October 18, 2008 1

Advances in Adjuvant Systemic Therapy of Breast Cancer

Anne F. Schott, MD

University of Michigan

October 18, 2008 2

Who to Treat With What?

Current struggles in the real world…

3

When all you have is a hammer…

• Chemotherapy• Endocrine therapy• Targeted therapy

(ie trastuzumab)• Radiotherapy

4

Patient Example

• A 44 year old healthy premenopausal woman has the following pathologic diagnosis:– Left breast lumpectomy: Invasive ductal

carcinoma (1.8 cm), Bloom-Richardson grade 2. No angiolymphatic invasion.

– Sentinel lymph node biopsy: 2/4 lymph nodes positive, ALND no more nodes +

– ER positive (96%), PR positive (84%), Her-2/neu 2+, FISH negative (ratio 1.37)

5

Adjuvant! 8.0 10-Year Prognosis

6

NCCN Guidelines 2008

7

Worldwide Overview: Chemotherapy vs no chemotherapy, by age &ER, ratio of recurrence rates in years 0-4

Age ER-poor ER+

<50 0.57 (0.07) 0.51 (0.06)

50-59 0.65 (0.07) 0.75 (0.05)

60-69 0.78 ( 0.08) 0.81 (0.05)

Sir Richard Peto, SABCS, 2007

8

Common Adjuvant Regimens

First Generation → Second

Generation → Third Generation

CMF*6 → CAF*6, CEF*6

CMF*6 → FAC*6 → TAC*6

CE(50)F*6 → CE(100)F*6 → FEC*3→D*3

AC*4 →AC*4→Txl*4

q3wk →Dose Dense (CA*4→Txl*4

q2wk)

AC*4 → TC*4

20% 20%

9

Worldwide Overview: Taxane vs no chemo: Age <50

RECURRENCE rate ratio

years 0-4 only

BREAST CANCER MORTALITY

rate ratio

CMF vs no chem 0.56 (0.05) 0.68 (0.05)

Anthr. Vs CMF 0.84 (0.05) 0.81 (0.05)

Taxane vs Anthr. 0.84 ( 0.04) 0.86 (0.05)

Taxan vs no chem 0.38 (0.07)

Multiplying 3 RR 2p<0.00001

0.46 (0.08)

2p>0.00001

Sir Richard Peto, SABCS, 2007

10

What is “standard treatment”?

Trastuzumab-containing regimen Oncotype Dx, treat if intermediate or high

risk No chemotherapy 2nd Generation chemotherapy (TC, FEC) 3rd Generation chemotherapy (TAC,

FEC-D, ddAC-Taxol)

XX

X

11

2nd Versus 3rd Generation Regimen: Differences in Relapse at 10 years (Adjuvant! 8.0)

2nd Generation Regimen

3rd Generation Regimen

12

Years

Pro

po

rtio

n

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 < 50% / ER negative

No TaxolTaxol

Years

Pro

po

rtio

n

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 < 50% / ER positive

No TaxolTaxol

Years

Pro

po

rtio

n

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 >= 50% / ER negative

No TaxolTaxol

Years

Pro

po

rtio

n

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 >= 50% / ER positive

No TaxolTaxol

ER Neg ER Pos

HE

R2

NE

GH

ER

2 P

OS

HER2 is Predictive of Paclitaxel Benefit

By Estrogen Receptor

Disease Free Survival

n = 1322

paclitaxel

No paclitaxel

paclitaxel

No paclitaxel

paclitaxel

No paclitaxel

paclitaxel

No paclitaxel

n=390 (29%)

n=144 (11%)

n=703 (53%)

n=79 (6%)

YearsHayes D.F., et al. N Engl J Med. 357:1496-506, 2007

13

Common Adjuvant Regimens

First Generation → Second

Generation → Third Generation

CMF*6 → CAF*6, CEF*6

CMF*6 → FAC*6 → TAC*6

CE(50)F*6 → CE(100)F*6 → FEC*3→D*3

AC*4 →AC*4→Txl*4

q3wk →Dose Dense (CA*4→Txl*4

q2wk)

AC*4 → TC*4

20% 20%

14

US Oncology: TC vs AC

RANDOMIZE

Doxorubicin 60 mg/m2 IV Day 1

Cyclophosphamide 600 mg/m2 IV Day 1

Every 21 days x 4 cycles

Docetaxel 75 mg/m2 IV Day 1

Cyclophosphamide 600 mg/m2 IV Day 1

Every 21 days x 4 cycles

15

16

17

2nd Generation Adjuvant Chemo Trials

First Generation → Second

Generation → Third Generation

CMF*6 → CAF*6, CEF*6

CMF*6 → FAC*6 → TAC*6

CE(50)F*6 → CE(100)F*6 → FEC*3→D*3

AC*4 →AC*4→Txl*4

q3wk →Dose Dense (CA*4→Txl*4

q2wk)

AC*4 → TC*4

CALGB 40101

ddAC versus ddTaxol

18

3rd Generation Adjuvant Chemo TrialsTrial Name

Patient Population

Control Arm Experimental Therapy

Concept

S0221 High Risk Dose dense AC-Taxol

metronomic AC-Taxol

Optimal scheduling

E5103 Her-2 negative

AC-weekly Taxol

bevacizumab Adds new agent

PACS08 Triple Negative

FEC-docetaxel ixabepilone Substitutes new agent

ALTTO Her-2 positive

Anthracycline regimen and trastuzumab

lapatinib Adds/substitutes new agent

October 18, 2008 19

Can Bisphosphonates Prevent Bone Metastasis?

20

Effects of Bisphosphonates on Antitumor Activity in Preclinical Models

Tumor-induced osteolysis

Tumor cell proliferation and viability

Metastatic behavior of tumor cells

Activity of cytostatic drugs

Angiogenesis

Tumor burden in vivo

21

Comparison of Adjuvant Breast Cancer Trials of Clodronate vs. Placebo/Control

Diel/Jaschke Powles Saarto

No. of patients 290 1069 299

Treatment site single multi-center single institution institution

Selection BM+ Stage I-III LN+

Treatment length (y) 2 2 3

Control arm observation placebo observation

Follow-up time (y) 8.5 10 10

Skeletal effect + (5 yrs) + NS

Overall survival + + NS

Jaschke Jaschke et al. Proc ASCO, 2004et al. Proc ASCO, 2004 Powles Powles et al. Breast Cancer Res, 2006et al. Breast Cancer Res, 2006Saarto Saarto et al. Acta Oncol 43:80-82, 2004et al. Acta Oncol 43:80-82, 2004

22

Adjuvant Clodronate vs Placebo: Survival

Powles TJ et al, Br Cancer Res, 2006

23

Phase III Studies of Bisphosphonates Vs. Placebo/Control as Adjuvant Therapy for Breast Cancer with DFS Endpoint

• NSABP B-34: (3 years) n=3,200 stage I-IIPlacebo

vs.Clodronate 1,600 mg po qd

• BIG/AZUREBIG/AZURE: (5 years) n=3,300 stage II-III: (5 years) n=3,300 stage II-IIIControlControl

vs.vs.Zoledronic acid 4 mg IV q mo x 6, followed by q3 mo x 2 yrs, Zoledronic acid 4 mg IV q mo x 6, followed by q3 mo x 2 yrs,

followed by q6 mofollowed by q6 mo

ClosedClosed

ClosedClosed

• German/GAINGerman/GAIN: (2 years) LN positive: (2 years) LN positiveETC vs. EC-TXETC vs. EC-TX

xxIbandronate 50 mg po qd vs observationIbandronate 50 mg po qd vs observation

OpenOpen

24

ABCSG-12 Trial Design

• 1,803 premenopausal breast cancer patients

• Endocrine-responsive• Stage I&II, <10 positive nodes• No chemotherapy except

neoadjuvant• Treatment duration: 3 years

Surgery

(+RT)

Goserelin

3.6 mg q28dRandomize

1:1:1:1

Tamoxifen 20 mg/d

Tamoxifen 20 mg/d + Zoledronic Acid

4 mg q 6 mo

Anastrozole 1 mg/d

Anastrozole 1 mg/d + Zoledronic Acid

4 mg q 6 mo

25

First DFS Events (ITT Population)

No ZOL vs ZOL

1010 8

20

10

9

29

41

0102030405060708090

No ZOL (n=904) ZOL (n=899)

Nu

mb

er o

f p

atie

nts

Locoregional

Distant

Contralateral

Secondary malig

Death w/o recur

ASCO 2008 meeting, Gnant

60 months

HR=0.64

P=.011

26

SWOG 0307

Drug Dose Route Interval

Arm 1Zoledronic acid 4 mg* IV q4 wks x 6,

then q3mo x 2.5 yrs

Arm 2Clodronate 1,600 mg oral daily x 3

yrsArm 3Ibandronate 50 mg oral daily x 3

yrs

*Zoledronic acid dose adjusted for baseline renal function*Zoledronic acid dose adjusted for baseline renal function

Current accrual 1958/4500Current accrual 1958/4500

27

First DFS Events (ITT Population)

TAM vs ANA

9 1010 6

1614

29 41

0

10

20

30

40

50

60

70

80

TAM (n=900) ANA (n=903)

Nu

mb

er o

f p

atie

nts

Locoregional

Distant

Contralateral

Secondary malig

Death w/o recur

ASCO 2008 meeting, Gnant

60 months

HR=1.096

P=.593

28

What Endocrine Therapy?

• Aromatase inhibitors are indicated in the adjuvant treatment of postmenopausal women, either alone or following tamoxifen

• Early data does not support superiority of aromatase inhibitors in premenopausal women

• Many women become menopausal with chemotherapy

29Petrek et al JCO 2006

Bleeding after Chemotherapy by Patient Age

30

Bleeding after Chemotherapy by Type of Regimen

Petrek et al JCO 2006

31

32

SchemaSchema

HR+ patients with postmenopausal E2,amenorrhea > 8 weeks

Start AI therapy

Monitor E2 levels at 2, 4, 6, 8, 10, 12 wksMeasure other hormone levels less often

E2<10 E2 10-20 E2>20

Continue AI therapy,monitoring (18 mo)

Off studyRecheck E2 levels

in 1 week

E2<10 E2>10

33

Patient Example: Adjuvant Systemic Therapy Recommendations

• 2nd or 3rd generation chemotherapy– Chemotherapy trial– Bisphosphonate trial – S0307

• Tamoxifen– SOFT clinical trial

• If menopausal, switch to AI after 2-5 years of tamoxifen– “Early switch” endocrine therapy trial APPEL

October 18, 2008 34

Neoadjuvant Chemotherapy: Issues and Controversies

35

Patient Example

• BL is a 58 year old postmenopausal woman who was discovered to have a 3.0 cm breast mass on imaging

• ER 89%, PR 7%, H2N 1+

• Surgeon feels breast conservation possible but better cosmesis after neoadjuvant therapy

StratificationStratification• • AgeAge• • Clinical Tumor SizeClinical Tumor Size• • Clinical Nodal StatusClinical Nodal Status

+ TAM if + TAM if >>50 y50 y

AC x 4AC x 4+ TAM if + TAM if >>50 yrs.50 yrs.

AC x 4AC x 4

NSABP B-18

Operable Breast CancerOperable Breast Cancer

OperationOperation

OperationOperation

P < 0.01P < 0.01

PreopPreopChemoChemo

PostopPostopChemoChemo

B-18Lumpectomy Rate

60%60%68%68%

80%80%

60%60%

40%40%

20%20%

00

38

Local Therapy

Pros• Downstaging of

primary tumor and lymph nodes

• Less radical local-regional therapy needed

• Breast conservation possible more often

Cons• Pathologic nodal staging

requires additional procedure– FNA of nodes– up-front SLNB

• Local treatment delayed for nonresponders

• Decisions for XRT complicated

39

Systemic Therapy

Pros• In vivo assessment of

response, could potentially improve treatment by “tailoring” based on response

• Good biologic model to evaluate effects of chemotherapy tumors – Predicitve factor

development– Acceleration of adjuvant

regimen development

Cons• Potential for

overtreatment in some subsets of patients

• Unclear what to do in ER positive, node negative disease

40

Which tumors > 1, <5 cm definitely get chemotherapy (pre or post)?

ER or PR positive

ER/PR both negative

Node negative ?? ++

Node positive ++ ++

41

Which tumors > 1, <5 cm definitely get endocrine therapy (pre or post)?

ER or PR positive

ER/PR both negative

Node negative ++ -

Node positive ++ -

42

Patient Recommendations

• Sentinel Lymph Node Biopsy– 0/1 lymph node positive

43

Patient Example: OncotypeDX Results

44

Gianni, L. et al. J Clin Oncol; 23:7265-7277 2005

Probability of pathologic complete response (pCR) as a function of Recurrence Score

Gianni, L. et al. J Clin Oncol; 23:7265-7277 2005

doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2) every 3 weeks x 3, followed by weekly paclitaxel (80 mg/m2) x 12.

45

Recurrence Score Predicts CR to Neoadjuvant Docetaxel (Chang, BCRT 2008)

46

Patient Recommendations (Level 3 evidence)

• Sentinel Lymph Node Biopsy– 0/1 lymph node positive

• Begin neoadjuvant hormonal therapy

• Send Recurrence Score– Low risk, no chemotherapy– Intermediate risk, consider chemotherapy if

poor response– High risk, chemotherapy

October 18, 2008 47

Using the Neoadjuvant Model To Develop New Systemic Therapies

48

Common Adjuvant Regimens

First Generation → Second

Generation → Third Generation

CMF*6 → CAF*6, CEF*6

CMF*6 → FAC*6 → TAC*6

CE(50)F*6 → CE(100)F*6 → FEC*3→D*3

AC*4 →AC*4→Txl*4

q3wk →Dose Dense (CA*4→Txl*4

q2wk)

AC*4 → TC*4

20% 20%

49

pCR as Surrogate Marker for DFS

Bear, et al. JCO. May 1, 2006

50

pCR in The Neoadjuvant Model Would Have Predicted Trastuzumab Efficacy

0

10

20

30

40

50

60

70

P-FEC n=19 P-FEC-H n=23

PD

SD

PR

CR

Journal of Clinical Oncology, Vol 23, No 16 (June 1), 2005: pp. 3676-3685

51

National Neoadjuvant Chemo TrialsTrial Name

Patient Population

Control Arm Experimental Therapy

Concept

ACOSOG-Z1041

Her-2 positive FEC-75 then paclitaxel-trastuzumab

Paclitaxel-trastuzumab then FEC-75-trastuzumab

Optimal scheduling, toxicity

NSABP B40

Palpable and operable cancer

Docetaxel then AC

Add gemcitabine or capecitabine, add bevacizumab or not

Adds new agents, data mines for predictive factors

CALGB 40601

Her-2 positive Anthracycline then taxane-trastuzumab

Add carbo or not, add or substitute lapatinib

Adds and/or substitutes new agent

S0800 Locally advanced, Her-2 negative

Nab-paclitaxel then AC

Add sunitinib or not, AC first or second

Adds new agent, support schedule “equivalence”

52

Diffusion MRI: Functional Diffusion Mapping

Red – increase ADCGreen – stable ADCBlue – decrease ADC

53

Schema

Pre-Treatment Evaluation

Baseline MRI

Repeat Baseline MRIRepeat Baseline MRI

Chemotherapy A

Post-Chemo A MRI

Chemotherapy BSurgery

Chemotherapy A

Post-Chemo A MRI

Chemotherapy B

Post-Chemo B MRI

Part One Part Two

Pre-Chemo B MRI

10 patients 14 patients

54

Diffusion MRI, Interim Results

% vol inc > 2.5%Response

Case #±.025 null

thresh±.05 null

threshafter Part A

only

1 1.02 1.61 cPR

2 1.14 1.75 cPR

4 1.04 1.40 cPR

5 -0.23 -0.33 cSD

7 -1.62 -2.40 cSD

55

Diffusion MRI Interim Results

% vol inc > 2.5%Response

Case #±.025 null

thresh±.05 null thresh

after Part A only

after Parts A & B

1 1.02 1.61 cPR cCR, pCR

3 1.14 1.75 cPR cPR, pCR

4 1.04 1.40 cPR cPR, pPR

5 -0.23 -0.33 cSD cPR, pPR

7 -1.62 -2.40 cSD cPR, pPR

56

What’s the Goal?

• Select patients who will require systemic therapy for neoadjuvant treatment

• Find predictive factors (either before or early in treatment) that allow for accurate tailoring of therapy