Advances In Adjuvant Systemic Therapy Of Breast Cancer
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Transcript of Advances In Adjuvant Systemic Therapy Of Breast Cancer
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October 18, 2008 1
Advances in Adjuvant Systemic Therapy of Breast Cancer
Anne F. Schott, MD
University of Michigan
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October 18, 2008 2
Who to Treat With What?
Current struggles in the real world…
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When all you have is a hammer…
• Chemotherapy• Endocrine therapy• Targeted therapy
(ie trastuzumab)• Radiotherapy
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Patient Example
• A 44 year old healthy premenopausal woman has the following pathologic diagnosis:– Left breast lumpectomy: Invasive ductal
carcinoma (1.8 cm), Bloom-Richardson grade 2. No angiolymphatic invasion.
– Sentinel lymph node biopsy: 2/4 lymph nodes positive, ALND no more nodes +
– ER positive (96%), PR positive (84%), Her-2/neu 2+, FISH negative (ratio 1.37)
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Adjuvant! 8.0 10-Year Prognosis
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NCCN Guidelines 2008
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Worldwide Overview: Chemotherapy vs no chemotherapy, by age &ER, ratio of recurrence rates in years 0-4
Age ER-poor ER+
<50 0.57 (0.07) 0.51 (0.06)
50-59 0.65 (0.07) 0.75 (0.05)
60-69 0.78 ( 0.08) 0.81 (0.05)
Sir Richard Peto, SABCS, 2007
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Common Adjuvant Regimens
First Generation → Second
Generation → Third Generation
CMF*6 → CAF*6, CEF*6
CMF*6 → FAC*6 → TAC*6
CE(50)F*6 → CE(100)F*6 → FEC*3→D*3
AC*4 →AC*4→Txl*4
q3wk →Dose Dense (CA*4→Txl*4
q2wk)
AC*4 → TC*4
20% 20%
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Worldwide Overview: Taxane vs no chemo: Age <50
RECURRENCE rate ratio
years 0-4 only
BREAST CANCER MORTALITY
rate ratio
CMF vs no chem 0.56 (0.05) 0.68 (0.05)
Anthr. Vs CMF 0.84 (0.05) 0.81 (0.05)
Taxane vs Anthr. 0.84 ( 0.04) 0.86 (0.05)
Taxan vs no chem 0.38 (0.07)
Multiplying 3 RR 2p<0.00001
0.46 (0.08)
2p>0.00001
Sir Richard Peto, SABCS, 2007
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What is “standard treatment”?
Trastuzumab-containing regimen Oncotype Dx, treat if intermediate or high
risk No chemotherapy 2nd Generation chemotherapy (TC, FEC) 3rd Generation chemotherapy (TAC,
FEC-D, ddAC-Taxol)
XX
X
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2nd Versus 3rd Generation Regimen: Differences in Relapse at 10 years (Adjuvant! 8.0)
2nd Generation Regimen
3rd Generation Regimen
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Years
Pro
po
rtio
n
0 2 4 6 8 10
0.0
0.2
0.4
0.6
0.8
1.0
DFS: Her2 CB11 < 50% / ER negative
No TaxolTaxol
Years
Pro
po
rtio
n
0 2 4 6 8 10
0.0
0.2
0.4
0.6
0.8
1.0
DFS: Her2 CB11 < 50% / ER positive
No TaxolTaxol
Years
Pro
po
rtio
n
0 2 4 6 8 10
0.0
0.2
0.4
0.6
0.8
1.0
DFS: Her2 CB11 >= 50% / ER negative
No TaxolTaxol
Years
Pro
po
rtio
n
0 2 4 6 8 10
0.0
0.2
0.4
0.6
0.8
1.0
DFS: Her2 CB11 >= 50% / ER positive
No TaxolTaxol
ER Neg ER Pos
HE
R2
NE
GH
ER
2 P
OS
HER2 is Predictive of Paclitaxel Benefit
By Estrogen Receptor
Disease Free Survival
n = 1322
paclitaxel
No paclitaxel
paclitaxel
No paclitaxel
paclitaxel
No paclitaxel
paclitaxel
No paclitaxel
n=390 (29%)
n=144 (11%)
n=703 (53%)
n=79 (6%)
YearsHayes D.F., et al. N Engl J Med. 357:1496-506, 2007
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Common Adjuvant Regimens
First Generation → Second
Generation → Third Generation
CMF*6 → CAF*6, CEF*6
CMF*6 → FAC*6 → TAC*6
CE(50)F*6 → CE(100)F*6 → FEC*3→D*3
AC*4 →AC*4→Txl*4
q3wk →Dose Dense (CA*4→Txl*4
q2wk)
AC*4 → TC*4
20% 20%
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US Oncology: TC vs AC
RANDOMIZE
Doxorubicin 60 mg/m2 IV Day 1
Cyclophosphamide 600 mg/m2 IV Day 1
Every 21 days x 4 cycles
Docetaxel 75 mg/m2 IV Day 1
Cyclophosphamide 600 mg/m2 IV Day 1
Every 21 days x 4 cycles
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2nd Generation Adjuvant Chemo Trials
First Generation → Second
Generation → Third Generation
CMF*6 → CAF*6, CEF*6
CMF*6 → FAC*6 → TAC*6
CE(50)F*6 → CE(100)F*6 → FEC*3→D*3
AC*4 →AC*4→Txl*4
q3wk →Dose Dense (CA*4→Txl*4
q2wk)
AC*4 → TC*4
CALGB 40101
ddAC versus ddTaxol
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3rd Generation Adjuvant Chemo TrialsTrial Name
Patient Population
Control Arm Experimental Therapy
Concept
S0221 High Risk Dose dense AC-Taxol
metronomic AC-Taxol
Optimal scheduling
E5103 Her-2 negative
AC-weekly Taxol
bevacizumab Adds new agent
PACS08 Triple Negative
FEC-docetaxel ixabepilone Substitutes new agent
ALTTO Her-2 positive
Anthracycline regimen and trastuzumab
lapatinib Adds/substitutes new agent
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October 18, 2008 19
Can Bisphosphonates Prevent Bone Metastasis?
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Effects of Bisphosphonates on Antitumor Activity in Preclinical Models
Tumor-induced osteolysis
Tumor cell proliferation and viability
Metastatic behavior of tumor cells
Activity of cytostatic drugs
Angiogenesis
Tumor burden in vivo
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Comparison of Adjuvant Breast Cancer Trials of Clodronate vs. Placebo/Control
Diel/Jaschke Powles Saarto
No. of patients 290 1069 299
Treatment site single multi-center single institution institution
Selection BM+ Stage I-III LN+
Treatment length (y) 2 2 3
Control arm observation placebo observation
Follow-up time (y) 8.5 10 10
Skeletal effect + (5 yrs) + NS
Overall survival + + NS
Jaschke Jaschke et al. Proc ASCO, 2004et al. Proc ASCO, 2004 Powles Powles et al. Breast Cancer Res, 2006et al. Breast Cancer Res, 2006Saarto Saarto et al. Acta Oncol 43:80-82, 2004et al. Acta Oncol 43:80-82, 2004
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Adjuvant Clodronate vs Placebo: Survival
Powles TJ et al, Br Cancer Res, 2006
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Phase III Studies of Bisphosphonates Vs. Placebo/Control as Adjuvant Therapy for Breast Cancer with DFS Endpoint
• NSABP B-34: (3 years) n=3,200 stage I-IIPlacebo
vs.Clodronate 1,600 mg po qd
• BIG/AZUREBIG/AZURE: (5 years) n=3,300 stage II-III: (5 years) n=3,300 stage II-IIIControlControl
vs.vs.Zoledronic acid 4 mg IV q mo x 6, followed by q3 mo x 2 yrs, Zoledronic acid 4 mg IV q mo x 6, followed by q3 mo x 2 yrs,
followed by q6 mofollowed by q6 mo
ClosedClosed
ClosedClosed
• German/GAINGerman/GAIN: (2 years) LN positive: (2 years) LN positiveETC vs. EC-TXETC vs. EC-TX
xxIbandronate 50 mg po qd vs observationIbandronate 50 mg po qd vs observation
OpenOpen
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ABCSG-12 Trial Design
• 1,803 premenopausal breast cancer patients
• Endocrine-responsive• Stage I&II, <10 positive nodes• No chemotherapy except
neoadjuvant• Treatment duration: 3 years
Surgery
(+RT)
Goserelin
3.6 mg q28dRandomize
1:1:1:1
Tamoxifen 20 mg/d
Tamoxifen 20 mg/d + Zoledronic Acid
4 mg q 6 mo
Anastrozole 1 mg/d
Anastrozole 1 mg/d + Zoledronic Acid
4 mg q 6 mo
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First DFS Events (ITT Population)
No ZOL vs ZOL
1010 8
20
10
9
29
41
0102030405060708090
No ZOL (n=904) ZOL (n=899)
Nu
mb
er o
f p
atie
nts
Locoregional
Distant
Contralateral
Secondary malig
Death w/o recur
ASCO 2008 meeting, Gnant
60 months
HR=0.64
P=.011
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SWOG 0307
Drug Dose Route Interval
Arm 1Zoledronic acid 4 mg* IV q4 wks x 6,
then q3mo x 2.5 yrs
Arm 2Clodronate 1,600 mg oral daily x 3
yrsArm 3Ibandronate 50 mg oral daily x 3
yrs
*Zoledronic acid dose adjusted for baseline renal function*Zoledronic acid dose adjusted for baseline renal function
Current accrual 1958/4500Current accrual 1958/4500
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First DFS Events (ITT Population)
TAM vs ANA
9 1010 6
1614
29 41
0
10
20
30
40
50
60
70
80
TAM (n=900) ANA (n=903)
Nu
mb
er o
f p
atie
nts
Locoregional
Distant
Contralateral
Secondary malig
Death w/o recur
ASCO 2008 meeting, Gnant
60 months
HR=1.096
P=.593
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What Endocrine Therapy?
• Aromatase inhibitors are indicated in the adjuvant treatment of postmenopausal women, either alone or following tamoxifen
• Early data does not support superiority of aromatase inhibitors in premenopausal women
• Many women become menopausal with chemotherapy
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29Petrek et al JCO 2006
Bleeding after Chemotherapy by Patient Age
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Bleeding after Chemotherapy by Type of Regimen
Petrek et al JCO 2006
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SchemaSchema
HR+ patients with postmenopausal E2,amenorrhea > 8 weeks
Start AI therapy
Monitor E2 levels at 2, 4, 6, 8, 10, 12 wksMeasure other hormone levels less often
E2<10 E2 10-20 E2>20
Continue AI therapy,monitoring (18 mo)
Off studyRecheck E2 levels
in 1 week
E2<10 E2>10
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Patient Example: Adjuvant Systemic Therapy Recommendations
• 2nd or 3rd generation chemotherapy– Chemotherapy trial– Bisphosphonate trial – S0307
• Tamoxifen– SOFT clinical trial
• If menopausal, switch to AI after 2-5 years of tamoxifen– “Early switch” endocrine therapy trial APPEL
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October 18, 2008 34
Neoadjuvant Chemotherapy: Issues and Controversies
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Patient Example
• BL is a 58 year old postmenopausal woman who was discovered to have a 3.0 cm breast mass on imaging
• ER 89%, PR 7%, H2N 1+
• Surgeon feels breast conservation possible but better cosmesis after neoadjuvant therapy
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StratificationStratification• • AgeAge• • Clinical Tumor SizeClinical Tumor Size• • Clinical Nodal StatusClinical Nodal Status
+ TAM if + TAM if >>50 y50 y
AC x 4AC x 4+ TAM if + TAM if >>50 yrs.50 yrs.
AC x 4AC x 4
NSABP B-18
Operable Breast CancerOperable Breast Cancer
OperationOperation
OperationOperation
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P < 0.01P < 0.01
PreopPreopChemoChemo
PostopPostopChemoChemo
B-18Lumpectomy Rate
60%60%68%68%
80%80%
60%60%
40%40%
20%20%
00
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Local Therapy
Pros• Downstaging of
primary tumor and lymph nodes
• Less radical local-regional therapy needed
• Breast conservation possible more often
Cons• Pathologic nodal staging
requires additional procedure– FNA of nodes– up-front SLNB
• Local treatment delayed for nonresponders
• Decisions for XRT complicated
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Systemic Therapy
Pros• In vivo assessment of
response, could potentially improve treatment by “tailoring” based on response
• Good biologic model to evaluate effects of chemotherapy tumors – Predicitve factor
development– Acceleration of adjuvant
regimen development
Cons• Potential for
overtreatment in some subsets of patients
• Unclear what to do in ER positive, node negative disease
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Which tumors > 1, <5 cm definitely get chemotherapy (pre or post)?
ER or PR positive
ER/PR both negative
Node negative ?? ++
Node positive ++ ++
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Which tumors > 1, <5 cm definitely get endocrine therapy (pre or post)?
ER or PR positive
ER/PR both negative
Node negative ++ -
Node positive ++ -
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Patient Recommendations
• Sentinel Lymph Node Biopsy– 0/1 lymph node positive
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Patient Example: OncotypeDX Results
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Gianni, L. et al. J Clin Oncol; 23:7265-7277 2005
Probability of pathologic complete response (pCR) as a function of Recurrence Score
Gianni, L. et al. J Clin Oncol; 23:7265-7277 2005
doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2) every 3 weeks x 3, followed by weekly paclitaxel (80 mg/m2) x 12.
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Recurrence Score Predicts CR to Neoadjuvant Docetaxel (Chang, BCRT 2008)
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Patient Recommendations (Level 3 evidence)
• Sentinel Lymph Node Biopsy– 0/1 lymph node positive
• Begin neoadjuvant hormonal therapy
• Send Recurrence Score– Low risk, no chemotherapy– Intermediate risk, consider chemotherapy if
poor response– High risk, chemotherapy
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October 18, 2008 47
Using the Neoadjuvant Model To Develop New Systemic Therapies
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Common Adjuvant Regimens
First Generation → Second
Generation → Third Generation
CMF*6 → CAF*6, CEF*6
CMF*6 → FAC*6 → TAC*6
CE(50)F*6 → CE(100)F*6 → FEC*3→D*3
AC*4 →AC*4→Txl*4
q3wk →Dose Dense (CA*4→Txl*4
q2wk)
AC*4 → TC*4
20% 20%
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pCR as Surrogate Marker for DFS
Bear, et al. JCO. May 1, 2006
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pCR in The Neoadjuvant Model Would Have Predicted Trastuzumab Efficacy
0
10
20
30
40
50
60
70
P-FEC n=19 P-FEC-H n=23
PD
SD
PR
CR
Journal of Clinical Oncology, Vol 23, No 16 (June 1), 2005: pp. 3676-3685
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National Neoadjuvant Chemo TrialsTrial Name
Patient Population
Control Arm Experimental Therapy
Concept
ACOSOG-Z1041
Her-2 positive FEC-75 then paclitaxel-trastuzumab
Paclitaxel-trastuzumab then FEC-75-trastuzumab
Optimal scheduling, toxicity
NSABP B40
Palpable and operable cancer
Docetaxel then AC
Add gemcitabine or capecitabine, add bevacizumab or not
Adds new agents, data mines for predictive factors
CALGB 40601
Her-2 positive Anthracycline then taxane-trastuzumab
Add carbo or not, add or substitute lapatinib
Adds and/or substitutes new agent
S0800 Locally advanced, Her-2 negative
Nab-paclitaxel then AC
Add sunitinib or not, AC first or second
Adds new agent, support schedule “equivalence”
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Diffusion MRI: Functional Diffusion Mapping
Red – increase ADCGreen – stable ADCBlue – decrease ADC
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Schema
Pre-Treatment Evaluation
Baseline MRI
Repeat Baseline MRIRepeat Baseline MRI
Chemotherapy A
Post-Chemo A MRI
Chemotherapy BSurgery
Chemotherapy A
Post-Chemo A MRI
Chemotherapy B
Post-Chemo B MRI
Part One Part Two
Pre-Chemo B MRI
10 patients 14 patients
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Diffusion MRI, Interim Results
% vol inc > 2.5%Response
Case #±.025 null
thresh±.05 null
threshafter Part A
only
1 1.02 1.61 cPR
2 1.14 1.75 cPR
4 1.04 1.40 cPR
5 -0.23 -0.33 cSD
7 -1.62 -2.40 cSD
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Diffusion MRI Interim Results
% vol inc > 2.5%Response
Case #±.025 null
thresh±.05 null thresh
after Part A only
after Parts A & B
1 1.02 1.61 cPR cCR, pCR
3 1.14 1.75 cPR cPR, pCR
4 1.04 1.40 cPR cPR, pPR
5 -0.23 -0.33 cSD cPR, pPR
7 -1.62 -2.40 cSD cPR, pPR
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What’s the Goal?
• Select patients who will require systemic therapy for neoadjuvant treatment
• Find predictive factors (either before or early in treatment) that allow for accurate tailoring of therapy