Neo-Adjuvant Systemic Treatment: Current Modalities Luc Y. Dirix Medical Oncology Oncologisch Centrum GvA, Antwerp. October 14, 2006

Neo-Adjuvant or Pre-operative Systemic Chemotherapy in Patients with Primary Operable Breast Cancer (POBC) To improve surgical options –Reduce size Increase BCS Decrease local recurrences To obtain improved long-term survival –Systemic therapy prior to S S releases and/or stimulates TC CT more early To obtain information on response –In-vivo drug sensitivity test To answer biological questions

Pre-operative Systemic Therapy (PST) in Patients with Primary Operable Breast Cancer (POBC) A)Endpoints B)Types of PST C) Surgical Considerations

Pre-operative Systemic Therapy (PST) in Patients with Primary Operable Breast Cancer (POBC) Endpoints Pathological assessment MRI - PET CTC - CEC DTC

Neo-Adjuvant Chemotherapy and pCR NSABP definition pCR –No residual invasive tumor in the breast –DCIS allowed –LNN Stringent definition of pCR –No invasive tumor in breast –No DCIS allowed –LNN are free Methodological issues

PST in POBC : Definitions of Pathological Response

PST in POBC : Role of MRI DCE-MRI accurately predicts response early on Relation tumor diameter on pathology and DCE- MRI DCE-MRI in is superior in predicting pCR (PE, Mammography, US) DCE-MRI over- and underestimates pCR DCE-MRI effect of bevacizumab Is MRI defined CR a prognostic factor ? ACRIN,CALGB Intergroup : utility of MRI ( current protocol section)

PST in POBC : Role of F 18 FDG PET Early decrease in SUV in responders Reliable in defining non-responders or PD SUVp RR n = 50 a RR -88% threshold pCR and pPR Sensitivity 100%, Specificity 56.5% AUC PET is able to differentiate pathological responders after 1-2 cycles CT with an accuracy of 91%, a sensitivity of 100% PET is a poor discriminator of pCR

PST in POBC : Role of DTC/CTC CTC and PST Pachman et al., n=30 epi-based PST 100% CEC ,150 cells/ml R 2 = 0.97 change TV and log fold decrease CEC REMAGUS 02 RPII study (PASCO 2006) CTC CellSearch, n=60 1CTC in 15/56, >2CTC 8/56 CEC and EPC and PST Füstenberger et al., n=10 Decrease in CEnC correlated with PST Increase in VEGF,EPC No data on DTC in BM and PST

Pre-operative Systemic Therapy (PST) in Patients with Primary Operable Breast Cancer (POBC) A) Types of PST –Chemotherapy Anthracycline-based Taxane based Anti-HER2 Anti-VEGF –Endocrine therapy –Predictors of efficacy

Randomized Clinical Trials on PST with an Anthracycline Based Regimen Study N Regimen BCT pCR DFSOS% NSABP ACx46813nono EORTC698FECx4304nono Scholl390FACx482NAnono Mauriac 272EVM-MTV62-nono

Randomized Clinical Trials on PST with a Taxane Based Regimen StudyN Regimen %pCR NASBP ACx4-Dx426 ACx4 14 ECTO451APaclx4-CMFx423 GEPARDUO913ACx4-Tx422 2wADx411 ACCOG363ACx624 ADx621 MDACC2583wTx4-FACx414 wTx12-FACx429 AGO6312wEx3-2wTx318 Epacli x 410

NSABP B-27 IIIIII Operable Breast Cancer AC x 4 Tam x 5y SurgeryDocetaxel x 4 Surgery Docetaxel x 4 AC x 4 Tam x 5y AC x 4 Tam x 5y

NSABP B-27: pCR in Breast % *p<0.001 for test of heterogeneity across groups n=764 n= %* 26.1%* 14.3%* n=775

NSABP B-27 Overall Survival % Surviving Years after Surgery TRTNDeaths Group I Group II803143HR=0.94p=0.57 Group III799163HR=1.07p=0.53

NSABP B-27: RFS % Relapse-free Years after Surgery TRTNEvents Group I Group II803210HR=0.81p=0.03 Group III799230HR=0.91p=0.32

NSABP B-27: DFS pCR vs. non-pCR Patients % Disease-free Years after Surgery TRTNEvents Non pCR pCR40971 HR=0.45 p<0.0001

NSABP B-27: OS pCR vs. non- pCR Patients % Surviving Years after Surgery TRTNDeaths Non pCR pCR40931 HR=0.33 p<

PST with Single Agent Trastuzumab Gennari et al. Clin Cancer Res, 5050, patients HER2+ POBC Trastuzumab 4mg/kg, 2mg/kg/we S by day cCR and 7cPR No difference in TC proliferation All tumors showed ly infiltration TR - ADCC

PST with Trastuzumab and Chemotherapy AuthorNRegimenpCRcRR Burstein PH18%75% Harris NH-93% Bines TH12%95% Wenzel TEHw-86 % Buzdar P-FEC+H65%87% Hurley TCH13% Coudert TH47%96%

PST with Trastuzumab: RCT 42 pts HER-2 + BC (4T1,28T2,9T31T4) 4xPac 225mg/sqm/24h, 4xFEC(d1,4)+/-H pCR = in breast and LNN = no invasive T 2 pts FISH negative pCR 26.3% vs 65,2% (43%-84%) pCR irrespective of ER status 10% decrease in LVEF in five and seven

Wedam, S. B. et al. J Clin Oncol; 24: DCE-MRI and clinical responses in a patient with partial response

Wedam, S. B. et al. J Clin Oncol; 24: ( p-VEGFR2) by immunohistochemistry

PST : Effect of Bevacizumab

Candidate Single Gene Predictive Markers : HR

Neo-Adjuvant Chemotherapy and pCR

Hess, K. R. et al. J Clin Oncol; 24: Learning curve for Diagonal Linear Discriminant Analysis-30 classifier

Mean area above the receiver operating characteristic (ROC) curves plotted against the number of top genes included in the classifiers

Hess, K. R. et al. J Clin Oncol; 24: ROC curves of three distinct pathologic complete response prediction models

Genome Wide Expression Profiling: The Ultimate Predictor ?

PST with Chemotherapy & BCS BCT after AT -CMF (ECTO) BCSLNN- S-Ax4-CMFx438%35% ATx4-CMFx4-S61%71%

PST in Patients with POBC Breast conserving treatment is feasible and safe. Pre-treatment assessment (SLN) is advisable. pCR is possible both in breast and LNN. Surgery is not be omitted even in cCR. A taxane-anthracycline combination seems optimal. Sequential therapy seems preferable. Addition of Herceptin increases pCR if HER-2 ampl. Optimal duration of PST is unclear. PET and DCE-MRI allow for recognition of non- responders. Is pCR a surrogate for “activity” on CTC-DTC? pCR in nodes remains a prognostic factor pCR predicts survival (most convincingly if ER-)