Implications of NSABP B- Implications of NSABP B- 32 and Loco-Regional 32 and Loco-Regional Therapy Considerations Therapy Considerations After Neoadjuvant After Neoadjuvant Chemotherapy 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 Surgery Professor of Surgery Northeastern Ohio Medical University Northeastern Ohio Medical University Medical Director Medical Director Aultman Cancer Center Aultman Cancer Center
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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.
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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
• 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)
• 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
• 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
RandomizationRandomization
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
• 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.
Krag D et al: Lancet Oncol 2010Krag D et al: Lancet Oncol 2010
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?
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
Weaver D et al: N Engl J Med 2011
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
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
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
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