Marjorie Green Assistant Professor and Associate Medical Director of the Nellie B. Connally Breast...
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Transcript of Marjorie Green Assistant Professor and Associate Medical Director of the Nellie B. Connally Breast...
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