update on the nsabp surgical treatment trials - … on the nsabp surgical treatment trials thomas b....

Update on Update on The NSABP Surgical Treatment TrialsThe NSABP Surgical Treatment TrialsThe NSABP Surgical Treatment TrialsThe NSABP Surgical Treatment Trials

Thomas B. Julian, MD, FACSThomas B. Julian, MD, FACS

Senior Surgical Director Senior Surgical Director --

Director Director –– Breast Surgical OncologyBreast Surgical Oncology

Allegheny Cancer Center Allegheny Cancer Center --

Associate Professor Associate Professor

Dreexel University College of MedicineDreexel University College of Medicine

Pittsburgh, PAPittsburgh, PA

Update on Update on The NSABP Surgical Treatment TrialsThe NSABP Surgical Treatment TrialsThe NSABP Surgical Treatment TrialsThe NSABP Surgical Treatment Trials

Thomas B. Julian, MD, FACSThomas B. Julian, MD, FACS

-- Medical Affairs Medical Affairs -- NSABPNSABP

Breast Surgical OncologyBreast Surgical Oncology

Allegheny General HospitalAllegheny General Hospital

Associate Professor Associate Professor –– Human OncologyHuman Oncology

Dreexel University College of MedicineDreexel University College of Medicine

Pittsburgh, PAPittsburgh, PA

NNational ational SSurgical urgical

BBreast and reast and BB

50 Years50 Years

urgical urgical AAdjuvant djuvant

BBowel owel PProjectroject

50 Years50 Years

Dr. Marcia ValenzuelaDr. Marcia Valenzuela

NSABP BreastProtocol Timeline

Neo AdjuvantNeo Adjuvant

43 Trials

*

1970 1975 1980 1985

Surgical B-04 B-06

B-05 B-09 B-10B-11B-12

B-15B-16

B-13B-14

B

PositiveNodes

Negative NodesNegative Nodes

DCISDCIS

Neo AdjuvantNeo Adjuvant

B-07

*

*

* B-18 B-27

B-34BisphosphonateBisphosphonate

B-33Extended AdjuvantExtended Adjuvant

LocalLocal--Regional RecurrenceRegional Recurrence B-37

B-42

B-40B-41

1990 1995 2000 2005

B-19B-23

B-32

16B-22 B-25 B-28

B-30B-31

B-29 B-36

B-17 B-24 B-35

B-38

B-18 B-27

B-39

B-20

B-41B-45

BP59

B-

43

B-44

BETH

NSABP Breast Cancer TrialsNSABP Breast Cancer TrialsSix Broad Research ThemesSix Broad Research Themes

1.1. Optimizing localOptimizing local--regional managementregional management

2.2. Optimizing adjuvant hormonal therapy in Optimizing adjuvant hormonal therapy in

earlyearly--stage BCstage BC

3.3. Identifying prognostic and predictive factors Identifying prognostic and predictive factors

for outcome and response to therapyfor outcome and response to therapy


regional managementregional management

Optimizing adjuvant hormonal therapy in Optimizing adjuvant hormonal therapy in

Identifying prognostic and predictive factors Identifying prognostic and predictive factors

for outcome and response to therapyfor outcome and response to therapy


4.4. Optimizing adjuvant chemotherapy in earlyOptimizing adjuvant chemotherapy in early

stage BCstage BC

5.5. Evaluating novel targeted therapies alone or Evaluating novel targeted therapies alone or 5.5. Evaluating novel targeted therapies alone or Evaluating novel targeted therapies alone or

in combination with standard adjuvant in combination with standard adjuvant

therapytherapy

6.6. Evaluating neoadjuvant chemotherapy in Evaluating neoadjuvant chemotherapy in

order to individualize Lorder to individualize L

and identify predictive markers of responseand identify predictive markers of response


Optimizing adjuvant chemotherapy in earlyOptimizing adjuvant chemotherapy in early--

Evaluating novel targeted therapies alone or Evaluating novel targeted therapies alone or Evaluating novel targeted therapies alone or Evaluating novel targeted therapies alone or

in combination with standard adjuvant in combination with standard adjuvant

Evaluating neoadjuvant chemotherapy in Evaluating neoadjuvant chemotherapy in

order to individualize Lorder to individualize L--R therapy, outcome, R therapy, outcome,

and identify predictive markers of responseand identify predictive markers of response

Optimizing Optimizing LocoLoco--Regional Regional LocoLoco--Regional Regional ManagementManagement

Optimizing Optimizing Regional Regional Regional Regional

ManagementManagement

Operable Operable Breast CancerBreast Cancer

ClinicallyClinicallyNodeNode--NegativeNegative

NSABP BNSABP B

100100

8080

6060

Radical Radical Mast.Mast.

Total Total Mast.Mast.

Total Total Mast.Mast.

++XRTXRT

4040

2020

00

NSABP BNSABP B--0404

100100

8080

6060

Global p=0.68Global p=0.68

Overall SurvivalOverall Survival

4040

2020

00

Years

0 5 10 15 20 25 0 5 10 15 20 25

Patients Deaths

RM 362 259

TMR 352 274

TM 365 259

Fisher B: NEJM, 2002

NSABP B

Operable Operable Breast CancerBreast Cancer

Clinical Tumor Size Clinical Tumor Size << 4 cm4 cm

Total Mast.Total Mast.++

Ax. Diss.Ax. Diss.

Lump.Lump.++

Ax. Diss.Ax. Diss.

Lump.Lump.++

Ax. Diss.Ax. Diss.++

XRTXRT

100

80

60

NSABP B-06

Global p=0.57Global p=0.57

Overall SurvivalOverall Survival

40

20

0

P < 0.001

0 5 10 15 20

Years

Fisher B: NEJM, 2002

Patients DeathsMAST 589 299LUMP 634 338LUMP/XRT 628 317

B-06 Cumulative Incidence of IBTR

30

40

50

60

70L 570 pts., 220 IBTR’sL+XRT 567 pts., 78 IBTR’s

P < 0.001%

0

10

20

30

0 2 4 6 8Year

06 Cumulative Incidence of IBTR

570 pts., 220 IBTR’s567 pts., 78 IBTR’s

39

10 12 14 16 18 20Year

14

Breast Conserving TherapyBreast Conserving Therapy

NSABP Trials in Patients with DCISNSABP Trials in Patients with DCIS

Lumpectomy + XRTLumpectomy + XRTTAM vs. TAM vs.

BB--17:17:Lumpectomy Lumpectomy ++ XRTXRT

BB--24:24:Lumpectomy + XRTLumpectomy + XRT

Placebo vs. Placebo vs. TAMTAM

TAM vs. TAM vs.

NSABP Trials in Patients with DCISNSABP Trials in Patients with DCIS

BB--35:35:Lumpectomy + XRTLumpectomy + XRTTAM vs. TAM vs. AnastrozoleAnastrozole

BB--43:43:Lumpectomy + XRT Lumpectomy + XRT

++ TrastuzumabTrastuzumab

Lumpectomy + XRTLumpectomy + XRTTAMTAM

TAM vs. TAM vs. AnastrozoleAnastrozole

DCIS patients afterDCIS patients afterlumpectomy lumpectomy

StratificationStratification

NSABP B

ObservationObservation

•• AgeAge



NSABP B-17

XRTXRT

AgeAge

NSABP BNSABP BLumpectomy vs. Lumpectomy + XRTLumpectomy vs. Lumpectomy + XRT

for Localized DCISfor Localized DCIS

Invasive Ipsilateral BCInvasive Ipsilateral BC

P=0.00001P=0.00001

L 403 Pts., 66 eventsL 403 Pts., 66 events3030

YearYear

00

1010

2020

%%L+XRT 410 Pts., 29 eventsL+XRT 410 Pts., 29 events

L 403 Pts., 66 eventsL 403 Pts., 66 events

00 22 44 66 101088 1212

17%

8%

NSABP BNSABP B--1717Lumpectomy vs. Lumpectomy + XRTLumpectomy vs. Lumpectomy + XRT

for Localized DCISfor Localized DCIS

NonNon--Invasive Ipsilateral BCInvasive Ipsilateral BC

P=0.001P=0.001

L 403 Pts., 57 eventsL 403 Pts., 57 events3030

Fisher B: Sem Oncol, 2001

YearYear

00

1010

2020

%%

L+XRT 410 Pts., 32 eventsL+XRT 410 Pts., 32 events

L 403 Pts., 57 eventsL 403 Pts., 57 events

00 22 44 66 101088 1212

8%

15%

100100

6060

8080

NSABP BOverall Survival

00

2020

4040

6060%%

00 22 44 66YearYear

L+XRT 410 Pts., 43 deaths

L 403 Pts., 45 deaths

p = 0.8

NSABP B-17Overall Survival

87%

86%

101088

L+XRT 410 Pts., 43 deaths

L 403 Pts., 45 deaths

1212Fisher B: Sem Oncol, 2001



NSABP B

TamoxifenTamoxifen+ XRT+ XRT

•• AgeAge



NSABP B-24

PlaceboPlacebo+ XRT+ XRT

AgeAge

NSABP BCumulative Incidence of All Breast Cancer Events

15

20

PlaceboTamoxifen

0

5

10

0 1 2 3

%%

Year

Tamoxifen

NSABP B-24Cumulative Incidence of All Breast Cancer Events

17 %

4 5 6 7

Fisher B: Sem Oncol, 2001

p = 0.003

11 %

NSABP BCumulative Incidence of

12

15B-24 Placebo

B-24 Tamoxifen

B-17 ( L+XRT)

B-17 ( L only)

0

3

6

9

0 1 2 3

B-24 Tamoxifen

%%

YearYear

NSABP B-17/B-24Cumulative Incidence of Invasive IBT

24 Placebo

24 Tamoxifen

17 ( L+XRT)

4 5 6 7

24 Tamoxifen

NSABP BTime to 1st Breast Cancer Event

Pro

po

rtio

n D

ise

as

e-F

ree

0.8

0.9

1

Years Since Surgery

Pro

po

rtio

n D

ise

as

e

0.6

0.7

0.8

0 1 2 3 4

ER-pos tamoxifen (n=264)ER-pos placebo (n=257)ER-neg tamoxifen (n=87)ER-neg placebo (n=66)

ER-pos tamoxifen (n=264)ER-pos placebo (n=257)ER-neg tamoxifen (n=87)ER-neg placebo (n=66)

NSABP B-24Time to 1st Breast Cancer Event

Years Since Surgery

4 5 6 7 8 9

pos tamoxifen (n=264)pos placebo (n=257)neg tamoxifen (n=87)neg placebo (n=66)

pos tamoxifen (n=264)pos placebo (n=257)neg tamoxifen (n=87)neg placebo (n=66)

15

20

25

Patients

(%

)

Anastrozole (A)

HR+

ITT

A

424

575

T

497

651

ATACDisease-Free Survival

Curves shown for HR+ patientsHR

0.83

0.87

DFS includes all deaths as a first event

At risk:

A 2618 2540 2448T 2598 2516 2398

Follow-up time (years)

0

5

10

0 1 2

1.6%

Patients

(%

)

Tamoxifen (T)

ATACFree Survival

Curves shown for HR+ patients95% CI

(0.73–0.94)

(0.78-0.97)

p-value

0.005

0.01

2355 2268 2014 8302304 2189 1932 774

up time (years)

3 4 5 6

Absolutedifference:

1.6% 2.6% 2.5% 3.3%

Incidence of Contralateral Breast Cancer HR+ PatientsHR+ Patients

50

60Number of

HR

0.47

0.58

HR+

ITT

95% CI

(0.29–

(0.38-

0

10

20

30

40

50

21 Invasive*

Anastrozole(n=2618)

26

ofcases

5 DCIS

*p=0.001 for invasive cancers

Incidence of Contralateral Breast Cancer HR+ PatientsHR+ Patients

53

5 DCIS

95% CI

–0.75)

-0.88)

p-value

0.001

0.01

Tamoxifen(n=2598)

5 DCIS

48 Invasive*

Postmenopausal WomenPostmenopausal WomenER or PR PositiveER or PR PositiveDCIS Treated with DCIS Treated with

Lumpectomy + XRTLumpectomy + XRT

NSABP B

AnastrozoleAnastrozoleTamoxifenTamoxifen

Primary endpoint: BC eventSecondary endpoints: DFS, OS, IBTR, CBC, fractures, QOL

Postmenopausal WomenPostmenopausal WomenER or PR PositiveER or PR PositiveDCIS Treated with DCIS Treated with

Lumpectomy + XRTLumpectomy + XRT

NSABP B-35

Opened: 1/6/03Opened: 1/6/03Closed: 6/2006Closed: 6/2006

AnastrozoleAnastrozole

Closed: 6/2006Closed: 6/2006Accrual: 3104Accrual: 3104

Secondary endpoints: DFS, OS, IBTR, CBC, fractures, QOL

•• Compared with invasive Compared with invasive

ductal cancer (IDC), DCIS ductal cancer (IDC), DCIS

is more likely to is more likely to

overexpress HER2/neuoverexpress HER2/neu

Perc

ent H

ER

2+

NSABP BNSABP BRationale for HERRationale for HER--2 Targeting in DCIS2 Targeting in DCIS

overexpress HER2/neuoverexpress HER2/neu

•• HER2/neu HER2/neu

overexpression often overexpression often

associated with large associated with large

cell, comedo variety DCIScell, comedo variety DCIS

Perc

ent H

ER

2+

Allred C, J Clin Oncol 10:566

56

30

40

50

60

Perc

ent H

ER

2+

NSABP BNSABP B--43:43:2 Targeting in DCIS2 Targeting in DCIS

22

11

0

10

20

30

Perc

ent H

ER

2+

DCIS D+I IDC

Allred C, J Clin Oncol 10:566-605, 1992, Hum Pathol 23:974-9, 1992

•• Radiation enhances the antitumor effect of Radiation enhances the antitumor effect of trastuzumab on ctrastuzumab on c--neuneu/HER2 mammary cancer in /HER2 mammary cancer in transgenic micetransgenic mice

BB--43: Rationale (cont.)43: Rationale (cont.)

Tumor Volume as Percent of Day 0Tumor Volume as Percent of Day 0

200200

p<.05 for H+R vs H or R p<.01 between H+R and Hp<.05 for H+R vs H or R p<.01 between H+R and H

00

5050

100100

150150

D7, 5 GyD7, 5 Gy

%%

Radiation enhances the antitumor effect of Radiation enhances the antitumor effect of /HER2 mammary cancer in /HER2 mammary cancer in

43: Rationale (cont.)43: Rationale (cont.)

Tumor Volume as Percent of Day 0Tumor Volume as Percent of Day 0

Rodrigues L, et al. AACR Abstract 132, 2003Rodrigues L, et al. AACR Abstract 132, 2003

p<.05 for H+R vs H or R p<.01 between H+R and Hp<.05 for H+R vs H or R p<.01 between H+R and H

D7, 15 GyD7, 15 Gy

ControlControl

TrastuzumabTrastuzumab

RTRT

Trastuzumab + RTTrastuzumab + RT

NSABP BNSABP BTrastuzumab + XRT for HERTrastuzumab + XRT for HER

HER2+HER2+DCISDCIS

Radiation TherapyRadiation Therapy

DCISDCISLxLx

Radiation Therapy + TrastuzumabRadiation Therapy + Trastuzumab

q3q3--week Trastuzumab cycles x week Trastuzumab cycles x 22 Trastuzumab 8 mg/kg loading doseTrastuzumab 8 mg/kg loading dose

Trastuzumab 6 mg/kg final doseTrastuzumab 6 mg/kg final dose

NSABP BNSABP B--4343Trastuzumab + XRT for HERTrastuzumab + XRT for HER--2 + DCIS2 + DCIS

Radiation TherapyRadiation Therapy

HormonalHormonalRx PRNRx PRN

Radiation Therapy + TrastuzumabRadiation Therapy + Trastuzumab

week Trastuzumab cycles x week Trastuzumab cycles x

Trastuzumab 8 mg/kg loading doseTrastuzumab 8 mg/kg loading dose

Trastuzumab 6 mg/kg final doseTrastuzumab 6 mg/kg final dose

Rx PRNRx PRN

Accrual: Accrual: 109/2000109/2000

Sentinel Node Concept•• Metastasis to regional lymph Metastasis to regional lymph

nodes is nodes is not a random eventnot a random event but but

instead there is instead there is orderly orderly

progressionprogression of tumor cells within of tumor cells within

the lymphatic system.the lymphatic system.

•• Primary draining orPrimary draining or sentinel sentinel

nodenode is the first to contain is the first to contain

metastases.metastases.

•• Biopsy of this Biopsy of this sentinel node can sentinel node can

accurately predict axillary accurately predict axillary

involvementinvolvement

Sentinel Node Concept

but but

of tumor cells within of tumor cells within

sentinel node can sentinel node can

Clinically Negative Axillary Nodes

Randomization

Stratification• Age• Clinical Tumor Size• Type of Surgery

NSABP B

GROUP 1Sentinel Node

Biopsy

Axillary Dissection

Randomization

Clinically Negative Axillary Nodes

Randomization

Stratification

Clinical Tumor SizeType of Surgery

NSABP B-32

Accrual: 5611Accrual: 5611(5/99(5/99--2/04)2/04)

GROUP 2Sentinel Node

Biopsy*

Randomization

*Axillary node dissection

only if the SN is positive

NSABP BUpdate

• SN identification rate: 97.2%

• SN positive rate: 26%

• False negative rate: 9.8%

– FNA/Core needle bx: 8.1%– FNA/Core needle bx: 8.1%

– Excision bx/Lumpectomy: 15.3%

• Average SNs: 3

• SLNs were the only positive node in 61.4% of node positive patients

NSABP B-32Update

SN identification rate: 97.2%

SN positive rate: 26%

False negative rate: 9.8%

FNA/Core needle bx: 8.1%FNA/Core needle bx: 8.1%

Excision bx/Lumpectomy: 15.3%

positive node in 61.4% of node positive patients

Julian T, SABCS 2004Krag, el al., Lancet Oncology, 2007, 8: 881-88

Partial Breast IrradiationPartial Breast IrradiationDefinition Definition

•• Delivery of larger doses/fraction of radiation therapy Delivery of larger doses/fraction of radiation therapy

(RT) to the lumpectomy cavity (plus 1(RT) to the lumpectomy cavity (plus 1

after breast conserving surgery in patients with after breast conserving surgery in patients with

early stage breast cancer using brachytherapy or early stage breast cancer using brachytherapy or

external beam irradiation techniquesexternal beam irradiation techniques

•• Complete RT in < 4Complete RT in < 4--5 days after lumpectomy 5 days after lumpectomy

instead of 6instead of 6--7 weeks7 weeks

Partial Breast IrradiationPartial Breast IrradiationDefinition Definition

Delivery of larger doses/fraction of radiation therapy Delivery of larger doses/fraction of radiation therapy

(RT) to the lumpectomy cavity (plus 1(RT) to the lumpectomy cavity (plus 1--2 cm margin) 2 cm margin)

after breast conserving surgery in patients with after breast conserving surgery in patients with

early stage breast cancer using brachytherapy or early stage breast cancer using brachytherapy or

external beam irradiation techniquesexternal beam irradiation techniques

5 days after lumpectomy 5 days after lumpectomy

NSABP BNSABP BPartial Breast IrradiationPartial Breast Irradiation

Potential Advantages of PBIPotential Advantages of PBI

•• Shorter duration (5 days vs. 5Shorter duration (5 days vs. 5•• Shorter duration (5 days vs. 5Shorter duration (5 days vs. 5

•• Can be given before adjuvant chemotherapyCan be given before adjuvant chemotherapy

•• Avoids radiation to parts of the axillaAvoids radiation to parts of the axilla

•• Delivers higher dose in the vicinity of Delivers higher dose in the vicinity of lumpectomy cavitylumpectomy cavity

NSABP BNSABP B--3939Partial Breast IrradiationPartial Breast Irradiation

Potential Advantages of PBIPotential Advantages of PBI

Shorter duration (5 days vs. 5Shorter duration (5 days vs. 5--6 weeks)6 weeks)Shorter duration (5 days vs. 5Shorter duration (5 days vs. 5--6 weeks)6 weeks)

Can be given before adjuvant chemotherapyCan be given before adjuvant chemotherapy

Avoids radiation to parts of the axillaAvoids radiation to parts of the axilla

Delivers higher dose in the vicinity of Delivers higher dose in the vicinity of

Multi-plane catheterRadiotherapy

plane catheter-based Radiotherapy

MammoSiteMammoSite® Catheter

3D Conformal External Beam 3D Conformal External Beam RadiotherapyRadiotherapy

3D Conformal External Beam 3D Conformal External Beam RadiotherapyRadiotherapy

NSABP BNSABP B--39/RTOG 041339/RTOG 0413

Whole Breast Irradiation after

Eligible Patients with Lumpectomy

RANDOMIZED

Whole Breast Irradiation after Adjuvant Chemotherapy

50 Gy (2.0 Gy/fraction) or

50.4 Gy (1.8 Gy/fraction) to whole breast,

followed by optional boost to > 60 Gy

Endpoints: 10 IBTR 20 DFS/OS

Accrual:3549/4300Accrual:3549/4300

39/RTOG 041339/RTOG 0413

Partial Breast Irradiation prior to

Eligible Patients with Lumpectomy

RANDOMIZED

Partial Breast Irradiation prior to Adjuvant Chemotherapy

For a total of 10 treatments given on 5 days over 5 to 10 days:

34 Gy in 3.4 Gy fractions

Interstitial Brachytherapy or

Mammosite Balloon Catheter

or

38.5 Gy in 3.85 Gy fractions

3D Conformal External Beam

Eligibility CriteriaEligibility Criteria

•• DCIS: < 50 yDCIS: < 50 y

•• Inv. Ca.: < 50 y NInv. Ca.: < 50 y N00--11, > 50 y N, > 50 y N

•• Positive nodes Positive nodes ≤ 3≤ 3

•• Negative margins (NSABP Criteria)Negative margins (NSABP Criteria)•• Negative margins (NSABP Criteria)Negative margins (NSABP Criteria)

•• EIC with negative marginsEIC with negative margins

•• Age Age >> 1818

•• Adequate preAdequate pre--randomization CT scanrandomization CT scan

Eligibility CriteriaEligibility Criteria

, > 50 y N, > 50 y N11, and > 50 y ER/PR , and > 50 y ER/PR --//--, N, N00--11

Negative margins (NSABP Criteria)Negative margins (NSABP Criteria)Negative margins (NSABP Criteria)Negative margins (NSABP Criteria)

EIC with negative marginsEIC with negative margins

randomization CT scanrandomization CT scan

NSABP B-39/RTOG 0413

• Primary endpoint: IBTR

• Quality of life• Quality of life

• QA/QC

39/RTOG 0413

Primary endpoint: IBTR

Evaluating Neoadjuvant Evaluating Neoadjuvant Chemotherapy in Order to Chemotherapy in Order to Individualize LIndividualize LIndividualize LIndividualize L

Outcome, and Identify Outcome, and Identify Predictive Markers of Predictive Markers of

ResponseResponse

Evaluating Neoadjuvant Evaluating Neoadjuvant Chemotherapy in Order to Chemotherapy in Order to Individualize LIndividualize L--R Therapy, R Therapy, Individualize LIndividualize L--R Therapy, R Therapy,

Outcome, and Identify Outcome, and Identify Predictive Markers of Predictive Markers of

ResponseResponse

NSABP Neoadjuvant TrialsNSABP Neoadjuvant Trials

BB--27:27:

BB--18:18:Adjuvant AC vs.Adjuvant AC vs.Neoadjuvant ACNeoadjuvant AC

BB--27:27:NeoadjuvantNeoadjuvantAC vs. AC vs. ACAC

NSABP Neoadjuvant TrialsNSABP Neoadjuvant Trials

27:27:

BB--40/B40/B--41:41:Neoadjuvant Neoadjuvant AA��T RegimensT Regimens

+/+/-- BiologicsBiologics

27:27:NeoadjuvantNeoadjuvant

ACAC��TT

Operable Breast Cancer

Stratification

• Age

NSABP BNeoadjuvant vs Adjuvant AC

•

•

•

•• Clinical Tumor Size

• Clinical Nodal Status

Operation

AC x 4 Operation

AC x 4

•

•

•

•

NSABP B-18Neoadjuvant vs Adjuvant AC

Clinical Response: 79%

cCR: 36% cPR: 43%

pCR: 13%

Increase in lumpectomy Increase in lumpectomy rate: 68% vs 60%

Downstaging of (+) axillary nodes: 58% vs 40%

No difference in DFS and S

Significant correlationbetween pCR and outcome

60

80

100

DFS

pCR (88 pts.)

0

20

40

60

0 1 2 3

%

YEAR

pINV (159 pts.)

cPR (295 pts.)

cNR (140 pts.)

pCR (88 pts.)60

80

100

DFS

4 5 6 7 8

0

20

40

60

%(159 pts.)

P=0.00005

JNCI Monographs #30 96 2001

BB--18: 1618: 16--Year UpdateYear Update

DFSDFS

Year UpdateYear Update

OSOS

Rastogi P et al: J Clin Oncol 2008Rastogi P et al: J Clin Oncol 2008

BB--18: Overall Survival by Age18: Overall Survival by Age

70

80

90

100

<50yrs<50yrs

QualitativeQualitativeTreatment by AgeTreatment by Age

30

40

50

60

70

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

N Ev HR PN Ev HR P

Post 388 167Post 388 167

Pre 381 139Pre 381 139 .81 0.06.81 0.06

Treatment by AgeTreatment by AgeInteractionInteraction

p=0.01p=0.01

18: Overall Survival by Age18: Overall Survival by Age

70

80

90

100

≥≥50yrs50yrs

QualitativeQualitativeTreatment by AgeTreatment by Age

30

40

50

60

70

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

N Ev HR PN Ev HR PPost 363 148Post 363 148Pre 361 171Pre 361 171 1.23 0.071.23 0.07

Treatment by AgeTreatment by AgeInteractionInteraction

p=0.01p=0.01

Wolmark et al: NCI State of the Science Conference 2007Wolmark et al: NCI State of the Science Conference 2007

60

70

80

90

100

DFS and pCRDFS and pCR

30

40

50

60

0 1 2 3 4 5 6 7

N Ev HR

No pCR 599 344pCR 86 29 .47

DFS and pCRDFS and pCR

75

pCR

P <0.0001

8 9 10 11 12 13 14 15 16

52

No pCR

70

80

90

100

Survival and pCRSurvival and pCR

30

40

50

60

0 1 2 3 4 5 6 7

N Ev HR

No pCR 599 263

pCR 86 14 .28

Survival and pCRSurvival and pCR

86

66

8 9 10 11 12 13 14 15 16

P <0.0001

NSABP BNSABP B--27 Schema27 Schema

Operable Breast CancerOperable Breast Cancer(2411 pts)(2411 pts)

RandomizationRandomization

AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs

SurgerySurgery Docetaxel x 4Docetaxel x 4


SurgerySurgery

27 Schema27 Schema

Operable Breast CancerOperable Breast Cancer(2411 pts)(2411 pts)

RandomizationRandomization

Docetaxel x 4Docetaxel x 4



SurgerySurgery

SurgerySurgery Docetaxel x 4Docetaxel x 4

Clinical ResponseClinical Response

40%

100100

8080

P < 0.001P < 0.001

65%

cCRcCR cPRcPR cNRcNR

BB--

Response in the BreastResponse in the Breast

40%

45%

8080

6060

4040

2020

00

%%

ACAC(1502 pts)(1502 pts)

AC Docetaxel AC Docetaxel (687 pts)(687 pts)

65%

26%

14% 9%

85%85% 91%91%

No TumorNo Tumor NonNon--InvasiveInvasive

Pathologic ResponsePathologic Response

--2727

Response in the BreastResponse in the Breast

P < 0.001P < 0.001

AC DocetaxelAC Docetaxel(718 pts)(718 pts)

ACAC(1,492 pts)(1,492 pts)

3.9%

9.8%

6.9%

18.7%

13.7%13.7%25.6%25.6%

2020

1010

00

3030

Bear H, et al: JCO 2003Bear H, et al: JCO 2003

BB--27: 827: 8--Year UpdateYear Update

DFSDFS

Year UpdateYear Update

RFSRFS

Rastogi P et al: J Clin Oncol 2008Rastogi P et al: J Clin Oncol 2008

BB--27: 827: 8--Year UpdateYear UpdateOverall SurvivalOverall Survival

Year UpdateYear UpdateOverall SurvivalOverall Survival

Wolmark et al: NCI State of the Science Conference 2007Wolmark et al: NCI State of the Science Conference 2007

NSABP BNSABP BpCR as a Surrogate for Clinical EndpointspCR as a Surrogate for Clinical Endpoints

60

80

100

-Fre

e

0

20

40

60

0 1 2

% D

isease-F

ree

Years after Surgery

Why is the curve for noWhy is the curve for nopCR not steeper?pCR not steeper?Why is the curve for noWhy is the curve for nopCR not steeper?pCR not steeper?

Hypothesis: Mixed with good Hypothesis: Mixed with good prognosis patients who did prognosis patients who did not benefit from not benefit from chemotherapy ??chemotherapy ??

NSABP BNSABP B--2727pCR as a Surrogate for Clinical EndpointspCR as a Surrogate for Clinical Endpoints

pCR

No-pCR

3 4 5

No-pCR

Years after Surgery

Why is the curve for noWhy is the curve for no--Why is the curve for noWhy is the curve for no--Hypothesis: Mixed with good Hypothesis: Mixed with good prognosis patients who did prognosis patients who did

NSABP BNSABP BGene Expression and Survival OutcomeGene Expression and Survival Outcome

0.6

0.6

0.8

0.8

1.0

1.0

Pro

ba

bilit

y o

f S

urv

iva

lP

rob

ab

ilit

y o

f S

urv

iva

l

00 2020 4040

0.0

0.0

0.2

0.2

0.4

0.4

0.6

0.6

Time (months)Time (months)

Pro

ba

bilit

y o

f S

urv

iva

lP

rob

ab

ilit

y o

f S

urv

iva

l

NSABP BNSABP B--2727Gene Expression and Survival OutcomeGene Expression and Survival Outcome

LowLow--risk (n=163)risk (n=163)

HighHigh--risk (n=163)risk (n=163)

6060 8080 100100Time (months)Time (months)

Paik et al: Unpublished dataPaik et al: Unpublished data

LowLow--Risk Patients Have Good Risk Patients Have Good Outcome Regardless of pCROutcome Regardless of pCR

0.6

0.6

0.8

0.8

1.0

1.0

Pro

ba

bilit

y o

f S

urv

iva

lP

rob

ab

ilit

y o

f S

urv

iva

l

00 2020 4040

0.0

0.0

0.2

0.2

0.4

0.4

0.6

0.6


Pro

ba

bilit

y o

f S

urv

iva

lP

rob

ab

ilit

y o

f S

urv

iva

l

Risk Patients Have Good Risk Patients Have Good Outcome Regardless of pCROutcome Regardless of pCR

pCRpCRlowlow--risk (16)risk (16)

NoNo--pCRpCRlowlow--risk (147)risk (147)

6060 8080 100100



Combination of Prognostic Genes and pCRCombination of Prognostic Genes and pCRDefines Residual Risk after ChemotherapyDefines Residual Risk after Chemotherapy

0.8

0.8

1.0

1.0

Pro

ba

bilit

y o

f S

urv

iva

lP

rob

ab

ilit

y o

f S

urv

iva

l

00 2020 4040

0.0

0.0

0.2

0.2

0.4

0.4

0.6

0.6


Pro

ba

bilit

y o

f S

urv

iva

lP

rob

ab

ilit

y o

f S

urv

iva

l

Candidates for postCandidates for posttrials for targeted therapytrials for targeted therapy

Combination of Prognostic Genes and pCRCombination of Prognostic Genes and pCRDefines Residual Risk after ChemotherapyDefines Residual Risk after Chemotherapy

HighHigh--Risk & pCR (34)Risk & pCR (34)

6060 8080 100100


HighHigh--risk & norisk & no--pCR (125)pCR (125)

Candidates for postCandidates for post--neoadjuvant chemoneoadjuvant chemotrials for targeted therapytrials for targeted therapy


•• Identification Rate: Identification Rate:

•• With blue dye: 78%With blue dye: 78%

•• With isotope With isotope ++ blue dye: blue dye:

NSABP BNSABP B--27: SNB After NC27: SNB After NCin a Multiin a Multi--Center SettingCenter Setting

(n=428)(n=428)


•• False Negative Rate: False Negative Rate:

•• With blue dye: 14%With blue dye: 14%


Identification Rate: Identification Rate: 85%85%

With blue dye: 78%With blue dye: 78%

blue dye: blue dye: 8888--89%89%

27: SNB After NC27: SNB After NCCenter SettingCenter Setting

(n=428)(n=428)

blue dye: blue dye: 8888--89%89%

False Negative Rate: False Negative Rate: 11%11%

With blue dye: 14%With blue dye: 14%

blue dye: blue dye: 8.4%8.4%

Mamounas EP: J Clin Oncol, 2005

Benefits of SNB after Neoadjuvant Chemotherapy

• Avoids axillary dissection in 25% of patients

• Reduces the morbidity of axillary dissection• Reduces the morbidity of axillary dissection

• Utilizes the downstaging of neoadjuvant therapy

Benefits of SNB after Neoadjuvant Chemotherapy

Avoids axillary dissection in 25% of patients

Reduces the morbidity of axillary dissectionReduces the morbidity of axillary dissection

Utilizes the downstaging of neoadjuvant therapy

NSABPNSABP

New Directions with New Directions with Neoadjuvant ChemotherapyNeoadjuvant Chemotherapy

•• Use pCR as a correlate of chemotherapy Use pCR as a correlate of chemotherapy efficacy to test new drugs and regimensefficacy to test new drugs and regimens

•• Utilize microUtilize micro--array technology to identify array technology to identify •• Utilize microUtilize micro--array technology to identify array technology to identify genomic profiles associated with pCR to genomic profiles associated with pCR to specific drugs or combinationsspecific drugs or combinations

•• Candidates: Candidates:

•• Sequential anthracycline taxane regimens Sequential anthracycline taxane regimens incorporating new chemotherapy agentsincorporating new chemotherapy agents

•• Regimens incorporation novel targeted agentsRegimens incorporation novel targeted agents

NSABPNSABP

New Directions with New Directions with Neoadjuvant ChemotherapyNeoadjuvant Chemotherapy

Use pCR as a correlate of chemotherapy Use pCR as a correlate of chemotherapy efficacy to test new drugs and regimensefficacy to test new drugs and regimens

array technology to identify array technology to identify array technology to identify array technology to identify genomic profiles associated with pCR to genomic profiles associated with pCR to specific drugs or combinationsspecific drugs or combinations

Sequential anthracycline taxane regimens Sequential anthracycline taxane regimens incorporating new chemotherapy agentsincorporating new chemotherapy agents

Regimens incorporation novel targeted agentsRegimens incorporation novel targeted agents

AngiogenesisAngiogenesis

Agents Targeting the VEGF

Pathway

VEGFAnti-VEGF antibodies

(eg, bevacizumab)

VEGFR-1

P

PP

P

Endothelial cell

ANGIOGENESIS

ProliferationSurvival

Agents Targeting the VEGF

Pathway

Soluble VEGF receptors

(eg, VEGF-Trap)

VEGF

VEGFR-2

P

PP

P

Small-moleculeVEGFR inhibitors

(eg, vatalanib, sunitinib, ZD6474, sorefinib, AZD2171)

Anti-VEGFR antibodies

(eg, IMC-1121b)

ANGIOGENESIS

Proliferation Migration

ECOG 2100 – Paclitaxel vs. Paclitaxel + Bevacizumab for MBC –

Paclitaxel

(n=339)

Response

All Patients 14%

Measurable

Disease

16%

Median PFS 6.11 mo

Median OS 25.2 mo

Miller, KD, SABCS 2005, Abstr. #3

Paclitaxel vs. Paclitaxel + Second Interim Analysis

Paclitaxel +

Bev

(N=341)

P Values

30% < 0.0001

38% < 0.0001

11.4 mo < 0.0001

28.4 mo 0.12

0.6

0.8

1.0

PF

S P

rob

ab

ilit

yECOG 2100

Progression-

0.0

0.2

0.4

Months

PF

S P

rob

ab

ilit

y

0 6 12

Miller et al. Breast Cancer Res Treat. 2005;94(Suppl 1):S6. Abstract

ECOG 2100

-Free Survival

484 events reported

HR = 0.51 (0.43-0.62)

Paclitaxel + Bevacizumab: 11.4 months

Paclitaxel: 6.11 months

Months

18 24 30

HR = 0.51 (0.43-0.62)

Log Rank Test P < 0.0001

2005;94(Suppl 1):S6. Abstract 3.

NSABP B

Operable Operable Breast Breast

Tissue forTissue forBiomarkersBiomarkers

RR

T TT T

T T T T

Breast Breast CancerCancer

X: Xeloda G: Gemcitabine B: BevacizumabEndpoints: pCR, cCR, DFS, OS, gene expression patterns

RRT

X

T

X

T

X

T

X

T

G

T

G

T

G

T

G

+/- B B B B

NSABP B-40

SSUURR


A

C

A

C

A

C

A

C

A A A A +/-RRGGEERRYY

X: Xeloda G: Gemcitabine B: BevacizumabEndpoints: pCR, cCR, DFS, OS, gene expression patterns

A

C

A

C

A

C

A

C

A

C

A

C

A

C

A

C

X 10

B B

B

+/-

Opened: 11/20/06Accrual: 834/1200 70%

HER2 Upregulates VEGF ExpressionHER2 Upregulates VEGF Expression

Epstein, et al., SABCS 2003Epstein, et al., SABCS 2003

HER2-negative

HER2 Upregulates VEGF ExpressionHER2 Upregulates VEGF Expression

Increased # of vesselsIncreased # of vessels* Vessel dilation* Vessel dilation* Vessel tortuosity* Vessel tortuosity

HER2-positive

Preclinical Evidence of Lapatinib Mechanism of Action/Activity

• Binds to intracellular ATP binding site of EGFR and HER2

• Blocks downstream signaling through homodimers and heterodimers of EGFR and HER2heterodimers of EGFR and HER2

• Active in HER2+ breast cancer cell lines resistant to trastuzumab

Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. OncogeneKonecny et al. Cancer Res. 2006;66:1630-1639

Preclinical Evidence of Lapatinib Mechanism of Action/Activity

Binds to intracellular ATP binding

heterodimers of EGFR and HER2

1+1 2+2 1+2

Lapatinib

heterodimers of EGFR and HER2

Active in HER2+ breast cancer cell

Downstream signaling cascade

Oncogene 2002;21:6255-6263;

Phase III study Capecitabine ± Lapatinib in Pretreated Advanced or

Metastatic HER2+ Breast CancerTime to Progession

50

60

70

80

90

100

Progressed or died

Median TTP, mo

No. of pts

Hazard ratio (95% CI)

% o

f p

ati

en

ts f

ree

fro

m p

rog

res

sio

n*

10

20

30

40

50

0

10 20 300Time (weeks)

P-value (log

Hazard ratio (95% CI)

% o

f p

ati

en

ts f

ree

fro

m p

rog

res

sio

n*

Phase III study - EGF100151Lapatinib in Pretreated Advanced or

Metastatic HER2+ Breast CancerTime to Progession – ITT Population

Capecitabine

Lapatinib + Capecitabine

7249Progressed or died

4.48.4Median TTP, mo

161163No. of pts

0.49 (0.34, 0.71)Hazard ratio (95% CI)

70

40 50 60Time (weeks)

0.00004value (log-rank, 1-sided)

0.49 (0.34, 0.71)Hazard ratio (95% CI)

EGF102580: Lapatinib Plus Paclitaxel in IBCEfficacy

Lapatinib Monotherapy

Overall response rate

Lapatinib/Paclitaxel

Overall response rate

Complete response

Partial response

Postsurgery

Pathologic CR*

EGF102580: Lapatinib Plus Paclitaxel in IBCEfficacy

Cohort A (HER2+)N = 30

Cohort B (HER2–) N = 5

10 (30%) 0

77% 80%

3 (10%) 0

20 (67%) 4 (80%)

3/18 (17%) 0/3

Cristofanilli et al Abs 1, SABCS 2006

NSABP B-41 Neoadjuvant StudyEvaluating Lapatinib and Trastuzumab

in Her-2 Positive Patients

AC AC �� WP + T WP + T Operable,


AC AC �� WP + T WP + T Operable,Palpable Breast CancerHER-2

Positive

R

Primary endpoints: pCR, cardiac events

AC AC �� WP + LWP + L

AC AC �� WP + TL WP + TL

41 Neoadjuvant StudyEvaluating Lapatinib and Trastuzumab

2 Positive Patients

WP + T WP + T S


WP + T WP + T

TrastuzumabTrastuzumabfor a total of for a total of

1 year 1 year

pCR, cardiac events

WP + LWP + L

WP + TL WP + TL

SURGERY

Open: 7-16-07Accrual: 207/522 40 %

NSABP BPBone marrow micrometastases studyBone marrow micrometastases study

NSABP BP-59Bone marrow micrometastases studyBone marrow micrometastases study

Braun et al, NEJM, 2005, 353:793-802

NSABP BPSummary

• Single arm, prospective study designed to collect bone marrow at the time of initial treatment and determine whether the presence of tumor cells in the marrow predicts OS.

• Eligibility-Patients with earlygoing to undergo breast surgery

• BM aspiration will be performed at the time of surgery

• Patients eligible for any other relevant therapy trial.

NSABP BP-59Summary

Single arm, prospective study designed to collect bone marrow at the time of initial treatment and determine whether the presence of tumor cells in the marrow predicts

Patients with early-stage breast cancer who are going to undergo breast surgery

BM aspiration will be performed at the time of surgery

Patients eligible for any other relevant therapy trial.

Summary (Cont)

• Two different methods for detecting tumor cells in BM will be evaluated.

– Conventional bright-field ICC

– Multicolor fluorescence ICC.

• Patients will be followed for 10 years to determine OS.

• ACCRUAL: 780/1634 48%

Summary (Cont)

Two different methods for detecting tumor cells in BM will

field ICC

Multicolor fluorescence ICC.

Patients will be followed for 10 years to determine OS.

Conclusions• Lumpectomy and RT provide excellent local control without a detriment to

survival or DFS for invasive or non-invasive cancers of the breast.

• Sentinel node biopsy in early stage breast cancer minimizes the need for axillary dissection with subsets of patients who do not require a completion axillary dissection or a sentinel node biopsy.

• Neoadjuvant chemotherapy extends the use of lumpectomy in locally advanced disease and if it is associated with a pCR provides for a better prognosis. Targeted therapies are now available to individualize therapay and maximize treatment. Sentinel node biopsy after neoadjuvant chemotherapy is feasible.

• Partial breast irradiation is under study in an attempt to increase access to lumpectomy and provide the same level of local control for patients with less breast irradiation.

ConclusionsLumpectomy and RT provide excellent local control without a detriment to

invasive cancers of the breast.

Sentinel node biopsy in early stage breast cancer minimizes the need for axillary dissection with subsets of patients who do not require a completion axillary dissection or a sentinel node biopsy.

Neoadjuvant chemotherapy extends the use of lumpectomy in locally advanced disease and if it is associated with a pCR provides for a better prognosis. Targeted therapies are now available to individualize therapay and maximize treatment. Sentinel node biopsy after neoadjuvant

Partial breast irradiation is under study in an attempt to increase access to lumpectomy and provide the same level of local control for patients with

AGH Cancer CenterAGH Cancer Center

update on the nsabp surgical treatment trials - … on the nsabp surgical treatment trials thomas b....

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