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

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

What Determines Local Control? Disease Burden

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

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

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

Molecular Portrait of Breast Cancers HER-2 Basal-like Luminal A Luminal B “Normal” Sorlie, PNAS 2001;98:10869-874

DFS and OS by Subtype Sorlie, PNAS 2001;98:10869-874

Overall Survival by Amsterdam Gene Signature Van De Vijver MJ, NEJM 2002;347:1999-2009

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;16:2705-10

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;16:2705-10

MVA of Multifocal/Centric Disease Variable Adjusted OR (95% CI) p-value Subgroup <.0001 Lum A 1.0 Lum B 1.2 (1.0-1.5) HER2 1.6 (1.2-2.1) Basal 0.8 (0.6-1.0) Tumor Size 1.02 (0.97-1.07) 0.50 Age .098 (0.98-0.99) Nuclear Grade Low/Int .036 High 1.1 (0.9-1.3) Wiechmann L, Ann Surg Oncol 2009;16:2705-10

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;15:4181-90

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

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; 351:2817-26

B-20 Low RS < 18 Disease-Free Survival N Events 218 11 135 5 p = 0.76 Paik S, JCO 2006; 24:3726-34

B-20 High RS ≥ 31 Disease-Free Survival 10yr TAM 60% CT 88% N Events 117 13 47 18 p = 0.001 Paik, S JCO 2006;24:3726-34

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

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

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

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

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 1.11-5.72; p = .027 2.53, 95% CI 1.12-5.75; p = .026 Abdulkarim B, JCO 2011;29:2852

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)

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

Predictors of LRRFS in Triple Negative Breast Cancer MDACC n = 1325 1980-present Adkins FC, Ann Surg Oncol 2011;18:3164

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

What Determines Local Control? Disease Burden Therapy Biology