adjuvant breast cancer therapy an analysis of current treatment paradigms mark d. pegram, md...
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![Page 1: Adjuvant Breast Cancer Therapy An Analysis of Current Treatment Paradigms Mark D. Pegram, MD UCLA/Jonsson Comprehensive Cancer Center](https://reader035.vdocuments.us/reader035/viewer/2022062322/56649e205503460f94b0b272/html5/thumbnails/1.jpg)
Adjuvant Breast Cancer Therapy
An Analysis of Current Treatment Paradigms
Mark D. Pegram, MDUCLA/Jonsson Comprehensive Cancer Center
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Case Study 1: Early Breast CancerHigh-Risk, Node-Negative, HER2+
• Age 47• Premenopausal breast carcinoma• Lumpectomy - 1.3 cm poorly differentiated, high grade
infiltrating ductal carcinoma• HER2 amplified, HER2/Chr17 (FISH) ratio = 8• ER/PR negative• SLN Bx – 2 LNs negative• Lymphovascular invasion – present• SPF – 20%; KI 67 = 30%• DNA content - aneuploid
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Case Study 1: Early Breast CancerHigh-Risk, Node-Negative, HER2+
• The patient is referred to you for adjuvant therapy recommendations. In addition to post-lumpectomy radiation, which treatment option would you recommend?1. Anthracycline and/or taxane-based adjuvant chemotherapy
2. Anthracycline and taxane-based adjuvant chemotherapy regimen incorporating trastuzumab for one year
3. Anthracycline-based adjuvant chemotherapy followed by trastuzumab for one year (no taxane)
4. Non-anthracycline combination chemotherapy with trastuzumab for one year (e.g. TCH or TC→H)
5. Combination chemotherapy with trastuzumab for a period of 9 weeks
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NSABP B-31: Quality Assurance
• Initial protocol– Patients were eligible if tumors were HER2+ by an accredited
laboratory (n = 104)– All samples were re-analyzed by a central laboratory– Only 82/104 were found to be HER2+ by HercepTest and
PathVysion– 21% false positive (82% of the false-positive results were
from smaller laboratories [≤ 99 cases per month])
• Amended protocol– To be eligible, tumors must be HER2+ by a central laboratory
(n = 240)– This reduced the number of false positives from 21% to 2%
(P = 0.003)Paik S, et al. J Natl Can Inst 2002;94:852–4
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HERA Trial: DFS Benefit in SubgroupsHR: 1-Year Trastuzumab vs. Observation
0 1 2
All
Any, neo-adjuvant chemotherapyNodalstatus
0 pos, no neo-adjuvant chemotherapy
3387
3581100
872
2032307
n
0.54
0.530.52
0.77
0.640.43
1-3 pos, no neo-adjuvant chemotherapy4 pos, no neo-adjuvant chemotherapy
No anthracycline or taxaneAdjuvant chemotherapy regimen
Anthracycline, no taxaneAnthracycline + taxane
NegativeReceptor status/endocrine therapy
Pos + no endocrine therapyPos + endocrine therapy
<35 yrsAge group
35-49 yrs50-59 yrs
60 yrs
Europe, Nordic, Canada, SA, Aus, NZRegion
Asia Pacific, JapanEastern Europe
Central + South America
972953
0.510.53
1674 0.514671234
0.490.68
251 0.4714901091
0.520.53
549 0.70
2430 0.58405364
0.420.31
188 0.90
FavorsTrastuzumab
FavorsObservation
0 1 2
All
Any, neo-adjuvant chemotherapyNodalstatus
0 pos, no neo-adjuvant chemotherapy
3387
3581100
872
2032307
0.54
0.530.52
0.77
0.640.43
Hazard Ratio
1-3 pos, no neo-adjuvant chemotherapy4 pos, no neo-adjuvant chemotherapy
No anthracycline or taxaneAdjuvant chemotherapy regimen
Anthracycline, no taxaneAnthracycline + taxane
NegativeReceptor status/endocrine therapy
Pos + no endocrine therapyPos + endocrine therapy
<35 yrsAge group
35-49 yrs50-59 yrs
60 yrs
Europe, Nordic, Canada, SA, Aus, NZRegion
Asia Pacific, JapanEastern Europe
Central + South America
972953
0.510.53
1674 0.514671234
0.490.68
251 0.4714901091
0.520.53
549 0.70
2430 0.58405364
0.420.31
188 0.90
Favors Favors
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In Vitro Drug Interactions With Trastuzumab
Pegram et al. J Natl Cancer Inst. 2004;96:739.
SK-BR-3BT-474MDA-MB-361MDA-MB-453
Combination index
Carboplatin Cyclophosphamide Vinorelbine
0 1 2 0 1 2 0 1 2
SK-BR-3BT-474MDA-MB-361MDA-MB-453
Combination index
Carboplatin Cyclophosphamide Vinorelbine
0 1 2 0 1 2 0 1 2
Doxorubicin Epirubicin
SK-BR-3BT-474MDA-MB-361MDA-MB-453
Combination index 0 1 2 0 1 2
Doxorubicin Epirubicin
SK-BR-3BT-474MDA-MB-361MDA-MB-453
Combination index 0 1 2 0 1 2
Docetaxel Paclitaxel
SK-BR-3BT-474MDA-MB-361MDA-MB-453
Combination index 0 1 2 0 1 2 0 1 2
GemcitabineDocetaxel Paclitaxel
SK-BR-3BT-474MDA-MB-361MDA-MB-453
Combination index 0 1 2 0 1 2 0 1 2
Gemcitabine
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N9831: Concurrent vs Sequential Trastuzumab on Disease-Free Survival
Perez. Presentation at ASCO 2005 Symposium. http://www.asco.org.
→
0 1 2 3 4Years
ARM BAC P→ TEvents = 84
AC → P + T → TEvents = 53
HR = 0.64Stratified log rank P = 0.0114
Per
cen
t
Number of patients followed:B 842 501 285 162 20C 840 520 285 178 17
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4Years
AC TEvents = 84
ARM CAC P + T TEvents = 53
Per
cen
t
Number of patients followed:B 842 501 285 162 20C 840 520 285 178 17
100
90
80
70
60
50
40
30
20
10
0
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BCIRG 006: Schema
4 x Docetaxel100 mg/m2
HER2+(Central FISH)
N+ or high-risk N–
N = 3,222
4 x AC60/600 mg/m2
6 x Docetaxel and Carboplatin 75 mg/m2 AUC 6
1 Year Trastuzumab
1 Year Trastuzumab
ACT
ACTH
TCH
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
Stratified by nodes and
hormonal status
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BCIRG 006DFS Lymph Node Negative: 2nd Interim Analysis
99%
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events
309 35 AC→T
310 12 AC→TH
309 17 TCH
92%
97%
88%
95%
94%
86%
94%
93%
HR (AC→TH vs AC→T) = 0.32 [0.17;0.62] P = 0.0007
HR (TCH vs AC→T) = 0.47 [0.26;0.83] P = 0.0096
Year from Randomization
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BCIRG 006Cardiac Deaths and CHF
(Independent Review Panel)
AC-T
n = 1,050
AC-TH
n = 1,068
TCH
n = 1,056
Cardiac related death 0 / 0 0 / 0 0 / 0
Cardiac left ventricular function (CHF)
Grade 3 / 43 / 4 17 / 20 4 / 4
First interim analysisSecond interim analysis P = 0.0015
Slamon D. SABCS 2006
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BCIRG 006 Mean LVEF - All Observations
2nd Interim Analysis
AC→T (N=1014)
AC→TH (N=1042)
TCH (N=1030)
58
59
60
61
62
63
64
65
66
0
LVE
F p
oint
s, %
100 200 300 400 500 600 700 800 900 1000
Time since Randomization (days)
AC→T
TCH
AC→TH
Slamon D. SABCS 2006
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Patient Eligibility(Adjuvant Trastuzumab)
• Normal left ventricular ejection fraction• No past or active cardiac disease including:
– History of myocardial infarction– History of congestive heart failure– Angina pectoris requiring medication– Arrhythmia requiring medication– Clinically significant valvular disease– Uncontrolled hypertension– LVH– Cardiomegaly on CXR
Slamon D. SABCS 2006
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Asymptomatic PatientsRules for Trastuzumab Continuation
Based on Serial LVEFs
* Repeat LVEF assessment after 4 weeks – If criteria for continuation met – resume trastuzumab– If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumab
Relationship of LVEF to LNN
Absolute Decrease of
< 10%
Absolute Decrease of
10 - 15%
Absolute Decrease of
≥ 16%
Within Normal Limits Continue Continue Hold*
1-5% below LLN Continue Hold* Hold*
≥ 6% below LLN Continue Hold* Hold*
Slamon D. SABCS 2006
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n = 1,010; median follow-up 3.2 years
All patients were randomized between docetaxel and vinorelbine.HER amplified patients (n = 232) were randomized between additional trastuzumab or not.
Arm A
Arm B
FEC 600/60/600 mg/m2 Q3W * 3
Trastuzumab Q1W * 9
Docetaxel 100 mg/m2 Q3W * 3
Vinorelbine 25 mg/m2 Q1W * 3
Analysis of 4 Treatments of Fin-HerPatients (age ≤65, no HTN) either NP or NN with tumor size > 2 cm and
PgR negative. HER2 amplification determined by CISH.
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Recurrence-Free Survival (%)
No. at Risk
T 115 112 97 64 21
No T 116 109 91 51 18
0 1 2 3 4
Years
Trastuzumab
No Trastuzumab
0
20
40
60
80
10089.3%
77.6%
N Events HR P T 115 12No T 116 27 0.42 0.01
(0.21-0.83)
% P
atie
nts
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Case Study 2: Early Breast Cancer LN-positive, ER-positive
• Age 47• Premenopausal breast carcinoma• Lumpectomy - 1.3 cm poorly differentiated, high grade
infiltrating ductal carcinoma• HER2 non-amplified HER2/Chr17 (FISH) ratio = 1.91• ER/PR positive• SLN Bx – 2 LNs positive; axillary dissection – one
additional positive LN out of 20 examined• Lymphovascular invasion – present• SPF – 20%; KI 67 = 30%• DNA content - aneuploid
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Case Study 2: Early Breast Cancer LN-positive, ER-positive
• The patient is referred to you for adjuvant therapy recommendations. In addition to post-lumpectomy radiation and standard adjuvant endocrine therapy, which treatment option would you recommend?
1. Dose-dense AC followed by paclitaxel
2. AC x 4 q 3 weeks followed by weekly paclitaxel x 12
3. TAC x 6
4. FEC x 3 → docetaxel x 3
5. FEC x 6
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Larry Norton, M.D., MSKCC; Oncologic Drug Advisory Committee
“Normal” Dose Intensity & Increased Dose Density
1
102
104
106
108
1010
1012
10 765432Months
Cel
l Num
ber
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Sequential Therapy is Dose Dense
Larry Norton, M.D., MSKCC; Oncologic Drug Advisory Committee
Months
Cel
l Num
ber
1
102
104
106
108
1010
1012
10 765432
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dL = 1 - 2 (L – L0)dt
Time
Tu
mo
r V
olu
me
Braun, et al., Journal of Clinical Oncology, Vol 19, No 5 (March 1), 2001: pp 1468-1475
Comparative Analysis of Micrometastasis to the BoneMarrow and Lymph Nodes of Node-Negative Breast Cancer
Patients Receiving No Adjuvant Therapy
Micrometastasis
Lymph Node
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“…the hypothesis of uninterrupted constant growth for locally recurring tumors should be rejected.”
Demicheli, R. Sem Cancer Biol 2001:11: 297-305
Non-Gompertzian Growth of HumanSolid Tumors
Number of Tumor Cells over Time
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Intergroup/CALGB 9741 Node-Positive Stage II-IIIA
Doxorubicin (A) 60 mg/m2
Paclitaxel (T) 175 mg/m2
Cyclophosphamide (C) 600 mg/m2
3-Week Cycles 2-Week Cycles (w/ G-CSF)
24 wks36 wks
16 wks24 wks
Citron, et al. JCO 2003, 21:1431-1439
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DFS by Sequential vs Concurrent Rx11/30/2005, Median F/U = 6.5 Years
Dis
ease
-Fre
e S
urvi
val
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7Year
N Events Con 996 252 P = 0.65Seq 976 256
Sequential
Concurrent
Citron, et al. JCO 2003, 21:1431-1439
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0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7Year
Ove
rall
surv
ival
N Events ER+ q2wk 636 81ER+ q3wk 639 92
ER– q2wk 336 83ER– q3wk 327 105
P = NS
P = 0.039
ER+ q3wk
ER– q3wk
ER– q2wk ER+ q2wk
OS by ER Status & Dose Density(Exploratory Analysis) 11/30/2005
Citron, et al. JCO 2003, 21:1431-1439
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Major Toxicities – During Rx
ISeq q 3
IISeq q 2
IIICon q 3
IVCon q 2
No. Treated 488 493 501 495
No. With Data 99 96 101 101
Granulocytes < 0.5/ul 24% 3% 43% 9%
Febrile Neutropenia Hospitalized
3% 2% 5% 2%
Red Cell Transfusion 0% 2% 3% 13%
Platelet Transfusion 0% 0% 0% 0%
Neurologic: Severe Sensory Loss or Motor Weakness
1.9% 1.9% 3.9% 4.5%
Citron, et al. JCO 2003, 21:1431-1439
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Dose-dense “Confirmatory” TrialPhase III FEC q2w vs FEC q3w
• 1,214 patients (1992 – 1997)• Node positive or high-risk node negative BC• FEC 600/60/600 mg/m2 x 6 q2w G-CSF support • Median age 53 years
– 43% premenopausal– 33% hormone receptor negative
• 6.7 years median follow up• DFS: Hazard ratio 0.92, P = NS • OS: Hazard ratio 0.82, P = NS
Venturini M et al. SABCS 2003
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TAX 316/BCIRG 001 Trial Design
Stratification• Nodes
1-34+
• Center
R
F 5-FU 500 mg/m2
A Doxorubicin 50 mg/m2
C Cyclophosphamide 500 mg/m2
T Docetaxel 75 mg/m2
A Doxorubicin 50 mg/m2
C Cyclophosphamide 500 mg/m2
Dexamethasone premedication, 8 mg bid, 3 days
Prophylactic ciprofloxacin 500 mg bid, day 5-14
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TAX 316/BCIRG 001 DFS and Overall Survival
(Median Follow-Up 55 Months)
Disease-Free Survival Overall Survival
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G-CSF Prophylaxis Reduces Febrile Neutropenia Rate
Study Regimen 1° Prophylaxis FN Rate
BCIRG 001
(NEJM 2005)TAC Ciprofloxacin 24.7%
GEICAM
(ASCO 2005)TAC G-CSF 5.8%
BCIRG 005
(ASCO 2002)TAC G-CSF 6.7%
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TAX 316/BCIRG 001 Conclusions
• TAC demonstrated significantly improved disease-free survival compared to FAC – Median follow-up 55 months– 26% reduction in the risk of relapse (P = 0.0047)– Disease-free survival improved irrespective of nodal or
hormone receptor status
• Longer overall survival– Median follow-up 55 months– 31% reduction in the risk of mortality– Further analysis planned at the time survival data mature
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Intergroup E1199: Study DesignRandomized, Multicenter Phase III Study
Sparano JA et al. Protocol E-1199
Doxorubicin IV
Cyclophosphamide IV
q 3 wk x 12
ARM I
Paclitaxel 3-h IV infusion
q 3 wk x 4
ARM II
Paclitaxel 1-h IV infusion
weekly x 12
ARM III
Docetaxel 1-h IV infusion
q 3 wk x 4
ARM IV
Docetaxel 1-h IV infusion
weekly x 12
N = 4,988
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E1199: Efficacy Comparisons Disease-Free Survival
Sparano et al. Breast Cancer Res Treat. 2005; Late-Breaking Abstract 48.
Months from Randomization
66
4-Year DFS Rates (%)P3: 80.6 P1: 83.5 D3: 83.1 D1: 80.5
Percent at Risk
P3 95 86 74 333
P1 96 90 80 374
D3 96 89 77 364
D1 95 89 77 353
DF
S P
roba
bilit
y
60544842363024181260
0.0
0.2
0.4
0.6
0.8
1.0
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NSABP B-38: Schema
R
Op
era
ble
Bre
ast
Ca
nce
rH
isto
log
ica
lly P
osi
tive
No
des
Group 1Doxorubicin 50 mg/m2
Cyclophosphamide 500 mg/m2
Docetaxel 75 mg/m2 q3 weeks x 6 cycles
Group 2Doxorubicin 60 mg/m2
Cyclophosphamide 600 mg/m2 q2 weeks x 4 cyclesPaclitaxel 175 mg/m2 q2 weeks x 4 cycles
Group 3Doxorubicin 50 mg/m2
Cyclophosphamide 500 mg/m2 q2 weeks x 4 cyclesPaclitaxel 175 mg/m2 Gemcitabine 2000 mg/m2 q2 weeks x 4 cycles
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Evidence for Benefit of Taxanesin Early Stage Breast Cancer
• CALGB 9344– AC vs. AC Paclitaxel
• BCIRG 001– TAC vs. FAC
• PACS 01– FEC X 6 vs. FEC X 3 Docetaxel
• TAX 301 (Aberdeen)– Neoadjuvant CVAP X 4 vs. CVAP X 4 Docetaxel X 4
• USON– AC vs. TC
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Case Study 3: Early Breast CancerLN-negative, ER-positive
• Age 47• Premenopausal breast carcinoma• Lumpectomy - 1.5cm poorly differentiated, high grade
infiltrating ductal carcinoma• HER2 non-amplified HER2/Chr17 (FISH) ratio = 1.91• ER/PR positive• SLN Bx – 2 LNs negative• Lymphovascular invasion – present• SPF – 20%; KI 67 = 30%• DNA content - aneuploid
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Case Study 3: Early Breast CancerLN-negative, ER-positive
The patient is referred to you for adjuvant therapy recommendations. In addition to post-lumpectomy radiation and standard adjuvant endocrine therapy, which treatment option would you recommend?
1. Dose-dense AC followed by paclitaxel
2. AC x 4 q 3 weeks followed by weekly paclitaxel x 12
3. TAC x 6
4. FEC x 3 → docetaxel x 3
5. FEC x 6
6. TC x 6
7. Other
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Phase III Trial Comparing AC vs. TC as Adjuvant Therapy for Operable Breast Cancer
Jones S, et al. JCO 2006; 24:5381-5387
RANDOMIZE
Doxorubicin 60 mg/m2 IV Day 1Cyclophosphamide 600 mg/m2 IV Day 1
Every 21 days x 4 Cycles
Docetaxel 75 mg/m2 IV Day 1Cyclophosphamide 600 mg/m2 IV Day 1
Every 21 days x 4 Cycles
AC
TC
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Phase III Trial Comparing AC vs. TC as Adjuvant Therapy for Operable Breast Cancer
0 12 24 36 48 60 72
Months
0.70
0.75
0.80
0.85
0.90
0.95
1.00
Dis
ea
se
-Fre
e S
urv
iva
l
TC
AC
P = 0.015HR = 0.67
89%
86%
86%
80%
Disease-Free Survival
Jones S, et al. JCO 2006; 24:5381-5387
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Phase III Trial Comparing AC vs. TC as Adjuvant Therapy for Operable Breast Cancer
0 12 24 36 48 60 72
Months
0.70
0.75
0.80
0.85
0.90
0.95
1.00
Pro
po
rtion
Su
rviv
ing
TC
AC
P = 0.131HR = 0.76
90%
87%
94%
93%
Overall Survival
Jones S, et al. JCO 2006; 24:5381-5387
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Phase III Trial Comparing AC vs. TC as Adjuvant Therapy for Operable Breast Cancer
• Conclusions – Toxicity by Regimen
TC AC
All grades Myalgia Nausea
Arthralgia Vomiting
Edema
Grades 3&4 Febrile neutropenia Nausea
Vomiting
Jones S, et al. JCO 2006; 24:5381-5387
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Adjuvant Breast Cancer Therapy
An Analysis of Current Treatment Paradigms
Discussion