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

Treatment advances for earlybreast cancer: selecting patients

for optimal outcome

Marjorie GreenMD Anderson Cancer Center

Houston, Texas, USA

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

*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

NSABP B-31 (USA)(n=2,030)

HERA (ex-USA)(n=5,090)

NCCTG N9831 (USA)(n=3,505)

BCIRG 006 (global)(n=3,222)

P q3w x 4 or qw x 12P q3w x 4 or qw x 12 + T qw x 52

ObservationT q3w x 12 monthsT q3w x 24 months

Any CT ± RT

P qw x 12P qw x 12P qw x 12 + T qw x 52

D + Carbo q3w x 6 + T qw x 18

T qw x 52

AC x 4AC x 4

D q3w x 4 + T qw x 12 T q3w x 13T q3w x 11

AC x 4AC x 4AC x 4

AC x 4AC x 4

D q3w x 4

FinHer (Finland)(n=232*)

D q3w x 3 or V qw x 8 D q3w x 3 or V qw x 8 + T qw x 9

CEF q3w x 3CEF q3w x 3

Trastuzumab in early breast cancer

Baselga J, et al. Oncologist2006;11(Suppl. 1):4–12

Control

Trastuzumab

NSABP B-31 arm 1

NSABP B-31 arm 2

NCCTG N9831 arm A

NCCTG N9831 arm C

NSABP B-31/NCCTG N9831combined analysis: trial design

= 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)

NSABP B-31/NCCTG N9831 combined analysis: disease-free survival (DFS)

*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)

100

80

60

40

20

0

Aliv

e an

d di

seas

e-fr

ee (%

)

0 1 2 3 4 5 6 7Follow-up (years)

Updated N9831/B-31 Joint AnalysisDFS*

ACP+T(n=1,989; 222 events)

ACP(n=1,979; 397 events)

92.3%

86.4%89.9%

77.6%

85.9%

73.1%

1,854 1,347 868 522 202 41,800 1,235 753 460 168 8

No.at risk

n=619 eventsHR* adjuvant = 0.48 (95% CI: 0.41–0.57)*Nodes, receptor status, paclitaxel schedule, protocolp<0.00001

NSABP B-31/NCCTG N9831 combined analysis: cumulative incidence of cardiac events

*Patients randomised to ACP who received H were censored at the date that H was first administered

Perez EA, et al. J Clin Oncol 2007;512:185 (Abstract 512)

Cardiac tolerability – N9831Cumulative incidence of cardiac events

ACP+T(n=875)

%

ACP*(n=767)

%Time from start of T3 months 1.4 06 months 1.8 0.21 year 2.5 0.22 years 2.5 0.23 years 2.5 0.2Number of events 22 CHF 1 CHF

1 cardiac death

CHF = congestive heart failure

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

ACP+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)

After ASCO 2005, option of switch to trastuzumab

HERA trial design

Primary endpoint: DFS Secondary endpoints: overall survival (OS), time to

recurrence (TTR), time to distant recurrence (TTDR),safety (three interim analyses of cardiac endpoints)

1-year trastuzumab8mg/kg → 6mg/kg3 weekly schedule

Surgery + (neo)adjuvant chemotherapy ± radiotherapy

Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%

Randomisation

2 years trastuzumab8mg/kg → 6mg/kg3 weekly schedule

Observation

Women with locally determined HER2-positive invasive early breast cancer

X

IHC = immunohistochemistry; FISH = fluorescent in situ hybridisationLVEF = left ventricular ejection fraction

1,703 1,591 1,434 1,127 742 383 1401,698 1,535 1,330 984 639 334 127

100

80

60

40

20

0

Patie

nts

(%)

Months from randomisation

1-year trastuzumab

Observation

0 6 12 18 24 30 36

No. at risk

Events HR 95% CI p value0.64 0.54, 0.76 <0.0001

3-yearDFS80.674.3

218321

HERA: DFS (intent-to-treat)

6.3%

Smith I, et al. Scientific special session, ASCO 2006

Median follow-up = 2 years

Observation

1-year trastuzumab

0.66 0.47, 0.91 0.011592.489.7

5990

HERA: OS (intent-to-treat)Median follow-up = 2 years

Months from randomisation0 6 12 18 24 30 36

Events HR 95% CI p value3-yearDFS

1,627 1,498 1,190 794 407 1461,608 1,453 1,097 711 366 139

No. at risk 1,7031,698

2.7%100

80

60

40

20

0

Patie

nts

(%)

Smith I, et al. Scientific special session, ASCO 2006

*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%

HERA: adverse eventsPatients, n (%)

Observation(n=1,466)

1-year trastuzumab(n=1,688)

Patients with 1 grade 3/4 AE 88 (6.0) 190 (11.3)

Patients with 1 serious AE 97 (6.6) 156 (9.2)

Fatal AE 3* (0.2) 9† (0.5)

Treatment withdrawals 172 (10.2‡)

Smith I, et al. Scientific special session, ASCO 2006AE = adverse event

HERA: cardiac safety

Patients, n (%)Observation

(n=1,708)1-year trastuzumab

(n=1,678)Cardiac death 1 (0.1) 0

Severe CHF (NYHA III and IV) 0 10 (0.6)

Symptomatic CHF (II, III and IV) 3 (0.2) 36 (2.1)

Confirmed significant LVEF drop 9 (0.5) 51 (3.0)

Trastuzumab discontinued due to cardiac problems 72 (4.3)

Smith I, et al. Scientific special session, ASCO 2006NYHA = New York Heart Association

Case presentation 1

Patient TK: history TK is a 57-year-old woman diagnosed

with 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

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

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 EFACE = angiotensin-converting enzyme

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

BCIRG 006: trial design

1-year trastuzumab

AC D

AC DT

DCarboT

HER2-positiveby FISH

n=3,222

4 x AC60/600mg/m2

4 x docetaxel100mg/m2

1-year trastuzumab

6 x docetaxel and carboplatin75mg/m2

Node-positiveand high-risk node-negative EBC

AUC 6

Slamon D, et al. Breast Cancer Res Treat 2005;94(Suppl. 1) (Abstract 1)EBC = early breast cancer

Patie

nts

(%)

Years from randomisation

100

90

80

70

60

50 0 1 2 3 4 5

93%

86% 84%

80%80%

91%

86%

77%73%n

1,0741,0751,073

Events 77 98147

ACDTDCarboTACD

HR=0.49HR=0.61

BCIRG 006: DFS

First interim efficacy analysis(cut-off date 30 June 2005)

Median follow-up = 23 months

Slamon D, et al. Breast Cancer Res Treat 2005;94(Suppl. 1) (Abstract 1)

BCIRG 006: interim cardiac safety analysis –clinically significant events

*5/20 arrhythmias not yet adjudicated by independent review panel(two in ACD, one in ACDT, two in DCarboT)

Patients, n

ACD(n=1,050)

ACDT(n=1,068)

DCarboT(n=1,056)

Cardiac death 0 0 0

Cardiac ischaemia/infarction Grade 3/4 0 4 1

Arrhythmia Grade 3/4 7* 4* 9*

CHF Grade 3/4 3 17 4

Slamon D, et al. Breast Cancer Res Treat 2005;94(Suppl. 1) (Abstract 1)

FinHer: trial design

Primary endpoint = recurrence-free survival Secondary endpoints = adverse events, effect of treatment on

LVEF, TTDR, OS

HER2-positivebreast cancer(n=232)

Docetaxelq3w x 3 ORvinorelbineqw x 8

Docetaxelq3w x 3 ORvinorelbineqw x 8+ trastuzumab qw x 9

Fluorouracil, epirubicin, cyclophosphamide q3w x 3

Fluorouracil, epirubicin, cyclophosphamide q3w x 3

Joensuu H, et al. N Engl J Med 2006;354:809–20

FinHer: recurrence-free survival

Recurrence-free survival significantly improved in the trastuzumab group

Median follow-up = 3 years

Joensuu H, et al. N Engl J Med 2006;354:809–20

Patie

nts

(%)

100

80

60

40

20

00 1 2 3 4

YearsNo. at riskTrastuzumab 115 112 97 64 21No trastuzumab116 109 91 51 18

HR=0.42 (95% CI: 0.21–0.83)p=0.01

97.4

94.091.3

83.6

89.3

77.6

Trastuzumab

No trastuzumab

Summary of trastuzumab efficacy in early breast cancer: DFS

0 1 2Favours trastuzumab Favours no trastuzumab

HR

Median follow-up

FinHer VH/DH*(n=231) 3 years

BCIRG 006 DCarboH(n=2,148) 2 years

BCIRG 006 AC DH(n=2,147) 2 years

HERA(n=3,387) 1 year

Combined analysis(n=3,351) 2 years

*Recurrence-free survival Baselga J, et al. Oncologist 2006;11(Suppl. 1):4–12

Case presentation

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

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

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

Retreatment with adjuvanttrastuzumab (RHEA): trial design

Primary endpoint = overall response rate Secondary endpoints = clinical benefit rate, survival, safety Planned cohort size = 40 patients in each

HER2-positive breast cancerIHC 3+/FISH+Baseline LVEF 50%Relapsed 12 months after 10 months of adjuvant trastuzumab-based therapy

Cohort ATrastuzumab 4mg/kg loading dose then 2mg/kg qw

Cohort BTrastuzumab +docetaxel 100mg/m2 q3w x 6 orpaclitaxel 175mg/m2 q3w x 6 or75mg/m2 qw x 18

Bell R, et al.ASCO Breast Cancer Symposium 2007 (Abstract 245)

RHEA = Retreatment after HErceptin Adjuvant trial

RHEA: trastuzumab is effective after recurrenceof disease following adjuvant trastuzumab

10 patients enrolled into cohort B to date Recruitment into both cohorts ongoing

Cohort B (trastuzumab + taxane) (n=10)

PR 4

Duration of response (months) 4.2–12

Stable disease 4

Bell R, et al. ASCO Breast Cancer Symposium 2007 (Abstract 245)

HER2 targeting consensus pollingQuestion Poll Comment

Premenopausal: should HER2-positive patients get anthracyclines

85% Yes

Premenopausal: should HER2-positive patients avoid anthracyclines

80% No

Premenopausal: should HER2-positive patients get alkylating agents

82% Yes; no consensus on administration of platinum

‘Triple negative’ patients versus HER2-positive only; should they get the same chemotherapy

>80%

Yes; no consensus on which chemotherapy regimen, but most did not like the FEC regimen

Postmenopausal: should HER2-positive get anthracyclines 50% No consensus

Postmenopausal: should HER2-positive get taxanes 50% No consensus

Should you use the HERA model 64% Yes

Should you use chemotherapy and trastuzumab concurrently 64% Yes

Which regimen do you prefer: HERA modelConcurrent regimenNo preference

37%41%22%

To get breakdown of expert preference for trastuzumab-containing adjuvant regimens

Neoadjuvant therapy: give trastuzumab to HER2-positve patients

82% Yes

Question Poll Comment

Use trastuzumab if IHC testing is 3+ 92% Yes

Do you need FISH amplification before giving trastuzumab 84% Yes

Will you give trastuzumab as adjuvant therapy in patients with very small T1 tumours, node negative and hormone non-responsive

56% Yes

Will you give trastuzumab as adjuvant therapy in patients with <2cm T1 tumours, node negative and hormone responsive

60% Yes

In hormone responsive patients give hormones alone and trastuzumab

60% Yes; no data available for this position

Give trastuzumab for 1 year 92% Yes

Use the FinHer regimen (9 weeks) 14% No (20% don’t know)

Use trastuzumab if <50% LEVF 74% Avoid trastuzumab

Use trastuzumab in elderly patients not suitable for chemotherapy 60% Would still use trastuzumab

Use ACE inhibitors for patients on trastuzumab 80% No

Use lapatinib if there was cardiotoxicity from trastuzumab 21% Yes; 13% abstain

HER2 targeting consensus polling (cont’d)

Neoadjuvant trastuzumab in LABC (NOAH): trial design

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)

HER2-positive LABC(IHC 3+ or FISH+)

HER2-negative LABC(IHC 0/1+)

APq3w x 3 cycles

n=115 n=113 n=99

Primary endpoint: event-free survival

Pq3w x 4 cycles

CMFq4w x 3 cycles

APq3w x 3 cycles

Pq3w x 4 cycles

CMFq4w x 3 cycles

Surgery followed byradiotherapy*

T + APq3w x 3 cycles

T + P q3w x 4 cycles

T q3w x 4 cycles+ CMF q4w x 3 cycles

T continued q3wto week 52

Surgery followed byradiotherapy*

Surgery followed byradiotherapy*

Neoadjuvant trastuzumab doubles the pathological response rates

43

23

17

38

2016

50

40

30

20

10

0 With T Without T HER2- negative

With T Without T HER2- negative

Patie

nts

(%)

HER2-positive HER2-positive

pCR tpCRpCR = pathological complete responsetpCR = total pCR in breast and nodes Gianni L, et al. J Clin Oncol 2007;25:18s (Abstract 532)

p=0.29

p=0.002

p=0.003

p=0.43

*Lung artery embolism <24 hours from surgery

NOAH: serious adverse events

Gianni L, et al. J Clin Oncol 2007;25:18s (Abstract 532)

HER2-positiveHER2-negative

(n=99)With T (n=115) Without T (n=113)Total patients with ≥1 serious AE 17 9 10Sudden post-surgery death* 0 0 1Cardiac toxicity 1 0 0Febrile neutropenia 9 4 3Neutropenia grade 4, hospitalised 0 3 0Fever with pneumonitis 0 0 1Fever and pharyngitis 2 0 0Infection 2 0 3Stomatitis 0 1 2Diarrhoea 0 2 0Vomiting 1 1 0

NOAH: conclusions In patients with LABC, neoadjuvant trastuzumab in

combination with APPCMF 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)

Paclitaxel q3w x 4

Paclitaxel q3w x 4+

trastuzumab x 124mg/kg loading dose

then 2mg/kg qw

MD Anderson phase III trial of neoadjuvant trastuzumab/chemotherapy

Accrual: 42 patients

T1–3, N0–1, M0breast cancerHER2-positive(IHC 3+/FISH+)

Buzdar AU, et al. J Clin Oncol 2005;23:3676–85

FEC x 4

FEC x 4+

trastuzumab x 124mg/kg loading dose

then 2mg/kg qw

pCR (%)Paclitaxel + FEC

(n=19)Paclitaxel + FEC +

trastuzumab (n=23)Overall 26.3 65.2

p value 0.016 0.016

Hormone receptor-positive 27.2 61.5

Hormone receptor-negative 25.0 70.0

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

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

HER2-negative disease

Rationale for evaluatingcapecitabine in HER2-negative EBC

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;5:273–8X = capecitabine; T = docetaxel

Capecitabine

High efficacy and well-toleratedmonotherapy in MBC X improves OS vs CMF

(p=0.02)1

High efficacy and well toleratedin combination with taxanes in MBCXT extends OS by 3 months

vs T alone (p<0.01)2,3

A logical partner to further improve outcomes ± taxanes in EBC

RANDO MISATION

US Oncology adjuvant phase III trial:ACXT

Primary endpoint: 5-year DFS Interim data analysis planned for 2008

N0, tumour > 2cmN0, ER/PR-negativeN1–2

HER2-positive or -negativen=2, 610 (complete)

XT (4 cycles)X: 825mg/m2 b.i.d. d1–14T: 75mg/m2 d1 q21d

Docetaxel (4 cycles)T: 100mg/m2 d1 q21d

AC (4 cycles)A: 60mg/m2

C: 600mg/m2

q21d

AC (4 cycles)A: 60mg/m2

C: 600mg/m2 q21d

5 years’ tamoxifen or aromatase inhibitor for ER/PR-positive; Herceptin for 1 year in HER2-positive disease

XT (3 cycles)X: 900mg/m2 b.i.d. d1–15T: 60mg/m2 d1 q21d

>25% 5-year risk of recurrencenode-positive or -negative with tumour >2cmPR-negative

n=1,500 (complete)

FinXX adjuvant phase III trial:sequential Xeloda-based combinations

Primary endpoint: relapse-free survival

Docetaxel (3 cycles)T: 80mg/m2

d1 q21d

FEC (3 cycles)F: 500mg/m2 d1E: 75mg/m2 d1C: 600mg/m2 d1 q21d

CEX (3 cycles)C: 600mg/m2 d1 E: 75mg/m2 d1X: 900mg/m2 b.i.d. d1–15 q21d

5 years’ tamoxifen or anastrozolefor ER-positive or PR-positive Joensuu H, et al. J Clin Oncol 2007;25:18s (Abstract 11035)

RANDO MISATION

Capecitabine improves tolerability: FinXXGrade 3/4 AEs: interim safety results (n=600)

Neutro

penic

feve

r

Infectio

n +

neutro

penia

Diarrhoea HFS

Myalgia

Fatigue

Nail

chan

ges

Patie

nts

(%)

14

12

10

8

6

4

2

0

Joensuu H, et al. J Clin Oncol 2007;25:18s (Abstract 11035)

TFECXTCEX

HFS = hand foot syndrome

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

Histological complete resection 10 axillary nodes(n=2,143/3,000) XP

X: 1,000mg/m2 b.i.d. d1–14 q21d x 4P: 67.5mg/m2 d1 q7d x 10

RANDO MISATION

Radiotherapy and endocrine therapy: current AGO recommendations

P (q14d x 3)225mg/m2 d1

C (q14d x 3)2,000mg/m2 d1

Primary prophylaxis: pegfilgrastim + oral ciprofloxacin + epoetin beta or darbepoetin alfa

E (q14d x 3)150mg/m2 d1

EC (q14d x 4)E: 112.5mg/m2 d1C: 600mg/m2 d1

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 + BX: 1,000mg/m2 b.i.d. d1–14

q21d x 6B: 50mg/day p.o. or 6mg i.v.

q28d for 2 years*

*Patient’s choice

ER-positive: aromatase inhibitor for 5 years

Reimer T, et al. Breast Cancer Res Treat2006;100(Suppl. 1) (Abstract 2094)

Age 65 years(n=1,058/1,400)

B aloneB: 50mg/day p.o. or 6mg i.v.

q28d for 2 years*

R

The mechanism of action of bevacizumab suggests that it has utility in early

breast cancer

EARLY EFFECTS CONTINUED EFFECTS

Normalisation of remaining tumour vasculature5–8

1

2

Regression of existing tumour microvasculature1–7

Inhibition of new tumour vasculature1,2,9,10

3

Reduces tumour massEnhances activity of concomitant therapiesPrevents 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;165:35–523Erber 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

Pilot study of bevacizumab plus adjuvant chemotherapy in breast cancer (E2104)

AC + Bx 4

ACx 4

P + Bx 4

P + B x 4

B x 18

B x 22

First 106 patients

Next 106 patients

Dose and schedule– doxorubicin (A): 60mg/m2 q2w– cyclophosphamide (C): 600mg/m2 q2w– bevacizumab (B): 10mg/kg q2w– paclitaxel (P): 175mg/m2 q2w

Resected, treatment-naïve, lymph node-positive breast cancerECOG PS 0–2Surgery 28–84 days prior to treatment

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)

P x 12+

B x 4

P x 12AC x 4

(n~1,000)

P x 12+

B x 4

AC + B x 4

(n~2,000)

B x 10AC + B

x 4(n~2,000)

Phase III trial of bevacizumab plus adjuvant chemotherapy in breast cancer (E5103)

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

PI: Kathy MillerER-negative

or high-risk ER-positive(n=4,950)

RANDO MISATION

Phase III trial of bevacizumab plus adjuvant chemotherapy in breast cancer (BEATRICE)

Primary endpoint: invasive DFS – secondary endpoints: OS, DFS, distant DFS, tolerability and safety

Global recruitment

Defined standard chemotherapies

Defined standard chemotherapies + bevacizumab followed by bevacizumab

single agent for up to 1 yearPI: David Cameron

Triple-negative breast cancer

(n=2,530)

Conclusions: adjuvant breast cancer The data support the use of trastuzumab with

chemotherapy as adjuvant treatment for women with HER2-positive early breast cancer

The benefits of trastuzumab far outweigh the risks of cardiac toxicity, although this should be discussed with the patient

Preliminary safety data suggest that capecitabine and bevacizumab may be well tolerated in adjuvant breast cancer– large ongoing trials are investigating these agents

in this setting