1. NSABP Neoadjuvant Chemotherapy and Axillary Staging
Thomas B. Julian, MD, FACS
Professor of Surgery - Drexel University College of Medicine
Senior Surgical Director-Medical Affairs - NSABP
Director-Breast Surgical Oncology - WPAHS
Pittsburgh, PA

2. NC for Operable Breast Cancer Results from First Generation RCTs
No difference in outcome between NC and adjuvant chemotherapy
NC increases the rate of lumpectomy
NC decreases the rate of axillary positivity
Achievement of pCR correlates with improved long-term outcome

3. Neoadjuvant Chemotherapy Potential Advantages
Increase in rate of breast-conserving surgery
Ability to correlate tumor response to outcome
Potential to correlate biomarker expression and changes in biomarkers with tumor response and outcome

4. NC for Operable Breast Cancer Continuing Clinical Rationale
Evaluation of more effective regimens in order to further reduce the extent of loco-regional therapy:
In the breast
In the axilla (SNB)
Use of primary tumor response as a guide of further loco-regional and systemic therapy

5. Neoadjuvant Anthracycline/Taxane Trials
Pathologic Complete Response (pCR)
Sequential A/E Taxane
AC – TXT %
4CVAP – 4TXT: 31%
4ATXL – 4CMF: 23%
3E – 3TXL: %
4AC – 4TXT: %
12TXLw – 4FAC: 29%
4TXL -- 4FAC: %
4(A+C): %
8 (CVAP) %
6(A+C): %
Combo A/E + Taxane
4(E+TXL): %
4(A+TXT): %
6(A+TXT): %
Bear H: San Antonio, 2001, Gianni L: ASCO, 2002,
Untch M: ASCO, 2002
von Minckwitz G, et al. ASCO, 2002
Evans T: ASCO 2004,
Green MC: ASCO 2002

6. NSABP B-18 Neoadjuvant vs Adjuvant AC
Operable Breast Cancer
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
Stratification
• Age
• Clinical Tumor Size
• Clinical Nodal Status
Operation
AC x 4
Operation
AC x 4

7. NSABP B-18 Neoadjuvant vs. Adjuvant AC
Operable Breast Cancer
Disease-Free Survival
Stratification 20 40 60 80
100 2 4 6 8
Year P=
pINV
cPR
cNR
pCR
• Age
• Clinical Tumor Size
• Clinical Nodal Status
Operation
AC x 4
AC x 4
Operation
Wolmark N: JNCI Monogr, 2001 7

8. B-18: 16-Year Update
DFS OS
Rastogi P et al: J Clin Oncol 2008

9. B-18: Overall Survival by Age
N Ev HR P
Post
Pre
<50yrs
N Ev HR P
Post
Pre
≥50yrs
Qualitative
Treatment by Age
Interaction
p=0.01
Wolmark et al: NCI State of the Science Conference 2007 9

10. Operable Breast Cancer
NSABP B-27 Schema
Operable Breast Cancer
(2411 pts)
Randomization
AC x 4
Tam X 5 Yrs
AC x 4
Tam X 5 Yrs
AC x 4
Tam X 5 Yrs
Surgery
Docetaxel x 4
Surgery
Surgery
Docetaxel x 4 10

11. B-27 Response in the Breast
Clinical Response
Pathologic Response
cCR
cPR
cNR
P < 0.001
No Tumor
Non-Invasive
100
40% 80
65% 30
P < 0.001 60
85%
91% % 20
18.7% 40
45%
9.8% 10
25.6%
26% 20
13.7%
14%
6.9% 9%
3.9% AC
(1502 pts)
AC Docetaxel
(687 pts) AC
(1,492 pts)
AC Docetaxel
(718 pts)
Bear H, et al: JCO 2003

12. B-27: 8-Year Update
DFS
RFS
Rfs PW
Rastogi P et al: J Clin Oncol 2008

13. B-27: 8-Year Update Overall Survival
Rfs PW
Wolmark et al: NCI State of the Science Conference 2007

14. NSABP B-27 pCR as a Surrogate for Clinical Endpoints
No-pCR
% Disease-Free
Hypothesis: Mixed with good prognosis patients who did not benefit from chemotherapy ??
Why is the curve for no-pCR not steeper?
Years after Surgery

15. NSABP B-27 Gene Expression and Survival Outcome
1.0
Low-risk (n=163)
0.8
High-risk (n=163)
0.6
Probability of Survival
0.4
0.2
0.0 20 40 60 80
100
Time (months)
Paik et al: Unpublished data

16. Low-Risk Patients Have Good Outcome Regardless of pCR
1.0
pCR
low-risk (16)
0.8
No-pCR
low-risk (147)
0.6
Probability of Survival
0.4
0.2
0.0 20 40 60 80
100
Time (months)
Paik et al: Unpublished data

17. Combination of Prognostic Genes and pCR Defines Residual Risk after Chemotherapy
High-Risk & pCR (34)
1.0
Probability of Survival
0.8
0.6
High-risk & no-pCR (125)
0.4
Candidates for post-neoadjuvant chemo
trials for targeted therapy
0.2
0.0 20 40 60 80
100
Time (months)
Paik et al: Unpublished data

18. Ki-67 Staining Can be Used to Identify High-Risk Group Among no-pCR Patients
Paik S: Unpublished data

19. NSABP B-45: Concept Under Development
Residual Invasive Cancer in Breast or Axillary Nodes
Following a Minimum of Six Cycles of NC
Triple-Negative, Clinical Stage II or Stage III
STRATIFICATION
Pathological nodal staging (ypNo or ypN1; ypN2; ypN3)
Postoperative radiation (yes; no)
Randomization
Arm 1 *
No adjuvant
chemotherapy
Arm 2 *
Eribulin mesylate 1.4 mg/m2 IV Days 1 and 8
Every 21 days X 4 cycles 19

20. Combined Analysis of B-18/B-27 Independent Predictors of LRF
Lumpectomy + XRT
(1890 Pts, 190 Events)
Mastectomy
(1070 Pts, 128 Events)
Age
(>50 years vs. <50 years)
Clinical Tumor Size
(>5 cm vs. <5 cm)
Clinical Nodal Status
(+) vs. (-)
Breast/Nodal Path Status
Node(-)/No pCR vs. Node(-)/pCR
Node(+) vs. Node(-) /pCR
Mamounas et al: ASCO Breast 2010, Abstr. 90

21. 10-Year Cum. Incidence of LRF Lumpectomy Patients, >50 years
Clin. Node (-)
Clin. Node (+)
n=58
n=348
n=212
n=90
n=31

22. 10-Year Cum. Incidence of LRF Lumpectomy Patients, <50 years
Clin. Node (-)
Clin. Node (+)
n=84
n=223
n=376
n=135
n=57

23. 10-Year Cum. Incidence of LRF Mastectomy Patients, < 5 cm
Clin. Node (-)
Clin. Node (+)
n=37
n=183
n=46
n=178
n=21

24. 10-Year Cum. Incidence of LRF Mastectomy Patients, > 5 cm
Clin. Node (-)
Clin. Node (+)
n=179
n=95
n=33
n=16
n=11

25. Development of a Nomogram to Predict LRF Following Neoadjuvant Chemotherapy
Results of multivariate analyses in which age and tumor size were used as continuous variables were similar to those in which age and tumor size were used as discrete variables
The independent predictors of LRF were then incorporated into two separate nomograms:
Lumpectomy + breast XRT
Mastectomy

26. Nomogram for Prediction of 10-Year Rate of LRF After NC
Lumpectomy + XRT
10-Year Probability of LRF
Age at Entry (Years)

27. Nomogram for Prediction of 10-Year Rate of LRF After NC
Mastectomy
10-Year Probability of LRF
Clinical Tumor Size at Entry (cm)

28. Summary I
In patients with operable breast cancer, the 10-year cum. incidence of LRF after neoadjuvant chemotherapy was 10-12%
Despite worse patient characteristics in B-27, LRF with AC in B-27 was lower than in B-18 and there was an effect of docetaxel (about 25% reduction)
Overall, the ratio of local vs. regional failure is about 3:1 but this ratio is influenced by type of surgery and other independent predictors of LRF

29. Summary II
Independent predictors of LRF in lumpectomy + breast XRT patients include: age, clinical nodal status (before NC) and pathologic breast/nodal response
Independent predictors of LRF in mastectomy patients include: clinical tumor size (before NC), clinical nodal status (before NC) and pathologic breast/nodal response
The effect of age (in lumpectomy patients), clinical tumor size (in mastectomy patients) and clinical nodal status on LRF appears to diminish with increasing pathologic response in the breast and axillary nodes

30. Summary III
These independent predictors of LRF after neoadjuvant chemotherapy can be incorporated to separate nomograms for lumpectomy + breast XRT and mastectomy patients to provide guidance on the need for regional XRT after lumpectomy or loco-regional XRT after mastectomy
Further development and validation of these nomograms with inclusion of treatment effect is planned

31. New Directions with Neoadjuvant Chemotherapy
NSABP
New Directions with Neoadjuvant Chemotherapy
Use pCR as a correlate of chemotherapy efficacy to test new drugs and regimens
Utilize micro-array technology to identify genomic profiles associated with pCR to specific drugs or combinations
Candidates:
Sequential anthracycline/taxane combinations
New targeted therapies in combination with chemo 31

32. New Directions with Neoadjuvant Chemotherapy
NSABP
New Directions with Neoadjuvant Chemotherapy
Use pCR as a correlate of chemotherapy efficacy to test new drugs and regimens
Utilize micro-array technology to identify genomic profiles associated with pCR to specific drugs or combinations
Candidates:
Sequential anthracycline/taxane combinations
New targeted therapies in combination with chemo 32

33. Agents Targeting the VEGF Pathway
Soluble VEGF receptors
(eg, VEGF-Trap)
Anti-VEGF antibodies
(eg, bevacizumab)
VEGF P P
Anti-VEGFR antibodies
(eg, IMC-1121b)
Endothelial cell
VEGFR-1
VEGFR-2
Small-molecule VEGFR inhibitors (eg, vatalanib, sunitinib, ZD6474, AZD2171)
ANGIOGENESIS
Proliferation
Survival
Migration
Manley et al. Expert Opin Investig Drugs. 2002;11:1715. 33

34. NSABP B-40 R SURGERY +/- X 10 +/- Accrual Completed: 1205 A A A A C C
Tissue for
Biomarkers
Tissue for
Biomarkers T T T T A A A A
SURGERY C C C C
Operable
Breast
Cancer R T T T T A A A A X X X X
+/- C C C C T T T T A A A A G G G G C C C C
X 10 B
+/- B B B B B B
Accrual Completed: 1205

35. NSABP B-40 Pathologic Complete Response (Breast and Nodes)
% pCR (Breast + Nodes)
OR = 1.27
Chi-square test: p=0.09

36. NSABP B-40 Pathologic Complete Response (Breast and Nodes) for HR+ and TN Breast Cancer
% pCR (Breast + Nodes)
N=349
N=351
OR = 1.59
p=0.033
OR = 1.15
p=0.458
Interaction p value = 0.256

37. Capecitabine +/- Lapatinib: Time to Progression (Intent-to-Treat)
Lapatinib + Capecitabine
P-value (log-rank, 1-sided)
69 (43%)
45 (28%)
Progressed or died*
19.7
36.9
Median TTP, wk
161
160
No. of pts
0.51 (0.35, 0.74)
Hazard ratio (95% CI)
% of Patients Progression Free*
100 10 20 30 40 50 60
Time (weeks) 10 20 30 40 50 60 70 80 90
*Censors 4 patients who died due to causes other than breast cancer 70
Geyer et al: N Engl J Med 2006

38. NSABP B-41: Neoadjuvant Study with Lapatinib vs. Trastuzumab vs. Combo
Tissue for
Biomarkers
Tissue for
Biomarkers
SURGERY
AC  TH
Operable
Breast
Cancer
HER-2 neu Positive R
Trastuzumab
for a total of 1 year
AC  TL
AC  THL
Endpoints: pCR, cardiac events, DFS, OS 38

39. 52 weeks of anti-HER2 therapy
NeoALTTO Study Design S U R
G E Y A N D O M I Z E
lapatinib
trastuzumab
paclitaxel
+ 12 wks
6 wks
34 weeks
52 weeks of anti-HER2 therapy
lapatinib
trastuzumab
F EC X 3
Stratification:
T ≤ 5 cm vs. T > 5 cm
ER or PgR + vs.
ER & PgR –
N 0-1 vs. N ≥ 2
Conservative surgery
or not
Invasive operable
HER2+ BC
T > 2 cm
(inflammatory BC
excluded)
LVEF  50%
N=450 39

40. NeoALTTO Efficacy - pCR and tpCR
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
pCR pathologic complete response 40

41. GEPARquinto Trial

42. Neoadjuvant Therapy Questions in Hormonally Sensitive BC
Role of neoadjuvant chemotherapy in certain ER-positive/HER-2 negative breast cancers has been questioned
Value of down-staging with neoadjuvant endocrine therapy has been shown
Potential for genomic profiling to assign ER-positive patients to neoadjuvant endocrine therapy vs. neoadjuvant chemotherapy
Is pCR the most appropriate endpoint for these patients?

43. Distant Recurrence at 10 Years
21-Gene Recurrence Score Predicts Degree of Benefit from Chemotherapy or Hormonal Therapy 43
Greater hormonal therapy benefit Greater chemotherapy benefit
Distant Recurrence at 10 Years
Main point: Results of exploratory neoadjuvant studies are consistent with findings from adjuvant studies in terms of predicting likelihood of response to chemotherapy and endocrine therapy.
Endocrine therapy benefit: the lower the RS, the greater the benefit of endocrine therapy.
Chemotherapy benefit: the higher the RS, the greater the benefit of chemotherapy.
Paik S, et al. N Engl J Med. 2004;351:2817.
Paik S, et al. J Clin Oncol. 2006;24:3726.
Gianni L, et al. J Clin Oncol. 2005;23:7265.
Chang JC, et al. Breast Cancer Res Treat. 2008;108 (2):233.
Dotted lines represent 95% CI
Recurrence Score
Paik S, et al. N Engl J Med. 2004;351:2817. Paik S, et al. J Clin Oncol. 2006;24:3726.
Gianni L, et al. J Clin Oncol. 2005;23(29): Chang JC, et al. Breast Cancer Res Treat. 2008;108 (2):
Akashi-Tanaka S et al. Breast Jun: 43 43

44. Neoadjuvant Trial Proposal for HR+ BC
HR+/Her-2 Neg. Breast Cancer
Needing Neo Rx to Achieve BCT
Core BX for 21-Gene RS
< 11
11-25
> 25
Neoadjuvant
Hormonal Tx
Randomize
Neoadjuvant Chemotherapy
Neoadjuvant
Hormonal Tx
Neoadjuvant Chemotherapy
SURGERY
Endpoints: Clinical Response, BCT, RCB, pCR

45. 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?

46. What if ?-- MRI Prior to Neoadjuvant Therapy
Axillary nodes
largest 2.1 x 2.3 x 3.5 cm
Positive for cancer on
US-guided biopsy

47. 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?

48. Axillary Node Down-Staging with NCT
More than 40% of initially node-positive
women could potentially avoid ALND! 50 40 30 20 10 %
Conversion
From
Node (+) To
Node (-) 43 37 30 19 AC
NSABP B-18
FEC
EORTC
AT→CMF
ECTO
AC→TXT
NSABP B-27*
*Assuming 30% nodal down-staging with neoadjuvant AC

49. Arguments Against SLN Biopsy After NCT
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)

50. False negative rate = 10.7% (15/140)
Pathologic Status of Sentinel Nodes and Non-Sentinel Nodes (N=343) - NSABP B-27
Identification Rate: 85% (343/428)
Sentinel
Node(s)
Positive
125 pts
Negative
218 pts
Non-Sentinel
Node(s)
Negative
70 pts
Positive
55 pts
Negative
203 pts
Positive
15 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

51. Comparison of False Negative Rates Between SN Multicenter Studies
Study FNR (SN-/N+)
Multicenter SB-2 Trial % (13/114)
Italian Randomized Trial % (8/91)
Ann Arundel % (25/193)
University of Louisville % (24/333)
NSABP B-32 Randomized Trial 10% (75/766)
NSABP B-27 (After NC) % (15/140)
Meta-Analysis (Xing, 2006) % (65/540)
Meta-Analysis (Kelly, 2009) 8% (~64/758)
Krag DN: N Engl J Med Veronesi U: N Engl J Med McMasters KM: J Clin Oncol 2000
Mamounas EP: J Clin Oncol Tafra L: Am J Surg Xing Y:Br J Surg Julian JB: SABCS Kelly, AM: Acad Radiol, 2009

52. FALSE NEGATIVE RATES (%)
M.D. Anderson Comparison of SLN After Chemotherapy to Primary Surgical Patients
Clinically node negative: Negative on PE and US
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

53. Axillary Dissections (%) Regional Recurrence Rates (%)
M.D. Anderson Comparison of SLN After Chemotherapy to Primary Surgical Patients
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

54. Arguments Against SLN Biopsy After NCT
Loss of important prognostic information derived from pre-chemo nodal pathology
(Leads to recommendation to do SLN prior to treatment)

55. (without pCR in Breast - 1881)
B-27 DFS By Nodes
(without pCR in Breast )
1-3
4-9
10+
#N %

56. 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

57. 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

58. 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

59. 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, 2007
P. Gimbergues et al., ASO, 2008

60. ACOSOG Z1071 Schema Accuracy of SLN After NCT in Node Positive Breast Cancer
T1-4, N1-2 invasive breast cancer
(pretreatment axillary ultrasound with FNA or core biopsy documenting axillary metastases)
REGISTER*
Patients receive neoadjuvant chemotherapy
(stratify patients by age, stage and
number of cycles and type of chemotherapy)
SLN and ALND
*Patients can be registered pre or post chemotherapy

61. 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

62. Summary
In pts with operable BC, NC results in equivalent outcomes to those achieved with adjuvant chemotherapy but has several potential advantages
Information on outcome based on response to NC can be obtained on an individualized basis
Loco-regional therapy can be tailored based on tumor response in the breast and axillary nodes
This approach holds great promise as NC regimens with targeted biologics become considerably more effective and as genomic and imaging technology allows for more accurate prediction and identification of pathologic complete responders