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

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