1. 18th Annual Perspectives in Breast Cancer
Memorial Sloan-Kettering Cancer Center
1275 York Avenue, New York, NY 10065
18th Annual Perspectives in Breast Cancer
New York, NY
18 August 2012
Role of New Genomic Classifiers
in the Locoregional Management of
Early-Stage Breast Cancer
Monica Morrow MD
Chief, Breast Surgery Service
Anne Burnett Windfohr Chair of Clinical Oncology
Memorial Sloan-Kettering Cancer Center

2. Impact of Local Control on Survival
Early Breast Cancer Trialists’ Collaborative Group, Lancet 2011;378:1707

3. What Determines Local Control?
Disease
Burden

4. Selection Criteria for BCT
Biological Histology Grade Nodal Status ER HER2
Mechanical Extent of Disease in Breast Negative margins Diffuse calcifications Multicentricity Ability to give RT Prior RT Active SLE, scleroderma

5. Selection Criteria for BCT
Biological Histology Grade Nodal Status ER HER2
Mechanical Extent of Disease in Breast Negative margins Diffuse calcifications Multicentricity Ability to give RT Prior RT Active SLE, scleroderma

6. Effective Systemic Therapy Contributes to Local Control
NSABP B13 ER neg
NSABP B14 ER pos
No Rx/Placebo
13.4%
14.7%
CTX/Tam
2.6%
4.3%
NSABP B31 HER2 +
N9831 HER2+
CTX
2.8%
2.7%
CTX + H
1.7%
1.5%
Fisher B, JCO 1996;14:1982
Romand, NEJM 2005;353:1673
Fisher B, JNCI 1996;88:1529

7. Molecular Portrait of Breast Cancers
HER-2
Basal-like
Luminal A
Luminal B
“Normal”
Sorlie, PNAS 2001;98:

8. DFS and OS by Subtype
Sorlie, PNAS 2001;98:

9. Overall Survival by Amsterdam Gene Signature
Van De Vijver MJ, NEJM 2002;347:

10. Do Presenting Features of Breast Cancer Differ by Molecular Subtype?
1/98 – 6/07
n = 6072
Markers
% Cases
ER+ PR+
HER2-
(Lum A)
71%
HER2+
(Lum B) 8%
ER- PR-
(HER2) 6%
(Basal)
15%
Wiechmann L, Ann Surg Oncol 2009;16:

11. Characteristics By Subtype
n = 6072
Lum A
Lum B
HER2
Basal
P-value
% High Grade 29 62 88 85
<.0001
% Multifocal/centric 27 30 37 22
% EIC 15 25 9
Wiechmann L, Ann Surg Oncol 2009;16:

12. MVA of Multifocal/Centric Disease
Variable
Adjusted OR (95% CI)
p-value
Subgroup
<.0001
Lum A
1.0
Lum B
1.2 ( )
HER2
1.6 ( )
Basal
0.8 ( )
Tumor Size
1.02 ( )
0.50
Age
.098 ( )
Nuclear Grade
Low/Int
.036
High
1.1 ( )
Wiechmann L, Ann Surg Oncol 2009;16:

13. Predictive Value of LR Profiles
Profile, Author
% Sensitivity
% Specificity
111 genes, Kreike 77 43
70 genes, Vant Veer 59 64
Wound response, Chang 75 41
Proliferation, Whitfield 63
Kreike B, Clin Cancer Res 2009;15:

14. Risk of LR By Molecular Phenotype
Subtype n
5yr
10yr
Lum A
394
1.0
3.6
Lum B 23
4.3
8.7
Basal (ER, PR, HER2-, CK5/6+ or EGFR+) 52
9.6
HER2 13
7.7
Unclassified
ER, PR, HER2, CK5/6,
EGFR negative 16
6.3
Millar EKA, JCO 2009;27:4701-8

15. 16 Cancer and 5 Reference Genes
Oncotype DX
16 Cancer and 5 Reference Genes
250 Candidate Genes, 3 Studies, 447 Pts
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN ER
PGR
Bcl2
SCUBE2
HER2
GRB7
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
INVASION
Stromolysin 3
Cathepsin L2
GSTM1
CD68
BAG1
Best RT-PCR performance
and most robust predictors
Paik S, NEJM 2004; 351:

16. B-20 Low RS < 18 Disease-Free Survival
N Events
p = 0.76
Paik S, JCO 2006; 24:

17. B-20 High RS ≥ 31 Disease-Free Survival
10yr
TAM %
CT %
N Events
p = 0.001
Paik, S JCO 2006;24:

18. 21 Gene Recurrence Score and LRR
Placebo
Tam
Chemo + Tam
Low Risk
10.8%
4.3%
1.6%
High Risk
18.4%
15.8%
7.8%
Mamounas E, Br Ca Res Treat 2005;S1 #29

19. Multivariate Predictors of LRR:
B14 and B20
Mamounas EP, J Clin Oncol 2010;28:1677

20. Molecular Subtype and LR After BCT
Study
Time n
Lum A
Lum B
HER2*
Basal
Nguyen
5yr
793
0.8
1.5
8.4
7.1
Millar
498
1.0
4.3
7.7
9.6
Voduc
10yr
1461 8 10 21 14
Arvold
1434
2.3
10.8
6.7
*No adjuvant trastuzumab
Nguyen PL, JCO 2008;26:2373 Millar EK, JCO 2009;27:4701
Voduc KD, JCO 2010;28:1684 Arvold ND, JCO 2011;29:3885

21. Molecular Subtype and LR After Mastectomy
Study
Time n
Lum A
Lum B
HER2*
Basal
Kyndi
5yr
489 2 3 13 21
Voduc
10yr
2985 8 14 17 19
*No adjuvant trastuzumab
Kyndi M, JC 2008;26:1419 Voduc KD, JCO 2010;28:1684

22. LRR in Triple Negative Breast Cancer T1, T2 N0
5 yr LRR free survival
BCT (n = 233)
MRM, No RT (n = 235)
96%
90% p = .022
Multivariate HR: MRM vs BCT
2.52, 95% CI ; p = .027
2.53, 95% CI ; p = .026
Abdulkarim B, JCO 2011;29:2852

23. Local Control in Triple Negative Breast Cancer
T1a-bN0
T1T2N0
BCT
TM, no RT
# pts
129 65
432
203
% LR
3.1
4.6
4.3
5.9
Ho A, Cancer 2012 Mar 5 (Epub ahead of print)

24. LRR-Free Survival by Type of Surgery in Triple Negative Breast Cancer
Adkins FC, Ann Surg Oncol 2011;18:3164

25. Predictors of LRRFS in Triple Negative Breast Cancer
MDACC n = present
Adkins FC, Ann Surg Oncol 2011;18:3164

26. Conclusions Rates of LR vary by molecular subtype.
Tumors with a high risk of distant failure have an increased risk of LR which is NOT altered with bigger surgery.
Systemic therapy results in a parallel improvement in local control.
Currently, there is no role for genomic classifiers
in selecting local therapy

27. What Determines Local Control?
Disease
Burden
Therapy
Biology