NSABP Neoadjuvant Chemotherapy and Axillary Staging Thomas B. Julian, MD, FACS Professor of Surgery...

NSABP Neoadjuvant Chemotherapy

and Axillary Staging

Thomas B. Julian, MD, FACSProfessor of Surgery - Drexel University College of Medicine

Senior Surgical Director-Medical Affairs - NSABPDirector-Breast Surgical Oncology - WPAHS

Pittsburgh, PA

NC for Operable Breast CancerNC for Operable Breast CancerResults from First Generation RCTsResults from First Generation RCTs

• No difference in outcome between NC and No difference in outcome between NC and adjuvant chemotherapyadjuvant chemotherapy

• NC increases the rate of lumpectomy NC increases the rate of lumpectomy

• NC decreases the rate of axillary positivityNC decreases the rate of axillary positivity

• Achievement of pCR correlates with Achievement of pCR correlates with improved long-term outcomeimproved long-term outcome

• Increase in rate of breast-conserving surgeryIncrease in rate of breast-conserving surgery

• Ability to correlate tumor response to Ability to correlate tumor response to outcomeoutcome

• Potential to correlate biomarker expression Potential to correlate biomarker expression and changes in biomarkers with tumor and changes in biomarkers with tumor response and outcomeresponse and outcome

Neoadjuvant ChemotherapyNeoadjuvant ChemotherapyPotentialPotential AdvantagesAdvantages

NC for Operable Breast CancerNC for Operable Breast CancerContinuing Clinical RationaleContinuing Clinical Rationale

• Evaluation of more effective regimens in Evaluation of more effective regimens in order to order to further reduce the extent of loco-further reduce the extent of loco-regional therapy:regional therapy:

• In the In the breast breast

• In the In the axillaaxilla (SNB) (SNB)

• Use of primary tumor response as a Use of primary tumor response as a guide guide of further of further loco-regional and systemicloco-regional and systemic therapytherapy

Sequential A/E Sequential A/E TaxaneTaxane

• AC – TXT AC – TXT 26%26%

• 4CVAP – 4TXT: 4CVAP – 4TXT: 31%31%

• 4ATXL – 4CMF: 4ATXL – 4CMF: 23%23%

• 3E – 3TXL:3E – 3TXL: 18% 18%

• 4AC – 4TXT:4AC – 4TXT: 22%22%

• 12TXLw – 4FAC: 12TXLw – 4FAC: 29%29%

• 4TXL -- 4FAC: 14%4TXL -- 4FAC: 14%

Neoadjuvant Anthracycline/Taxane TrialsNeoadjuvant Anthracycline/Taxane TrialsPathologic Complete Response (pCR)Pathologic Complete Response (pCR)

Combo A/E + TaxaneCombo A/E + Taxane

• 4(E+TXL): 10% 4(E+TXL): 10%

• 4(A+TXT): 12%4(A+TXT): 12%

• 6(A+TXT): 6(A+TXT): 21%21%

Bear H: San Antonio, 2001, Gianni L: ASCO, 2002,Evans T: ASCO 2004,

Untch M: ASCO, 2002von Minckwitz G, et al. ASCO, 2002

• 4(A+C):4(A+C): 13- 13-14%14%

• 8 (CVAP) 15%8 (CVAP) 15%

• 6(A+C):6(A+C): 24%24%

Green MC: ASCO 2002

Operable Breast Cancer

Stratification

• Age• Clinical Tumor Size• Clinical Nodal Status

Operation

AC x 4 Operation

NSABP B-18Neoadjuvant vs Adjuvant AC

AC x 4

• Clinical Response: 79%

• cCR: 36% cPR: 43%

• pCR: 13%

• Increase in lumpectomy rate: 68% vs 60%

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

• No difference in DFS and S

• Significant correlation between pCR and outcome

Operable Breast CancerOperable Breast Cancer

StratificationStratification

• • AgeAge• • Clinical Tumor SizeClinical Tumor Size

• • Clinical Nodal StatusClinical Nodal Status

OperationOperation

AC x 4AC x 4 OperationOperation

NSABP B-18NSABP B-18Neoadjuvant vs. Adjuvant ACNeoadjuvant vs. Adjuvant AC

AC x 4AC x 4

00

2020

4040

6060

8080

100100

00 22 44 66 88YearYear

P=0.00005pINVpINV

cPRcPR

cNRcNR

pCRpCR

Disease-Free SurvivalDisease-Free Survival

Wolmark N: JNCI Monogr, 2001

B-18: 16-Year UpdateB-18: 16-Year Update

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

DFSDFS OSOS

B-18: Overall Survival by AgeB-18: Overall Survival by Age

30

40

50

60

70

80

90

100

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

N Ev HR PN Ev HR PPost 388 167Post 388 167

Pre 381 139Pre 381 139 .81 0.06 .81 0.06

<50yrs<50yrs

30

40

50

60

70

80

90

100

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 0.07 1.23 0.07

≥≥50yrs50yrs

QualitativeQualitativeTreatment by AgeTreatment by Age

InteractionInteractionp=0.01p=0.01

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

NSABP B-27 SchemaNSABP B-27 Schema

Operable Breast Operable Breast CancerCancer

(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

SurgerySurgery Docetaxel x 4Docetaxel x 4

Clinical ResponseClinical Response

40%

45%

100100

8080

6060

4040

2020

00

%%

P < 0.001P < 0.001

ACAC(1502 pts)(1502 pts)

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

65%

26%

cCRcCR

14% 9%

8585%%

9191%%

P < 0.001P < 0.001

AC DocetaxelAC Docetaxel(718 pts)(718 pts)

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

3.9%

9.8%

No TumorNo Tumor Non-Non-InvasiveInvasive

6.9%

18.7%

13.7%13.7%25.6%25.6%

2020

1010

00

3030

cPRcPR cNRcNR

Pathologic Pathologic ResponseResponse

B-27B-27

Response in the BreastResponse in the Breast

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

B-27: 8-Year UpdateB-27: 8-Year Update

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

DFSDFS RFSRFS

B-27: 8-Year UpdateB-27: 8-Year UpdateOverall SurvivalOverall Survival

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

Ki-67 Staining Can be Used to Identify Ki-67 Staining Can be Used to Identify High-Risk Group Among no-pCR High-Risk Group Among no-pCR

PatientsPatients

Paik S: Unpublished data

NSABP B-45:NSABP B-45:Concept Under DevelopmentConcept Under Development

Arm 1 Arm 1 **No adjuvant No adjuvant

chemotherapychemotherapy

RandomizationRandomization

Arm 2 Arm 2 **Eribulin mesylate 1.4 mg/mEribulin mesylate 1.4 mg/m2 2

IV Days 1 and 8IV Days 1 and 8Every 21 days X 4 cyclesEvery 21 days X 4 cycles

STRATIFICATIONSTRATIFICATION• Pathological nodal staging (ypNo or ypN1; ypN2; Pathological nodal staging (ypNo or ypN1; ypN2;

ypN3)ypN3)• Postoperative radiation (yes; no)Postoperative radiation (yes; no)

Residual Invasive Cancer in Breast or Axillary Nodes Residual Invasive Cancer in Breast or Axillary Nodes Following a Minimum of Six Cycles of NCFollowing a Minimum of Six Cycles of NC

Triple-Negative, Clinical Stage II or Stage IIITriple-Negative, Clinical Stage II or Stage III

Combined Analysis of B-18/B-27Combined Analysis of B-18/B-27Independent Predictors of LRFIndependent Predictors of LRF

Lumpectomy + XRTLumpectomy + XRT

(1890 Pts, 190 Events)(1890 Pts, 190 Events)

MastectomyMastectomy

(1070 Pts, 128 Events) (1070 Pts, 128 Events)

AgeAge((>>50 years vs. <50 years)50 years vs. <50 years)

Clinical Tumor SizeClinical Tumor Size (>5 cm (>5 cm vs.vs. <<5 cm)5 cm)

Clinical Nodal StatusClinical Nodal Status(+) vs. (-)(+) vs. (-)

Clinical Nodal StatusClinical Nodal Status(+) vs. (-)(+) vs. (-)

Breast/Nodal Path StatusBreast/Nodal Path StatusNode(-)/No pCR vs. Node(-)/No pCR vs. Node(-)/pCRNode(-)/pCR

Node(+) vs. Node(-) /pCRNode(+) vs. Node(-) /pCR

Breast/Nodal Path StatusBreast/Nodal Path StatusNode(-)/No pCR vs. Node(-)/pCRNode(-)/No pCR vs. Node(-)/pCR

Node(+) vs. Node(-) /pCRNode(+) vs. Node(-) /pCR

Mamounas et al: ASCO Breast 2010, Abstr. 90Mamounas et al: ASCO Breast 2010, Abstr. 90

5. 2

1. 1

6. 8

1. 5

6. 7

0. 5

6. 5

0

8. 7

0

7. 2

7. 5

0

5

10

15

20

Node (-)

pCR

Node (-)

No pCR

Node (+) Node (-)

pCR

Node (-)

No pCR

Node (+)

IBTR Regional

10-Year Cum. Incidence of LRF 10-Year Cum. Incidence of LRF Lumpectomy Patients, Lumpectomy Patients, >>50 years50 years

n=31n=31n=212n=212

n=58n=58

n=122n=122

n=348n=348

n=90n=90

Clin. Node (-)Clin. Node (-) Clin. Node (+)Clin. Node (+)

6.9

0.7

8.3

0.5

10.5

2.3

5.3

1.8 11.4

2.4

13.6

8.7

0

5

10

15

20

25

Node (-)

pCR

Node (-)

No pCR

Node (+) Node (-)

pCR

Node (-)

No pCR

Node (+)

IBTR Regional

10-Year Cum. Incidence of LRF 10-Year Cum. Incidence of LRF Lumpectomy Patients, <50 yearsLumpectomy Patients, <50 years

n=57n=57

n=223n=223n=84n=84

n=154n=154

n=376n=376

n=135n=135


2.2

4.3

4

2.3

7.3

2.8

002.7

8.110.6

6.4

0

5

10

15

20

Node (-)

pCR

Node (-)

No pCR

Node (+) Node (-)

pCR

Node (-)

No pCR

Node (+)

Chest Wall Regional

10-Year Cum. Incidence of LRF 10-Year Cum. Incidence of LRF Mastectomy Patients, Mastectomy Patients, << 5 cm 5 cm

n=21n=21

n=183n=183 n=37n=37

n=143n=143

n=178n=178n=46n=46


0

6.28.6

3.2

12.3

1.7

00

9.2

0 17.6

4.8

0

5

10

15

20

25

Node (-)

pCR

Node (-)

No pCR

Node (+) Node (-)

pCR

Node (-)

No pCR

Node (+)

Chest Wall Regional

10-Year Cum. Incidence of LRF 10-Year Cum. Incidence of LRF Mastectomy Patients, > 5 cmMastectomy Patients, > 5 cm

n=11n=11

n=179n=179

n=33n=33

n=128n=128

n=95n=95

n=16n=16


• Results of multivariate analyses in which age Results of multivariate analyses in which age and tumor size were used as continuous and tumor size were used as continuous variables were similar to those in which age variables were similar to those in which age and tumor size were used as discrete and tumor size were used as discrete variablesvariables

• The independent predictors of LRF were then The independent predictors of LRF were then incorporated into two separate nomograms:incorporated into two separate nomograms:

– Lumpectomy + breast XRTLumpectomy + breast XRT

– MastectomyMastectomy

Development of a Nomogram to Predict Development of a Nomogram to Predict LRF Following Neoadjuvant LRF Following Neoadjuvant

ChemotherapyChemotherapy

Age at Entry (Years)

10

-ye

ar

pro

ba

bility (

%)

of b

ein

g L

oca

l F

ailu

re F

ree

40 45 50 55 60 65 70

05

10

15

20

25

30

CNS pos, Node (+)CNS pos, Node (-), No pCRCNS pos, Node (-), pCRCNS neg, Node (+)CNS neg, Node (-), No pCRCNS neg, Node (-), pCR

Nomogram for Prediction ofNomogram for Prediction of10-Year Rate of LRF After NC10-Year Rate of LRF After NC

Lumpectomy + XRTLumpectomy + XRT10

-Yea

r P

rob

abil

ity

of

LR

F

10-Y

ear

Pro

bab

ilit

y o

f L

RF

Age at Entry (Years)Age at Entry (Years)

Clinical Tumor Size (cm)

10

-ye

ar

pro

ba

bility (

%)

of b

ein

g L

oca

l F

ailu

re F

ree

0 1 2 3 4 5

05

10

15

20

25

30

CNS pos, Node (+)CNS pos, Node (-), No pCRCNS pos, Node (-), pCRCNS neg, Node (+)CNS neg, Node (-), No pCRCNS neg, Node (-), pCR

MastectomyMastectomy

Clinical Tumor Size at Entry (cm)Clinical Tumor Size at Entry (cm)

Nomogram for Prediction ofNomogram for Prediction of10-Year Rate of LRF After NC10-Year Rate of LRF After NC

10-Y

ear

Pro

bab

ilit

y o

f L

RF

10

-Yea

r P

rob

abil

ity

of

LR

F

Summary ISummary I

• In patients with operable breast cancer, the In patients with operable breast cancer, the 10-year 10-year cum. incidence of LRFcum. incidence of LRF after neoadjuvant after neoadjuvant chemotherapy was chemotherapy was 10-12%10-12%

• Despite Despite worse worse patient characteristics in B-27patient characteristics in B-27, LRF , LRF with AC in B-27 was lower than in B-18 with AC in B-27 was lower than in B-18 and there and there was anwas an effect of docetaxel (about 25% reduction) effect of docetaxel (about 25% reduction)

• Overall, the ratio of local vs. regional failure is Overall, the ratio of local vs. regional failure is about 3:1 but this ratio is influenced by type of about 3:1 but this ratio is influenced by type of surgery and other independent predictors of LRF surgery and other independent predictors of LRF

Summary IISummary II

• Independent predictors of LRF in Independent predictors of LRF in lumpectomy + breast lumpectomy + breast XRTXRT patients include: patients include: age, clinical nodal status (before age, clinical nodal status (before NC) and pathologic breast/nodal responseNC) and pathologic breast/nodal response

• Independent predictors of LRF in Independent predictors of LRF in mastectomy mastectomy patients patients include: include: clinical tumor size (before NC), clinical nodal clinical tumor size (before NC), clinical nodal status (before NC) and pathologic breast/nodal responsestatus (before NC) and pathologic breast/nodal response

• The effect of age (in lumpectomy patients), clinical The effect of age (in lumpectomy patients), clinical tumor size (in mastectomy patients) and clinical nodal tumor size (in mastectomy patients) and clinical nodal status on LRF appears to diminish with increasing status on LRF appears to diminish with increasing pathologic response in the breast and axillary nodespathologic response in the breast and axillary nodes

• These independent predictors of LRF after These independent predictors of LRF after neoadjuvant chemotherapy can be neoadjuvant chemotherapy can be incorporated to separate nomograms for incorporated to separate nomograms for lumpectomy + breast XRT and mastectomy lumpectomy + breast XRT and mastectomy patients to provide guidance on the need for patients to provide guidance on the need for regional XRT after lumpectomy or loco-regional XRT after lumpectomy or loco-regional XRT after mastectomyregional XRT after mastectomy

• Further development and validation of these Further development and validation of these nomograms with inclusion of treatment nomograms with inclusion of treatment effect is planned effect is planned

Summary IIISummary III

NSABPNSABPNew 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 micro-array technology to identify Utilize micro-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 combinationsSequential anthracycline/taxane combinations

• New targeted therapies in combination with New targeted therapies in combination with chemochemo

Agents Targeting the VEGF PathwayAgents Targeting the VEGF Pathway

VEGFR-2VEGFR-2VEGFR-1VEGFR-1PPPPPP

PPPPPPPP

PPEndothelial cellEndothelial cell

Small-moleculeSmall-moleculeVEGFR inhibitors VEGFR inhibitors

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

Anti-VEGFR Anti-VEGFR antibodiesantibodies

(eg, IMC-1121b)(eg, IMC-1121b)

Soluble VEGF Soluble VEGF receptorsreceptors

(eg, VEGF-Trap)(eg, VEGF-Trap)

VEGFVEGFAnti-VEGF Anti-VEGF antibodiesantibodies

(eg, bevacizumab)(eg, bevacizumab)

ANGIOGENESISANGIOGENESIS

ProliferationProliferationSurvivSurvivalal

MigratioMigrationn

NSABP B-40NSABP B-40

Operable Operable Breast Breast CancerCancer

SSUURRGGEERRYY

Tissue forTissue forBiomarkersBiomarkers


RR

T

TX

TX

TX

TX

TG

TG

TG

TG

AC

AC

AC

AC

AC

AC

AC

AC

AC

AC

AC

AC

+/-X 10

B B B B B B

B

+/-

Accrual Completed: 1205Accrual Completed: 1205

T TT

NSABP B-40NSABP B-40Pathologic Complete ResponsePathologic Complete Response

(Breast and Nodes(Breast and Nodes))

% p

CR (B

reas

t + N

odes

)%

pCR

(Bre

ast +

Nod

es)

OR = 1.27OR = 1.27Chi-square testChi-square test: : p=0.09p=0.09

N=588N=588 N=583N=583

NSABP B-40NSABP B-40Pathologic Complete Response (Breast and Pathologic Complete Response (Breast and

Nodes) for HR+ and TN Breast CancerNodes) for HR+ and TN Breast Cancer

11.517.1

40.644

0

5

10

15

20

25

30

35

40

45

50

HR+ TNBC

W/O BEV

BEV

% p

CR (B

reas

t + N

odes

)%

pCR

(Bre

ast +

Nod

es)

OR = 1.59OR = 1.59p=0.033p=0.033

OR = 1.15OR = 1.15p=0.458p=0.458

N=349N=349 N=351N=351

N=239N=239 N=232N=232

Interaction p value = 0.256Interaction p value = 0.256

Capecitabine +/- Lapatinib:Capecitabine +/- Lapatinib:Time to Progression (Intent-to-Treat)Time to Progression (Intent-to-Treat)

7700

1010

2200

3300

4400

5500

60607700

80809900

00

100100

*Censors 4 patients who died due to causes *Censors 4 patients who died due to causes other than breast cancer other than breast cancer

1100

2200

3300

4400

5500

6600

00Time (weeks)Time (weeks)

CapecitabineCapecitabineLapatinib + Lapatinib +

CapecitabineCapecitabine

0.000160.00016PP-value (log-rank, 1-sided)-value (log-rank, 1-sided)

69 (43%)69 (43%)45 (28%)45 (28%)Progressed or died*Progressed or died*19.719.736.936.9Median TTP, wkMedian TTP, wk

161161160160No. of ptsNo. of pts

0.51 (0.35, 0.74)0.51 (0.35, 0.74)Hazard ratio (95% CI)Hazard ratio (95% CI)

% o

f P

atie

nts

Pro

gre

ssio

n F

ree*

% o

f P

atie

nts

Pro

gre

ssio

n F

ree*

Geyer et al: N Engl J Med Geyer et al: N Engl J Med 2006 2006

NSABP B-41: Neoadjuvant StudyNSABP B-41: Neoadjuvant Studywith Lapatinib vs. Trastuzumab vs. Combowith Lapatinib vs. Trastuzumab vs. Combo

AC AC TH TH Operable Operable

Breast Breast CancerCancer

HER-2 neu HER-2 neu PositivePositive

TrastuzumabTrastuzumabfor a total of 1 for a total of 1

year year R

Endpoints:Endpoints: pCR, cardiac events, DFS, OS pCR, cardiac events, DFS, OS

AC AC TL TL

AC AC THL THL

SSUURRGGEERRYY



NeoALTTONeoALTTOStudy DesignStudy Design

Stratification:Stratification:• T ≤ 5 cm vs. T > 5 cmT ≤ 5 cm vs. T > 5 cm•ER or PgR + vs. ER or PgR + vs. ER & PgR –ER & PgR –• N 0-1 vs. N N 0-1 vs. N ≥ 2≥ 2•Conservative surgeryConservative surgery or notor not

Invasive operableInvasive operableHER2+ BCHER2+ BCT > 2 cm T > 2 cm (inflammatory BC(inflammatory BC excluded)excluded)LVEF LVEF 50% 50%N=450 N=450

34 weeks34 weeks

5252 weeks of anti-HER2 therapyweeks of anti-HER2 therapy

lapatiniblapatinib

trastuzumabtrastuzumab

lapatiniblapatinib


F F EEC C

XX

33

SSUURRGGEERRYY

RRAANNDDOOMMIIZZEE

lapatinib lapatinib


lapatiniblapatinib


paclitaxel paclitaxel

paclitaxel paclitaxel

paclitaxelpaclitaxel

+ 12 wks+ 12 wks6 wks6 wks

NeoALTTONeoALTTOEfficacy - pCR and tpCREfficacy - pCR and tpCR

L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumabL: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumabpCR pathologic complete responsepCR pathologic complete response

GEPARquinto TrialGEPARquinto Trial

Neoadjuvant Therapy Questions inNeoadjuvant Therapy Questions inHormonally Sensitive BCHormonally Sensitive BC

• Role of neoadjuvant chemotherapy in certain ER-Role of neoadjuvant chemotherapy in certain ER-positive/HER-2 negative breast cancers has been positive/HER-2 negative breast cancers has been questionedquestioned

• Value of down-staging with neoadjuvant endocrine Value of down-staging with neoadjuvant endocrine therapy has been shown therapy has been shown

• Potential for genomic profiling to assign ER-positive Potential for genomic profiling to assign ER-positive patients to neoadjuvant endocrine therapy vs. patients to neoadjuvant endocrine therapy vs. neoadjuvant chemotherapyneoadjuvant chemotherapy

• Is pCR the most appropriate endpoint for these Is pCR the most appropriate endpoint for these patients?patients?

21-Gene Recurrence Score Predicts Degree of Benefit from 21-Gene Recurrence Score Predicts Degree of Benefit from Chemotherapy or Hormonal TherapyChemotherapy or Hormonal Therapy

Dotted lines represent 95% CIDotted lines represent 95% CIDis

tan

t R

ecu

rren

ce a

t 10

Yea

rsD

ista

nt

Rec

urr

ence

at

10 Y

ears

Recurrence ScoreRecurrence Score

Greater hormonal therapy benefit Greater chemotherapy benefitGreater hormonal therapy benefit Greater chemotherapy benefit

Paik S, et al. Paik S, et al. N Engl J Med.N Engl J Med. 2004;351:2817. Paik S, et al. 2004;351:2817. Paik S, et al. J Clin Oncol.J Clin Oncol. 2006;24:3726. 2006;24:3726. Gianni L, et al. Gianni L, et al. J Clin OncolJ Clin Oncol. 2005;23(29):7265-7277. Chang JC, et al. . 2005;23(29):7265-7277. Chang JC, et al. Breast Cancer Res TreatBreast Cancer Res Treat. 2008;108 (2):233-240. . 2008;108 (2):233-240. Akashi-Tanaka S et al. Breast. 2009 Jun:171-174Akashi-Tanaka S et al. Breast. 2009 Jun:171-174

43

Endpoints: Clinical Response, BCT, RCB, pCREndpoints: Clinical Response, BCT, RCB, pCR

HR+/Her-2 Neg. Breast CancerHR+/Her-2 Neg. Breast CancerNeeding Neo Rx to Achieve BCTNeeding Neo Rx to Achieve BCT

Core BX for 21-Gene Core BX for 21-Gene RSRS

Neoadjuvant Neoadjuvant ChemotherapyChemotherapy

NeoadjuvantNeoadjuvantHormonal TxHormonal Tx

Neoadjuvant Neoadjuvant ChemotherapyChemotherapy

RandomizeRandomizeNeoadjuvantNeoadjuvantHormonal TxHormonal Tx

11-2511-25 > 25> 25< 11< 11

SURGERYSURGERY

Neoadjuvant Trial Proposal for HR+ BCNeoadjuvant Trial Proposal for HR+ BC

Axillary Node Surgery After Neoadjuvant Chemotherapy

• Assuming clinical nodal exam, MRI and/or axillary US pre-treatment are negative, what axillary node staging recommended?• Axillary node dissection?• Sentinel node biopsy?

• Before NCT?• After NCT?

What if ?--MRI Prior to Neoadjuvant Therapy

Axillary nodeslargest 2.1 x 2.3 x 3.5 cmPositive for cancer on US-guided biopsy

Role for Sentinel Lymph Node Biopsy in Patients Receiving NCT?

• NCCN and ASCO guidelines:• NCT is a contraindication to use of SLN

biopsy

• Many advocate SLN biopsy prior to NCT

• What are potential advantages and pitfalls to SLN biopsy AFTER NCT?

Axillary Node Down-Staging with NCTAxillary Node Down-Staging with NCT

ACACNSABP B-18NSABP B-18

5050

4040

3030

2020

1010

00

% % ConversionConversion

FromFromNode (+)Node (+)

ToToNode (-)Node (-)

ATAT→→CMFCMFECTOECTO

3037

FECFECEORTCEORTC

19

ACAC→→TXTTXTNSABP B-27*NSABP B-27*

43

*Assuming 30% nodal down-staging with neoadjuvant AC*Assuming 30% nodal down-staging with neoadjuvant AC

More than 40% of initially node-positive women could potentially avoid ALND!

Arguments Against SLN Biopsy After NCT

1. SLN mapping after NCT may fail and/or may not be accurate (i.e, high false negative rate)

(Failure to map is really NOT an issue – if can’t find SLN, then do ALND, which is what SLN opponents recommend in the first place)

Pathologic Status of Sentinel Nodes and Pathologic Status of Sentinel Nodes and Non-Sentinel Nodes (N=343) - NSABP B-27Non-Sentinel Nodes (N=343) - NSABP B-27

PositivePositive125 pts125 pts

NegativeNegative 218 pts218 pts



NegativeNegative203 pts203 pts

NegativeNegative70 pts70 pts

False negative rate = 10.7% (15/140)No significant difference between clinically node negative (12.4%) vs. node positive (7.0%)

Mamounas et al JCO, 2005

Identification Rate: Identification Rate: 85% (343/428)85% (343/428)

Sentinel Sentinel Node(s)Node(s)

Non-Sentinel Non-Sentinel Node(s)Node(s)

Comparison of False Negative Rates Comparison of False Negative Rates Between SN Multicenter StudiesBetween SN Multicenter Studies

StudyStudy FNR FNR (SN-/N+) (SN-/N+)Multicenter SB-2 TrialMulticenter SB-2 Trial 11% 11% (13/114) (13/114)

Italian Randomized Trial 9%Italian Randomized Trial 9% (8/91) (8/91)

Ann Arundel 13% (25/193)Ann Arundel 13% (25/193)

University of LouisvilleUniversity of Louisville 7% (24/333) 7% (24/333)

NSABP B-32 Randomized Trial 10%NSABP B-32 Randomized Trial 10% (75/766) (75/766)

NSABP B-27 (After NC) 11%NSABP B-27 (After NC) 11% (15/140) (15/140)

Meta-Analysis (Xing, 2006)Meta-Analysis (Xing, 2006) 12% 12% (65/540) (65/540)

Meta-Analysis (Kelly, 2009)Meta-Analysis (Kelly, 2009) 8%8% ( (~64~64/758)/758)Krag DN: N Engl J Med 1998 Veronesi U: N Engl J Med 2003 McMasters KM: J Clin Oncol 2000 Mamounas EP: J Clin Oncol 2005 Mamounas EP: J Clin Oncol 2005 Tafra L: Am J Surg 2001 Tafra L: Am J Surg 2001 Xing Y:Br J Surg 2005 Julian JB: Xing Y:Br J Surg 2005 Julian JB: SABCS 2004. Kelly, AM: Acad Radiol, 2009SABCS 2004. Kelly, AM: Acad Radiol, 2009

GROUP FALSE NEGATIVE RATES (%)

Planned SLN + ALND

Overall After 2000

Surgery 1st

(n = 542)

4.1 2.7

Chemo 1st

(n = 84)

5.9

(p = 0.39)

5.5

K. Hunt et al, Ann. Surg, 2009

M.D. Anderson Comparison of SLN After Chemotherapy to Primary Surgical Patients

Clinically node negative: Negative on PE and US

GROUP Axillary Dissections (%) Regional Recurrence Rates (%)

T2 T3

Surgery 1st

(n = 3171)

40.6 65.7 0.9

Chemo 1st

(n=575)

27.1

(p < 0.001)

45.1

(p<0.045)

1.2

K. Hunt et al, Ann.Surg,, 2009

M.D. Anderson Comparison of SLN After Chemotherapy to Primary Surgical Patients

Arguments Against SLN Biopsy After NCT

2. Loss of important prognostic information derived from pre-chemo nodal pathology

(Leads to recommendation to do SLN prior to treatment)

0 2 4 6 8

Years after Randomization

02

04

06

08

01

00

% D

isea

se-F

ree

0

1-3

4-9

10+

#N % 0 471-3 324-9 1610+ 5

B-27 DFS By Nodes (without pCR in Breast - 1881)

SLN Biopsy After Neoadjuvant Chemotherapy – Do We Lose Prognostic

Information?

• Post-treatment nodal status is at least as powerful as pre-treatment nodes

• In fact, by possibly removing the only positive nodes with SLNB prior to treatment, we lose even more important information

SLN Before Neoadjuvant Chemotherapy

• Two Major Disadvantages for patients with positive nodes at diagnosis:• Two separate axillary surgical

procedures• Many women (~ 40%) will undergo

unnecessary ALND

Eradication of LN Metastases with Chemotherapy + Trastuzumab

• 109 consecutive patients with HER-2+ BC and biopsy-proven LN metastases

• NCT + trastuzumab

• All had complete ALND at surgery

• 81 (74%) had all negative nodes

Dominici, et al., MDACC, SABCS 2009, Abstract # 1086

Caveat – Potentially High FN Rate for Node-Positive Patients

• 69 patients with biopsy- proven axillary LN metastases – 25% FNR (N2 & N3 included)

• 47 patients with clinical N1-N2 disease – 30% FNR

J. Shen et al., Cancer, 2007P. Gimbergues et al., ASO, 2008

ACOSOG Z1071 SchemaAccuracy of SLN After NCT in Node Positive

Breast Cancer

*Patients can be registered pre or post chemotherapy

T1-4, N1-2 invasive breast cancerT1-4, N1-2 invasive breast cancer(pretreatment axillary ultrasound with FNA or core (pretreatment axillary ultrasound with FNA or core

biopsy documenting axillary metastases)biopsy documenting axillary metastases)

REGISTER*REGISTER*

Patients receive neoadjuvant chemotherapyPatients receive neoadjuvant chemotherapy(stratify patients by age, stage and (stratify patients by age, stage and

number of cycles and type of chemotherapy)number of cycles and type of chemotherapy)

REGISTERREGISTER**

SLN and ALNDSLN and ALND

ASBD Consensus Statement on SLN in NCT Patients - 2010

• Clinically node negative initially - • SLN acceptable before or after NCT• Factor in impact of initial node status on

treatment

• Clinically node positive initially – • Pathologic confirmation recommended• Z1071 results pending• ALND “standard of care” at definitive

surgery

• In pts with operable BC, NC results in equivalent outcomes to those In pts with operable BC, NC results in equivalent outcomes to those achieved with adjuvant chemotherapy but has several potential advantagesachieved with adjuvant chemotherapy but has several potential advantages

• Information on outcome based on response to NC can be obtained on an Information on outcome based on response to NC can be obtained on an individualized basisindividualized basis

• Loco-regional therapy can be tailored based on tumor response in the Loco-regional therapy can be tailored based on tumor response in the breast and axillary nodesbreast and axillary nodes

• This approach holds great promise as NC regimens with targeted biologics This approach holds great promise as NC regimens with targeted biologics become considerably more effective and as genomic and imaging become considerably more effective and as genomic and imaging technology allows for more accurate prediction and identification of technology allows for more accurate prediction and identification of pathologic complete responderspathologic complete responders

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NSABP Neoadjuvant Chemotherapy and Axillary Staging Thomas B. Julian, MD, FACS Professor of Surgery...

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