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 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
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Marjorie Green Assistant Professor and Associate Medical Director of the Nellie B. Connally Breast Center at the MD Anderson Cancer Center, Houston, Texas,
Marjorie Green MD Anderson Cancer Center Houston, Texas, USA Treatment advances for early breast cancer: selecting patients for optimal outcome Marjorie Green MD Anderson Cancer Center Houston, Texas, USA
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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
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)
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
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)
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
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)
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