Implications of NSABP B-32 and Loco-Regional Therapy Considerations After Neoadjuvant Chemotherapy Terry Mamounas, M.D., M.P.H, F.A.C.S. Professor of Surgery

Implications of NSABP B-32 Implications of NSABP B-32 and Loco-Regional Therapy and Loco-Regional Therapy

Considerations After Considerations After Neoadjuvant ChemotherapyNeoadjuvant Chemotherapy

Terry Mamounas, M.D., M.P.H, F.A.C.S.Terry Mamounas, M.D., M.P.H, F.A.C.S.Professor of SurgeryProfessor of Surgery

Northeastern Ohio Medical UniversityNortheastern Ohio Medical UniversityMedical DirectorMedical Director

Aultman Cancer CenterAultman Cancer Center

Operable Operable Breast CancerBreast Cancer

N=1079N=1079

ClinicallyClinicallyNode-NegativeNode-Negative

Radical Radical Mast.Mast.

NSABP B-04NSABP B-04

Total Total Mast.Mast.

Total Total Mast.Mast.

++XRTXRT

100100

8080

6060

4040

2020

00

YearsYears

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

Patients DeathsPatients DeathsRMRM 362 362 259 259 TMRTMR 352 352 274 274TMTM 365 365 259 259

Global p=0.68Global p=0.68

Overall SurvivalOverall Survival

Fisher B: NEJM, 2002Fisher B: NEJM, 2002

• 40% of pts in the RM group had + nodes40% of pts in the RM group had + nodes• Thus, only about 290 pts contribute to the Thus, only about 290 pts contribute to the comparison of RM with TM (about 145/group) comparison of RM with TM (about 145/group)

HR: 1.03HR: 1.03(95% CI 0.87-1.23; P=0.72)(95% CI 0.87-1.23; P=0.72)

Clinically Negative Axillary NodesClinically Negative Axillary NodesN=5611N=5611

GROUP 1GROUP 1Sentinel Node Sentinel Node

BiopsyBiopsy

Axillary Axillary DissectionDissection


Biopsy*Biopsy*

RandomizationRandomization

StratificationStratification• AgeAge

• Clinical Tumor SizeClinical Tumor Size• Type of SurgeryType of Surgery

*Axillary node dissection *Axillary node dissection only if the SN is positiveonly if the SN is positive

NSABP B-32 SchemaNSABP B-32 Schema

NSABP B-32NSABP B-32Technical ResultsTechnical Results

Krag D, et al: Lancet Oncol 2007Krag D, et al: Lancet Oncol 2007

• Identification Rate: Identification Rate: 97%97%

• False Negative Rate:False Negative Rate: 9.7%9.7%

• Average number of SNs: Average number of SNs: 2.92.9

• Factors significantly affecting ID rate:Factors significantly affecting ID rate:–Age, Tumor Size and Tumor LocationAge, Tumor Size and Tumor Location

• Factors significantly affecting FN rate:Factors significantly affecting FN rate:–Type of Biopsy and Number of Removed SNsType of Biopsy and Number of Removed SNs

44

Clinically Negative Axillary NodesClinically Negative Axillary Nodes

GROUP 1GROUP 1SN +ADSN +AD

SN NegSN Neg(SN only)(SN only)

StratificationStratification• AgeAge

• Clinical Tumor SizeClinical Tumor Size• Type of SurgeryType of SurgeryB-32B-32

SN posSN pos+ AD+ AD

SN PosSN Pos SN NegSN Neg(SN+AD) (SN+AD)

Intraop cytology & Intraop cytology & postop HEpostop HE

FUFUFUFU

1,975 pts1,975 pts 2,011 pts2,011 pts


Krag D et al: ASCO 2010 Abstr. LBA 505Krag D et al: ASCO 2010 Abstr. LBA 505

829 pts829 pts 793 pts793 pts

GROUP 2GROUP 2SN SN

* * 300 deaths triggered the definitive analysis300 deaths triggered the definitive analysis** 309 reported as of 12/31/2009309 reported as of 12/31/2009

NSABP Protocol B-32NSABP Protocol B-32

Years After EntryYears After Entry

% S

urv

ivin

g%

Su

rviv

ing

00 22 44 66 88

00202

0404

0606

0808

010

010

0

TrtTrt NN DeathsDeathsSNR+ADSNR+AD 19751975 140 140

SNR 2011SNR 2011 169 HR=1.20 p=0.117 169 HR=1.20 p=0.117

Overall SurvivalOverall Survival for SN Negative Patients for SN Negative Patients

Data as of December 31, 2009Data as of December 31, 2009

Krag D et al: Lancet Oncol 2010Krag D et al: Lancet Oncol 2010

Years After EntryYears After Entry

% D

isea

se-F

ree

% D

isea

se-F

ree

00 22 44 66 88

00202

0404

0606

0808

010

010

0

NSABP Protocol B-32NSABP Protocol B-32Disease-Free SurvivalDisease-Free Survival for SN Negative Pts for SN Negative Pts

TrtTrt NN EventsEventsSNR+ADSNR+AD 19751975 315315

SNR SNR 2011 2011 336 HR=1.05 p=0.542336 HR=1.05 p=0.542

Data as of December 31, 2009Data as of December 31, 2009


B-32 Hazard Ratios Between GroupsB-32 Hazard Ratios Between GroupsAccording to Site of Treatment Failure According to Site of Treatment Failure

Hazard RatioHazard Ratio0.20.2 0.40.4 0.60.6 0.80.8 1.01.0 1.21.2 1.41.4 1.61.6

All eventsAll events HR= 1.05HR= 1.05

Local Regional RecurrencesLocal Regional RecurrencesDistant RecurrencesDistant Recurrences

Opposite Breast CancersOpposite Breast Cancers2nd cancers2nd cancersDead, NEDDead, NED

SNR+AD betterSNR+AD betterSNR betterSNR better


NSABP B-32: NSABP B-32: Local and Regional Local and Regional Recurrences as First EventsRecurrences as First Events

00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

LocalLocal AxillaryAxillary Extra-axillaryExtra-axillary

Pa

tien

ts (

%)

Pa

tien

ts (

%)

Recurrence TypeRecurrence Type

2.72.7

2.42.4

0.10.10.30.3 0.250.25 0.30.3

SNR + ALND (n = 1975)SNR + ALND (n = 1975)

SNR (n = 2011)SNR (n = 2011)

99


NSABP B-32: NSABP B-32: Significantly Lower Significantly Lower Morbidity Without vs. With ALNDMorbidity Without vs. With ALND

00

55

1010

1515

2525

3030

3535

Pa

tien

ts (

%)

Pa

tien

ts (

%)

SNR + ALND (n = 1975)SNR + ALND (n = 1975)

SNR (n = 2011)SNR (n = 2011)

Shoulder Shoulder Abduction Abduction

Deficit Deficit

1919

1313

Arm Volume Arm Volume Difference Difference

> 5% > 5%

2828

1717

1313

77

Arm Arm TinglingTingling

Arm Arm NumbnessNumbness

3131

88

2020

PP < .001 < .001

PP < .001 < .001PP < .001 < .001

PP < .001 < .001

1010

Ashikaga T: J Surg Oncol 2010Ashikaga T: J Surg Oncol 2010

B-32: ConclusionB-32: Conclusion

• No significant differences were observed No significant differences were observed OS, DFS, or Regional ControlOS, DFS, or Regional Control

• Morbidity decreasedMorbidity decreased

When the SN is negative, SN surgery aloneWhen the SN is negative, SN surgery alonewith no further AD is appropriate, safe, andwith no further AD is appropriate, safe, andeffective therapy for breast cancer patientseffective therapy for breast cancer patientswith clinically negative lymph nodes. with clinically negative lymph nodes.


B-32 In PerspectiveB-32 In Perspective• Could the B-32 trial ever show more than Could the B-32 trial ever show more than

2% difference in overall survival?2% difference in overall survival?

SNB + ANDSNB + AND

2807 pts2807 pts

SNB AloneSNB Alone

2804 pts2804 pts

2,011 pts2,011 pts

Neg SNNeg SN1,975 pts*1,975 pts*

Neg SNNeg SN

*3 pts had no F/U

829 pts829 pts 793 pts793 ptsNode-PositiveNode-Positive

SND + ANDSND + AND

ID Rate 97% ID Rate 97%

157 pts had no SNB157 pts had no SNB

75 Pts75 PtsHad Negative SN and Had Negative SN and Positive NSNs on ANDPositive NSNs on AND

About 75 PtsAbout 75 PtsPositive NSNs Positive NSNs

and did not have ANDand did not have AND

2.6%2.6%

Reg. NodalRecurrence

8 vs. 14

B-32 In PerspectiveB-32 In Perspective• Could the B-32 trial ever show more than Could the B-32 trial ever show more than

2% difference in overall survival?2% difference in overall survival?

SNB + ANDSNB + AND

2807 pts2807 pts

SNB AloneSNB Alone

2804 pts2804 pts

2,011 pts2,011 pts

Neg SNNeg SN1,975 pts*1,975 pts*

Neg SNNeg SN

*3 pts had no F/U

829 pts829 pts 793 pts793 ptsNode-PositiveNode-Positive

SND + ANDSND + AND

ID Rate 97% ID Rate 97%

157 pts had no SNB157 pts had no SNB

75 Pts75 PtsHad Negative SN and Had Negative SN and Positive NSNs on ANDPositive NSNs on AND

About 75 PtsAbout 75 PtsPositive NSNs Positive NSNs

and did not have ANDand did not have AND

2.6%2.6%

Reg. NodalRecurrence

8 vs. 14

1:40 Dilution of Any Real 1:40 Dilution of Any Real Benefit from ALND!Benefit from ALND!

Clinically Negative Axillary NodesClinically Negative Axillary Nodes


BiopsyBiopsy

Axillary Axillary DissectionDissection


Biopsy*Biopsy*


*Axillary node dissection *Axillary node dissection only if the SN is positiveonly if the SN is positive

NSABP B-32: Occult MetastasesNSABP B-32: Occult Metastases

IHC and detailed pathologic examination of the SNsIHC and detailed pathologic examination of the SNsperformed centrally and results were not disclosedperformed centrally and results were not disclosed

14

Weaver D et al: N Engl J Med 2011

15.9%15.9%

NSABP B-32: Effect of Occult Metastases on NSABP B-32: Effect of Occult Metastases on Survival in Node-Negative Breast CancerSurvival in Node-Negative Breast Cancer


NSABP B-32: Effect of Occult Metastases on NSABP B-32: Effect of Occult Metastases on Survival in Node-Negative Breast CancerSurvival in Node-Negative Breast Cancer


Loco-Regional Therapy Loco-Regional Therapy Considerations Considerations

After Neoadjuvant After Neoadjuvant ChemotherapyChemotherapy

Individualizing Loco-Regional Therapy with Individualizing Loco-Regional Therapy with Neoadjuvant ChemotherapyNeoadjuvant Chemotherapy

AchievementsAchievements

• Conversion of patients with inoperable tumors to Conversion of patients with inoperable tumors to operable candidatesoperable candidates

• Conversion of mastectomy candidates to Conversion of mastectomy candidates to candidates for BCScandidates for BCS

• Improvement in cosmesis by reducing the size of Improvement in cosmesis by reducing the size of lumpectomy in BCS candidates with large tumorslumpectomy in BCS candidates with large tumors

Individualizing Loco-Regional Therapy with Individualizing Loco-Regional Therapy with Neoadjuvant ChemotherapyNeoadjuvant Chemotherapy

PromisesPromises

• Reduction in the extent of axillary surgery by down-staging Reduction in the extent of axillary surgery by down-staging involved axillary nodes (SNB)involved axillary nodes (SNB)

• Reduction in the extent of L-R XRT by down-staging primary Reduction in the extent of L-R XRT by down-staging primary tumors and axillary nodestumors and axillary nodes

• Potential for eliminating some loco-regional therapy Potential for eliminating some loco-regional therapy altogether (surgery or XRT) with the use of more active altogether (surgery or XRT) with the use of more active regimens and/or with appropriate patient selection with regimens and/or with appropriate patient selection with biomarkersbiomarkers

Surgical Management of Axillary Nodes Surgical Management of Axillary Nodes After NCAfter NC

• NC down-stages axillary NC down-stages axillary

nodes in 20-40% of the nodes in 20-40% of the

patientspatients

• Potential for decreasing Potential for decreasing

the extent of axillary the extent of axillary

surgery with SNBsurgery with SNBACAC

NSABP B-18NSABP B-18

4040

3030

2020

1010

00

% Conversion% ConversionFrom Node (+)From Node (+)

To Node (-)To Node (-)

ATATCMFCMFECTOECTO

30303737

FECFECEORTCEORTC

1919

ACACTXTTXTNSABP B-27NSABP B-27**

4343

*Assuming 30% nodal down-*Assuming 30% nodal down-stagingstaging

with neoadjuvant ACwith neoadjuvant AC

• Identification Rate: Identification Rate: 85%85%

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

• With isotope With isotope ++ blue dye: blue dye: 88-89%88-89%

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

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

• With isotope With isotope ++ blue dye: blue dye: 8.4%8.4%

SNB After NCSNB After NCMulti-Center Studies: NSABP B-27Multi-Center Studies: NSABP B-27

(n=428)(n=428)

Mamounas EP: J Clin Oncol, 2005Mamounas EP: J Clin Oncol, 2005

Clinically Node (-):Clinically Node (-): 12.4% 12.4%Clinically Node (+):Clinically Node (+): 7.0% 7.0%

P=0.51P=0.51

SNB After NCSNB After NCMeta-Analysis of Single-Institution Meta-Analysis of Single-Institution

and Multi-Center Studiesand Multi-Center Studies

• 24 studies24 studies

• 1779 patients1779 patients

• Identification Rates: Identification Rates: 63-100%63-100%–Pooled estimate: Pooled estimate: 89.6%89.6%

• False Negative Rates: False Negative Rates: 0-33%0-33%–Pooled estimate:Pooled estimate: 8.4% 8.4%

Conclusion:Conclusion:SNB is a reliable tool forSNB is a reliable tool for

planning treatment after NCplanning treatment after NC

Kelly A et al: Acad Radiol 2009Kelly A et al: Acad Radiol 2009

AuthorAuthor StageStage # Pts # Pts (Node +)(Node +)

SuccessSuccess Rate ( %)Rate ( %)

FN RateFN Rate(%)(%)

AccurateAccurate

Shen, 2006Shen, 2006 T1-T4, N1-N3T1-T4, N1-N3 69(40)69(40) 9393 2525 NoNo

Lee, 2006Lee, 2006 T1-T4, N1T1-T4, N1(Palpable and FNA (+)(Palpable and FNA (+)or > 1cm thick withor > 1cm thick withloss of fat hilum onloss of fat hilum onUS and SUV > 2.5US and SUV > 2.5

219 (124)219 (124) 7878 66 YesYes

Newman, Newman, 20072007

ResectableResectableT1-3, N1T1-3, N1(FNA (+) under US)(FNA (+) under US)

40 (28)40 (28) 9898 1111 YesYes

AllAll 328 (172)328 (172) 8484 11.611.6

SNB After NC: Single Institution SeriesSNB After NC: Single Institution SeriesPositive Axillary Nodes Before NCPositive Axillary Nodes Before NC

Z1071: SLNB + AND After NCZ1071: SLNB + AND After NCT1-4 N1-2 invasive breast cancerT1-4 N1-2 invasive breast cancer

(pretreatment axillary ultrasound with FNA or core biopsy (pretreatment axillary ultrasound with FNA or core biopsy documenting axillary metastases)documenting axillary metastases)

↓↓

REGISTERREGISTER* * ↓↓

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 chemotherapynumber of cycles and type of chemotherapy))↓↓

REGISTERREGISTER** ↓↓

SLN and ALNDSLN and ALND

TargetTargetAccrual:Accrual:550 pts550 pts

• Helpful if the SN is negativeHelpful if the SN is negative

• Patients with large operable breast cancer have Patients with large operable breast cancer have high likelihood of positive nodes (50-high likelihood of positive nodes (50-70%)70%)

• Does not take advantage of the downstaging effects of NC on nodes: Does not take advantage of the downstaging effects of NC on nodes: 30-40% 30-40% conversion from (+) to (-)conversion from (+) to (-)

• RequiresRequires two surgical procedures two surgical procedures

SNB SNB BeforeBefore NC NC: : Pros and ConsPros and Cons

• Breast XRT:Breast XRT: Should be always given after Should be always given after lumpectomylumpectomy

• Chest Wall and Regional XRT:Chest Wall and Regional XRT: Consider factors Consider factors predicting local-regional failure after NCpredicting local-regional failure after NC

• These factors may predict LR failure more These factors may predict LR failure more accurately than the original pathologic nodal accurately than the original pathologic nodal status before NCstatus before NC

Can We Use Tumor and Nodal Can We Use Tumor and Nodal Response to NC in Order to Response to NC in Order to

Individualize the Use of L-R XRT?Individualize the Use of L-R XRT?

SNB SNB BeforeBefore NC: NC:Selection of Loco-Regional XRT?Selection of Loco-Regional XRT?

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(-)/pCRNode(-)/No pCR vs. Node(-)/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



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

• SNB alone is the standard of care for staging the axilla in SNB alone is the standard of care for staging the axilla in patients with negative SNBpatients with negative SNB

• SNB alone appears reasonable for patients with occult mets, SNB alone appears reasonable for patients with occult mets, micromets or macromets (not identified intraoperatively or micromets or macromets (not identified intraoperatively or by routine H & E assessment)by routine H & E assessment)

• Following neoadjuvant chemotherapy loco-regional therapy Following neoadjuvant chemotherapy loco-regional therapy can be tailored based on clinico-pathologic tumor response can be tailored based on clinico-pathologic tumor response in the breast and axillary nodesin the breast and axillary nodes

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

Summary/Conclusions Summary/Conclusions

3434

Documents

Implications of NSABP B-32 and Loco-Regional Therapy Considerations After Neoadjuvant Chemotherapy Terry Mamounas, M.D., M.P.H, F.A.C.S. Professor of Surgery