adjuvant breast cancer therapy an analysis of current treatment paradigms
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Adjuvant Breast Cancer Therapy An Analysis of Current Treatment Paradigms. Mark D. Pegram, MD UCLA/Jonsson Comprehensive Cancer Center. Age 47 Premenopausal breast carcinoma Lumpectomy - 1.3 cm poorly differentiated, high grade infiltrating ductal carcinoma - PowerPoint PPT PresentationTRANSCRIPT
Adjuvant Breast Cancer Therapy
An Analysis of Current Treatment Paradigms
Mark D. Pegram, MDUCLA/Jonsson Comprehensive Cancer Center
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
“…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
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
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
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
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
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
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
TAX 316/BCIRG 001 DFS and Overall Survival
(Median Follow-Up 55 Months)
Disease-Free Survival Overall Survival
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%
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
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
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
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
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
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
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
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
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
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
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
Adjuvant Breast Cancer Therapy
An Analysis of Current Treatment Paradigms
Discussion