Adjuvant Breast Cancer Therapy

An Analysis of Current Treatment Paradigms Mark D. Pegram, MD UCLA/Jonsson Comprehensive Cancer Center

Case Study 1: Early Breast Cancer

High-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 Cancer

High-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 Subgroups

HR: 1-Year Trastuzumab vs. Observation

Nodal status Any, neo-adjuvant chemotherapy 1-3 pos, no neo-adjuvant chemotherapy



4 pos, no neo-adjuvant chemotherapy Anthracycline, no taxane Anthracycline + taxane Receptor status/endocrine therapy Pos + no endocrine therapy Pos + endocrine therapy Age group 35-49 yrs 50-59 yrs



60 yrs Asia Pacific, Japan Eastern Europe Central + South America n 358 1100 972 953 203 2307 467 1234 1490 1091 405 364 Hazard Ratio 0.53

0.52

0.51

0.53

0.64

0.43

0.49

0.68

0.52

0.53

0.42

0.31

Favors Trastuzumab Favors Observation

In Vitro

Drug Interactions With Trastuzumab

Pegram et al. J Natl Cancer Inst. 2004;96:739.

N9831: Concurrent vs Sequential Trastuzumab on Disease-Free Survival

ARM C AC → P + T T ARM B AC → P → T Events = 84 HR = 0.64

Stratified log rank P = 0.0114

Perez. Presentation at ASCO 2005 Symposium. http://www.asco.org.

HER2+ (Central FISH) N+ or high-risk N – N = 3,222 Stratified by nodes and hormonal status

BCIRG 006: Schema

4 x AC 60/600 mg/m 2 4 x Docetaxel 100 mg/m 2 AC  T 4 x AC 60/600 mg/m 2 4 x Docetaxel 100 mg/m 2 AC  TH 1 Year Trastuzumab 6 x Docetaxel and Carboplatin 75 mg/m 2 AUC 6 TCH 1 Year Trastuzumab

BCIRG 006

DFS Lymph Node Negative: 2 nd Interim Analysis 99% 97% 92% 95% 94% 88% 94% 93% 86% 0 Patients Events 309 310 35 12 AC→T AC→TH 309 17 TCH 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

1 2 3 Year from Randomization 4 5

BCIRG 006

Cardiac Deaths and CHF (Independent Review Panel) Cardiac related death Cardiac left ventricular function (CHF) Grade 3 / 4 AC-T n = 1,050 AC-TH n = 1,068 TCH n = 1,056 0 / 0 0 / 0 0 / 0 3 / 4 17 / 20 4 / 4 First interim analysis Second interim analysis

P

= 0.0015

Slamon D. SABCS 2006

BCIRG 006 Mean LVEF - All Observations

2 nd Interim Analysis 66 65 64 63 62 61 60 59 58 0 100 200 AC→T (N=1014) AC→TH (N=1042) TCH (N=1030) 300 400 500 600 Time since Randomization (days) 700 800 900 TCH AC→T AC→TH 1000 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 Patients

Rules for Trastuzumab Continuation Based on Serial LVEFs Relationship of LVEF to LNN Within Normal Limits Absolute Decrease of < 10% Absolute Decrease of 10 - 15% Absolute Decrease of ≥ 16% 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

Analysis of 4 Treatments of Fin-Her

Patients (age ≤65, no HTN) either NP or NN with tumor size > 2 cm and PgR negative. HER2 amplification determined by CISH.

Arm A Arm B 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. Docetaxel 100 mg/m 2 Q3W * 3 Vinorelbine 25 mg/m 2 Q1W * 3 FEC 600/60/600 mg/m 2 Q3W * 3 Trastuzumab Q1W * 9

Recurrence-Free Survival (%)

100 80 60 40 20 0 0 No. at Risk T No T 115 116 1 112 109 89.3% Trastuzumab 77.6% No Trastuzumab

T No T N 115 116 Events HR

P

12 27 0.42 0.01

(0.21-0.83)

2 97 91 Years 3 64 51 4 21 18

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

“Normal” Dose Intensity & Increased Dose Density 10 12 10 10 10 8 10 6 10 4 10 2 1 0 1 2 3 Months 4 5 6 7 Larry Norton, M.D., MSKCC; Oncologic Drug Advisory Committee

Sequential Therapy is Dose Dense

10 12 10 10 10 8 10 6 10 4 10 2 1 0 1 2 3 Months 4 5 6 7 Larry Norton, M.D., MSKCC; Oncologic Drug Advisory Committee

Comparative Analysis of Micrometastasis to the Bone Marrow and Lymph Nodes of Node-Negative Breast Cancer Patients Receiving No Adjuvant Therapy Micrometastasis dL =  1 dt  2 (L – L 0 ) Lymph Node Time Braun, et al., Journal of Clinical Oncology, Vol 19, No 5 (March 1), 2001: pp 1468-1475

Non-Gompertzian Growth of Human Solid Tumors

“…the hypothesis of uninterrupted constant growth for locally recurring tumors should be rejected.” Number of Tumor Cells over Time Demicheli, R. Sem Cancer Biol 2001:11: 297-305

Intergroup/CALGB 9741

Node-Positive Stage II-IIIA 3-Week Cycles 24 wks 2-Week Cycles (w/ G-CSF) 16 wks 36 wks 24 wks Doxorubicin (A) 60 mg/m 2 Paclitaxel (T) 175 mg/m 2 Cyclophosphamide (C) 600 mg/m 2 Citron, et al. JCO 2003, 21:1431-1439

DFS by Sequential vs Concurrent Rx

11/30/2005, Median F/U = 6.5 Years 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2 3 Year 4 Concurrent Sequential N Events Con 996 252 Seq 976 256

P

= 0.65

5 6 7 Citron, et al. JCO 2003, 21:1431-1439

OS by ER Status & Dose Density

(Exploratory Analysis) 11/30/2005 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 ER – q2wk ER+ q2wk ER+ q3wk ER – q3wk N Events ER+ q2wk 636 81 ER+ q3wk 639 92

P

= NS ER – q2wk 336 83 ER – q3wk 327 105

P

= 0.039

1 2 3 Year 4 5 6 7 Citron, et al. JCO 2003, 21:1431-1439

Major Toxicities – During Rx

I Seq q 3 II Seq q 2 III Con q 3 IV Con q 2 No. Treated No. With Data Granulocytes < 0.5/ul Febrile Neutropenia Hospitalized Red Cell Transfusion Platelet Transfusion Neurologic: Severe Sensory Loss or Motor Weakness 488 99 24% 3% 0% 0% 1.9% 493 96 3% 501 101 43% 495 101 9% 2% 2% 0% 5% 3% 0% 2% 13% 0% 1.9% 3.9% 4.5% Citron, et al. JCO 2003, 21:1431-1439

Dose dense “Confirmatory” Trial Phase III FEC q2w vs FEC q3w

• 1,214 patients (1992 – 1997) • Node positive or high-risk node negative BC • FEC 600/60/600 mg/m 2 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

R

Stratification • Nodes 1-3 4+ • Center

TAX 316/BCIRG 001 Trial Design

F A C 5-FU Doxorubicin Cyclophosphamide 500 mg/m 2 50 mg/m 2 500 mg/m 2 T A C Docetaxel Doxorubicin Cyclophosphamide 75 mg/m 2 50 mg/m 2 500 mg/m 2 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 BCIRG 001 (NEJM 2005) GEICAM (ASCO 2005) BCIRG 005 (ASCO 2002) Regimen TAC 1 ° Prophylaxis Ciprofloxacin FN Rate 24.7% TAC TAC G-CSF G-CSF 5.8% 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 Design

Randomized, Multicenter Phase III Study Doxorubicin IV Cyclophosphamide IV q 3 wk x 12 N = 4,988

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 Sparano JA et al. Protocol E-1199

1.0

E1199:

Efficacy Comparisons Disease-Free Survival

0.8

0.6

0.4

0.2

0.0

P3 P1 D3 D1 P3: 80.6

95 96 96 95 4-Year DFS Rates (%) P1: 83.5

D3: 83.1

Percent at Risk 86 90 89 89 74 80 77 77 D1: 80.5

33 37 36 35 3 4 4 3 0 6 12 18 24 30 36 42 Months from Randomization 48 54 60 66 Sparano et al. Breast Cancer Res Treat. 2005; Late-Breaking Abstract 48.

R

NSABP B-38: Schema

Group 1 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 Docetaxel 75 mg/m 2 q3 weeks x 6 cycles Group 2 Doxorubicin 60 mg/m 2 Cyclophosphamide 600 mg/m 2 q2 weeks x 4 cycles Paclitaxel 175 mg/m 2 q2 weeks x 4 cycles Group 3 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 q2 weeks x 4 cycles Paclitaxel 175 mg/m 2 Gemcitabine 2000 mg/m 2 q2 weeks x 4 cycles

Evidence for Benefit of Taxanes in 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 Cancer

LN-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 Cancer

LN-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

R A N D O M I Z E

AC TC Doxorubicin Cyclophosphamide 60 mg/m 2 600 mg/m 2 IV Day 1 IV Day 1 Every 21 days x 4 Cycles Docetaxel Cyclophosphamide 75 mg/m 600 mg/m Every 21 days x 4 Cycles 2 2 IV Day 1 IV Day 1 Jones S, et al. JCO 2006; 24:5381-5387

Phase III Trial Comparing AC vs. TC as Adjuvant Therapy for Operable Breast Cancer

1.00

0.95

0.90

0.85

0.80

0.75

0.70

0 P = 0.015

HR = 0.67

12

Disease-Free Survival

24 89% 86% 36 M onths TC AC 86% 80% 48 60

Jones S, et al. JCO 2006; 24:5381-5387

72

Phase III Trial Comparing AC vs. TC as Adjuvant Therapy for Operable Breast Cancer

1.00

0.95

0.90

0.85

0.80

0.75

0.70

0

Overall Survival

94% 93% TC AC P = 0.131

HR = 0.76

12 90% 87% 24 36 M onths 48 60

Jones S, et al. JCO 2006; 24:5381-5387

72

Phase III Trial Comparing AC vs. TC as Adjuvant Therapy for Operable Breast Cancer • Conclusions – Toxicity by Regimen All grades TC Myalgia Arthralgia Edema Grades 3&4 Febrile neutropenia AC Nausea Vomiting Nausea Vomiting Jones S, et al. JCO 2006; 24:5381-5387

Adjuvant Breast Cancer Therapy

An Analysis of Current Treatment Paradigms

Discussion