): 15mg/kg q3w • paclitaxel (P): 80mg/m2 q3w P x 12 PI: Kathy Miller ER-negative or high-risk ER-positive (n=4,950) AC + B x 4(n~2,000) P x 12+B x 4 AC + B x 4(n~2,000) P x 12+B x 4 B x 10

  50. Primary endpoint: invasive DFS secondary endpoints: OS, DFS, distant DFS, tolerability and safety Global recruitment Phase III trial of bevacizumab plus adjuvant chemotherapy in breast cancer (BEATRICE) Defined standard chemotherapies Triple-negative breast cancer (n=2,530) Defined standard chemotherapies + bevacizumab followed by bevacizumab single agent for up to 1 year PI: David Cameron

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