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Adjuvant Breast Cancer Therapy An Analysis of Current Treatment Paradigms

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Title: Adjuvant Breast Cancer Therapy An Analysis of Current Treatment Paradigms


1
Adjuvant Breast Cancer Therapy An Analysis of
Current Treatment Paradigms
  • Mark D. Pegram, MDUCLA/Jonsson Comprehensive
    Cancer Center

2
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

3
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?
  • Anthracycline and/or taxane-based adjuvant
    chemotherapy
  • Anthracycline and taxane-based adjuvant
    chemotherapy regimen incorporating trastuzumab
    for one year
  • Anthracycline-based adjuvant chemotherapy
    followed by trastuzumab for one year (no taxane)
  • Non-anthracycline combination chemotherapy with
    trastuzumab for one year (e.g. TCH or TC?H)
  • Combination chemotherapy with trastuzumab for a
    period of 9 weeks

4
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 2002948524
5
HER2 Adjuvant (HERA) TrialSchema
Women HER2 IHC 3/FISH Node negative and node
positive N 4,482
Primary management (surgery chemotherapy
local, or locoregional radiation)

Stratify
Randomize
Trastuzumab q3w x 12 months n 1,530
Trastuzumab q3w x 24 months n 1,530
Observation
6
HERA TrialDisease-Free Survival
7
HERA Trial DFS Benefit in SubgroupsHR 1-Year
Trastuzumab vs. Observation
8
In Vitro Drug Interactions With Trastuzumab
Pegram et al. J Natl Cancer Inst. 200496739.
9
N9831 Concurrent vs Sequential Trastuzumab on
Disease-Free Survival
Perez. Presentation at ASCO 2005 Symposium.
http//www.asco.org.
10
BCIRG 006 Schema
11
BCIRG 006Patient Characteristics
Randomized (n 3,222) AC-Tn 1,073 AC-THn 1,074 TCHn 1,075

Age lt 50 years 52 52 54
KPS 100 80 79 80
Mastectomy 60 63 60
Radiotherapy 63 61 63
Hormonotherapy 50 51 51
Enrollment April 2001 to March 2004
12
BCIRG 006Tumor Characteristics
Randomized (n 3,222) AC-Tn 1,073 AC-THn 1,074 TCHn 1,075
Number of nodes
0 29 29 29
1 3 38 38 39
4 10 22 24 23
gt 10 11 9 10
Tumor Size (cm)
? 2 41 38 40
gt 2 and ? 5 53 55 54
gt 5 6 7 6
ER and/or PR 54 54 54
13
BCIRG 006Disease-Free Survival 2nd Interim
Analysis
14
BCIRG 006DFS Lymph Node Negative 2nd Interim
Analysis
15
BCIRG 006DFS in Subpopulations
Slamon D. SABCS 2006
16
BCIRG 006Grade 3/4 Hematological Toxicity
AC-Tn 1,050 AC-THn 1,068 TCH n 1,056
Neutropenia 63.3 71.3 66.2
Leucopenia 51.5 60.2 48.2
Febrile neutropenia 9.1 11.0 9.8
Neutropenic infection 11.3 12.0 11.0
Anemia 2.5 3.1 5.8
Thrombocytopenia 1.0 1.2 5.4
Leukemia () 3 pts (0.3) 1 pt (0.1) 0 pts
Orange numerically less events AC-TH or
TCH Statistically significant AC-TH or TCH
Slamon D. SABCS 2006
17
BCIRG 006Grade 3/4 Non-Hematological Toxicity
AC-Tn 1,050 AC-THn 1,068 TCH n 1,056
Arthralgia 3.2 3.3 1.4
Myalgia 5.2 5.2 1.8
Fatigue 7.0 7.3 7.2
Hand-foot syndrome 1.9 1.4 0.0
Stomatitis 3.6 3.1 1.4
Diarrhea 3.0 5.7 5.5
Nausea 6.0 5.7 4.8
Vomiting 6.1 6.8 3.4
Irregular menses 27.1 24.2 26.4
Orange numerically less events AC-TH or
TCH Statistically significant AC-TH or TCH
Slamon D. SABCS 2006
18
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 / 4 3 / 4 17 / 20 4 / 4
First interim analysis Second interim analysis
P 0.0015
Slamon D. SABCS 2006
19
BCIRG 006 Mean LVEF - All Observations2nd
Interim Analysis
Slamon D. SABCS 2006
20
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
21
Asymptomatic PatientsRules for Trastuzumab
ContinuationBased on Serial LVEFs
Relationship of LVEF to LNN Absolute Decrease of lt 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
  • 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

Slamon D. SABCS 2006
22
Therapeutic Index Most Recent Data
  • Difference in DFS, OS and BC death events (ITT)
    between the 2 trastuzumab-containing arms
  • DFS AC-TH 128 TCH 142
  • OS AC-TH 49 TCH 56
  • Br Ca Deaths AC-TH 44 TCH 47
  • Difference in critical adverse events between
    anthracycline and non-anthracycline containing
    arms
  • Grade 3/4 CHF AC-T 5 AC-TH 20 TCH
    4
  • Leukemia Anthracycline-Based Arms 4 TCH
    0
  • Global safety TCH gt AC-TH
  • In addition, 23 pts with bona fide HER2
    amplification who were randomized to the AC-TH
    arm never got trastuzumab due to unacceptable
    declines in LVEF before receiving the antibody

Slamon D. SABCS 2006
23
Analysis of 4 Treatments of Fin-HerPatients (age
65, no HTN) either NP or NN with tumor size gt 2
cm and PgR negative. HER2 amplification
determined by CISH.
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.
24
Recurrence-Free Survival ()
25
Fin-HER Summary
  • Brief use of adjuvant trastuzumab adminstered
    concomitantly with docetaxel or vinorelbine is
    well tolerated and effective for HER2-postive
    breast cancer
  • The optimal duration of adjuvant trastuzumab has
    not yet been defined
  • Results from the Fin-HER study opens the door for
    future trial designs exploring short vs. long
    adjuvant trastuzumab

26
Forest Plot for Disease-Free Survival
27
Monoclonal Antibody to HER-2/neu Receptor
Enhances Radiosensitivity of Human Breast Cancer
Cells Overexpressing HER-2/neu
Pietras et al. Cancer Res 59 (6) 1347 (1999).
28
  • Who? HER2-amplified ESBC
  • How much? 6 mg/kg q 3 weeks
  • How long? 1 year
  • During/after chemo? During
  • Which chemo? Non-anthracycline regimens work
    too,
  • and are less toxic
  • Endocrine therapy? Yes
  • With XRT? Yes

29
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

30
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?
  • Dose-dense AC followed by paclitaxel
  • AC x 4 q 3 weeks followed by weekly paclitaxel x
    12
  • TAC x 6
  • FEC x 3 ? docetaxel x 3
  • FEC x 6

31
Normal Dose Intensity Increased Dose Density
Larry Norton, M.D., MSKCC Oncologic Drug
Advisory Committee
32
Sequential Therapy is Dose Dense
Larry Norton, M.D., MSKCC Oncologic Drug
Advisory Committee
33
Intergroup 0137 Concurrent vs. Sequential Therapy
Haskell, Proc ASCO, 2002
34
3,176 patients randomized (4/18/94-5/1/97) Median
follow-up 5.3 years
5-Year Results IDENTICAL Sequential
Dose-Dense Regimen MORE TOXIC
The results do not support the hypothesis of
Norton Simon
Haskell, Proc ASCO Plenary, 2002
35
Comparative Analysis of Micrometastasis to the
BoneMarrow and Lymph Nodes of Node-Negative
Breast CancerPatients Receiving No Adjuvant
Therapy
Braun, et al., Journal of Clinical Oncology, Vol
19, No 5 (March 1), 2001 pp 1468-1475
36
Non-Gompertzian Growth of HumanSolid Tumors
the hypothesis of uninterrupted constant growth
for locally recurring tumors should be rejected.
Demicheli, R. Sem Cancer Biol 200111 297-305
37
Intergroup/CALGB 9741 Node-Positive Stage II-IIIA
Citron, et al. JCO 2003, 211431-1439
38
DFS by Sequential vs Concurrent Rx11/30/2005,
Median F/U 6.5 Years
Citron, et al. JCO 2003, 211431-1439
39
DFS by Sequential vs Concurrent Arm11/30/2005
Citron, et al. JCO 2003, 211431-1439
40
OS by ER Status Dose Density(Exploratory
Analysis) 11/30/2005
Citron, et al. JCO 2003, 211431-1439
41
Major Toxicities During Rx
I Seq q 3 II Seq q 2 III Con q 3 IV Con q 2
No. Treated 488 493 501 495
No. With Data 99 96 101 101
Granulocytes lt 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, 211431-1439
42
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
43
Effects of CT on ER-Node Breast Cancer20-Year
Experience of CALGB U.S. Breast Intergroup
Berry DA, et al. SABCS 2004. Abstract 29
44
Alternative to Dose-DenseAdjuvant Regimens
  • Use more active agents with conventional dosing
    intervals

45
TAX 316/BCIRG 001 Trial Design
46
TAX 316/BCIRG 001 Patient Characteristics
Randomized (n 1,491) TAC n 745 FAC n 746
Median age, yr 49 49
Median KPS, 100 100
Premenopausal, 50 48
Mastectomy, 60 59
Radiotherapy, 69 72
Tamoxifen, 68 69
Enrollment June 1997 to June 1999 Enrollment June 1997 to June 1999 Enrollment June 1997 to June 1999
Martin M et al. Presentation. SABCS, 2003
Abstract 43
47
TAX 316/BCIRG 001 Tumor Characteristics
TAC n 745 FAC n 746
Nodal status
1-3 62 62
4-10 30 31
gt 10 8 7
Tumor size, cm
2 40 43
gt 2 and 5 53 51
gt 5 7 6
ER and/or PR 76 76
HER2 (FISH) 19 20
Martin M et al. Presentation. SABCS, 2003
Abstract 43
48
TAX 316/BCIRG 001 Exposure to Treatment
Randomized (n 1,480) TAC n 744 FAC n 736
Completed 6 Cycles 678 (91) 711 (97)
Relative dose intensity
Median 0.99 0.98
gt 0.90 90 85
Median total dose, mg/m2
Docetaxel 449
Doxorubicin 299 300
Cyclophosphamide 2,995 2,998
5-FU 2,998
Martin M et al. Presentation. SABCS, 2003
Abstract 43
49
TAX 316/BCIRG 001 DFS and Overall
Survival(Median Follow-Up 55 Months)
50
TAX 316/BCIRG 001 Disease-Free Survival(Median
Follow-Up 55 Months)
51
TAX 316/BCIRG 001 Overall Survival(Median
Follow-Up 55 Months)
52
TAX 316/BCIRG 001 DFS by Nodal and Hormonal
Status
No. of Positive Nodes Number of Patients Hazard Ratio 95 CI
Overall 744 0.74 0.60, 0.92
1-3 467 0.64 0.47, 0.87
4 277 0.84 0.63, 1.12
Receptor Status
Positive 566 0.76 0.59, 0.98
Negative 178 0.68 0.48, 0.97
A hazard ratio lt 1 indicates that TAC is associated with longer disease-free survival compared to FAC A hazard ratio lt 1 indicates that TAC is associated with longer disease-free survival compared to FAC A hazard ratio lt 1 indicates that TAC is associated with longer disease-free survival compared to FAC A hazard ratio lt 1 indicates that TAC is associated with longer disease-free survival compared to FAC
Martin M et al. Presentation. SABCS, 2003
Abstract 43
53
TAX 316/BCIRG 001 Treatment Emergent Adverse
Events
Hematologic () TAC n 744 TAC n 744 FAC n 736 FAC n 736
All Gr 3/4 All Gr 3/4
Neutropenia 71.4 65.5 82.0 49.3
Febrile neutropenia 24.7 2.5
Neutropenic infection 12.1 6.3
Infection 39.4 3.9 36.3 2.2
Anemia 91.5 4.3 71.7 1.6
Thrombocytopenia 39.4 2.0 27.7 1.2
Blood Transfusions 4.6 1.5
No septic deaths in either treatment arm No septic deaths in either treatment arm No septic deaths in either treatment arm No septic deaths in either treatment arm No septic deaths in either treatment arm
Martin M et al. Presentation. SABCS, 2003
Abstract 43
54
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
55
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

56
Intergroup E1199 Study DesignRandomized,
Multicenter Phase III Study
Sparano JA et al. Protocol E-1199
57
E1199 Efficacy Comparisons Disease-Free Survival
Sparano et al. Breast Cancer Res Treat. 2005
Late-Breaking Abstract 48.
58
E1199 Toxicity
Toxicity P3 P1 D3 D1
Grade 3 24 24 21 39
Grade 4 6 4 50 6

Neutropenia 4 2 46 3
Febrile neutropenia lt 0.5 1 16 1
Infection 3 4 13 5
Stomatitis lt 0.5 0 5 2.5
Fatigue 2 3 9 11
Neuropathy 5 8 4 6
Tearing lt 0.5 0 lt 0.5 5
Sparano et al. Breast Cancer Res Treat. 2005
Late-Breaking Abstract 48.
59
NSABP B-38 Schema
60
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

61
Early Stage Breast CancerKey Points
  • Integration of taxanes into adjuvant therapy is
    an important advance
  • Choice of taxane, dose, and schedule are being
    defined in ongoing trials (NSABP B38, BCIRG 005,
    etc.)
  • Could dose density be of some benefit for
    selected patients?
  • ER-negative subset analysis consistent with
    hypothesis that only most rapidly dividing cells
    are sensitive to chemotherapy scheduling effects
    (i.e. dose density)
  • Dose dense chemo of no apparent benefit in ER dz
  • The use of more active combination regimens (i.e.
    TAC) may preclude the need for dose dense
    schedules, and are an acceptable alternative for
    management of LN ESBC

62
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

63
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?
  • Dose-dense AC followed by paclitaxel
  • AC x 4 q 3 weeks followed by weekly paclitaxel x
    12
  • TAC x 6
  • FEC x 3 ? docetaxel x 3
  • FEC x 6
  • TC x 6
  • Other

64
Final Analysis TC (Docetaxel/Cyclophosphamide,
4 Cycles) has a Superior Disease-Free Survival
Compared to Standard AC (Doxorubicin/Cyclophospham
ide) in 1,016 Women with Early Stage Breast
Cancer
  • Stephen Jones, Savin MA, Holmes FA ,
    OShaughnessy JA, Blum JL, Vukelja SJ, George TK,
    McIntyre KJ, Pippen JE, Sandbach J, Kirby RL,
    Bordelon JH, Hyman WJ, Negron AG, Khandelwal P,
    Richards DA, Anthony S, Monaghan GG, Nugent JE,
    Mennel RG, Banerji M, Edelman G, Good R, Ruxer
    RL, Amare M, Kampe CE, Koutrelakos N, Meyer WG,
    Asmar L. US Oncology Research, Houston, TX,
    USAResearch supported by sanofi-aventis, New
    York, NY

65
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
Jones S, et al. JCO 2006 245381-5387
66
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • Primary Objective
  • To compare the disease-free survival (DFS) of AC
    vs. TC in early operable breast cancer
  • Secondary Objectives
  • To determine overall survival with AC vs. TC
  • To determine the safety of the 2 regimens

Jones S, et al. JCO 2006 245381-5387
67
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • Inclusion Criteria
  • Patients with Stage I, II, or operable Stage III
    invasive breast cancer
  • Complete surgical excision of the primary tumor
  • Age gt18 years
  • Adequate renal function
  • Adequate hematologic function
  • Adequate hepatic function
  • Karnofsky PS gt80
  • Signed informed consent

Jones S, et al. JCO 2006 245381-5387
68
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • Exclusion Criteria
  • Invasive cancer gt7 cm or lt1 cm in size
  • Neo-adjuvant chemotherapy for locally advanced
    breast cancer
  • Prior chemotherapy or radiation therapy for other
    cancer within 3 years of date of diagnosis of
    breast cancer
  • Pregnant or lactating women
  • Other significant malignancy or other major
    illness

Jones S, et al. JCO 2006 245381-5387
69
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • Statistical Plan (I)
  • Trial designed to compare DFS with AC vs. TC
  • Projected 5-year DFS for TC 80
  • Sample size planned to detect a 10 improvement
    in DFS with TC
  • Planned N 1016
  • a 0.05 2-sided power (1-b) 0.90

Jones S, et al. JCO 2006 245381-5387
70
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • Statistical Plan (II)
  • Planned interim analysis based on 105 events
    (ASCO 2003)
  • Final analysis based on 174 events (SABCS 2005)

Jones S, et al. JCO 2006 245381-5387
71
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • Definition of Disease-Free Survival
  • Events used to determine DFS
  • Any recurrence (local or distant)
  • Death due to any cause without recurrence
  • A new second breast cancer or other cancer

Jones S, et al. JCO 2006 245381-5387
72
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • Randomization Stratification
  • Lymph node status
  • 0
  • 1-3
  • 4
  • Age
  • lt 50 years
  • 50 years

Jones S, et al. JCO 2006 245381-5387
73
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • Treatment Plan
  • All chemotherapy was administered before
    radiation therapy (XRT)
  • Full doses of AC and TC were used based on actual
    BSA (no cap)
  • Tamoxifen was administered to all patients with
    hormone receptor-positive breast cancer after
    chemotherapy XRT

Jones S, et al. JCO 2006 245381-5387
74
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • Results Patient Characteristics
  • Between June 1997 and December 1999, 1016
    patients were randomized
  • TC (n 506) or AC (n 510)
  • Median age 52 years (range, 27-77)
  • Treatment groups (TC and AC) were well balanced
    with respect to major prognostic features

Jones S, et al. JCO 2006 245381-5387
75
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • TC AC
  • 506 (100) 510 (100)
  • Race
  • White 432 (85.5) 430 (84)
  • Black 33 (6.5) 41 (8)
  • Hispanic 36 (7) 33 (7)
  • Other 5 (1) 6 (1)
  • Stage
  • I 104 (20) 112 (22)
  • II 373 (74) 364 (71)
  • III 27 (5) 34 (7)
  • Unknown 2 (1) 0
  • Histology
  • Infiltrating Ductal 446 (88)
    439 (86)
  • Infiltrating Lobular 34 (7)
    38 (7.5)
  • Mixed 26 (5) 33 (6.5)

Patient Demographics
Jones S, et al. JCO 2006 245381-5387
76
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • TC AC
  • 506 (100) 510 (100)
  • ER
  • ER PR 298 (59) 288 (56)
  • ER- PR 17 (3) 19 (4)
  • ER PR- 52 (10) 45 (9)
  • ER- PR- 137 (27) 157 (31)
  • Unknown 2 (1) 1 (lt1)
  • HER2 (FISH)
  • Positive 28 (5) 18 (4)
  • Negative 55 (11) 69 (13)
  • Unknown 423 (84) 423 (83)
  • Positive Nodes
  • 0 239 (47) 248 (49)
  • 1-3 209 (41) 212 (42)
  • 4 58 (12) 50 (9)

Patient Demographics (contd)
Jones S, et al. JCO 2006 245381-5387
77
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
Hematologic Toxicities () TC TC AC AC
All Grades Grades 3/4 All Grades Grades 3/4
Neutropenia 63 59 58 55
Neutropenic fever 6 3
Anemia 6 lt1 9 1
Throbocytopenia lt1 lt1 lt1 lt1
Significant (P 0.03). Actual number of
cases TC 31 and AC 16
Jones S, et al. JCO 2006 245381-5387
78
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
Hematologic Toxicities () TC TC AC AC
All Grades Grades 3/4 All Grades Grades 3/4
Asthenia 79 3 78 5
Infection 21 11 23 12
Nausea 53 2 81 7
Vomiting 16 lt1 43 5
Edema 35 lt1 2 lt1
Myalgia 33 1 17 lt1
Arthralgia 24 1 15 1
Paresthesia 6 0 4 lt1
CHF 0 0 0 0
Significant (P lt 0.01) Significant (P lt 0.01) Significant (P lt 0.01) Significant (P lt 0.01) Significant (P lt 0.01)
Jones S, et al. JCO 2006 245381-5387
79
Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
Results (median follow-up 66 months) Results (median follow-up 66 months) Results (median follow-up 66 months)
AC 506 () TC 510 ()
Local or distant relapses or second cancer 59 (12) 80 (16)
Death (all causes) 55 (11) 71 (14)
Death (without relapse) 7 (1) 12 (2)
Death on treatment 2 (lt1) 0
1 cardiac and 1 with sepsis and neutropenia 1 cardiac and 1 with sepsis and neutropenia 1 cardiac and 1 with sepsis and neutropenia
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Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
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Exploratory AnalysisForest Plot of DFS Hazard
Ratios for Major Subgroups
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Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
Overall Survival
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Phase III Trial Comparing AC vs. TC as Adjuvant
Therapy for Operable Breast Cancer
  • Conclusions
  • At a median follow-up of 66 months, TC compared
    to AC was associated with
  • Superior DFS (HR0.67, P 0.01)
  • Improved OS (HR0.76, P 0.13)
  • Different toxicity profile

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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 34 Febrile neutropenia
    Nausea
  • Vomiting

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Adjuvant Breast Cancer Therapy An Analysis of
Current Treatment Paradigms
  • Discussion
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