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 0.824 • 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 49808 : utility of MRI

(www.acrin.org, current protocol section)

PST in POBC : Role of F18FDG 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 0.788

• 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 600-273,150 cells/ml• R2 = 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 DFS OS

% %

NSABP-18 1523 ACx4 68 13 no no

EORTC 698 FECx4 30 4 no no

Scholl 390 FACx4 82 NA no no

Mauriac 272 EVM-MTV 62 - no no

Randomized Clinical Trials on PST with a Taxane Based Regimen

Study N Regimen %pCR NASBP-27 2411 ACx4-Dx4 26

ACx4 14ECTO 451 APaclx4-CMFx4 23GEPARDUO 913 ACx4-Tx4 22

2wADx4 11ACCOG 363 ACx6 24

ADx6 21MDACC 258 3wTx4-FACx4 14

wTx12-FACx4 29AGO 631 2wEx3-2wTx3 18

Epacli x 4 10

NSABP B-27

I II III

Operable Breast Cancer

AC x 4 Tam x 5y

Surgery Docetaxel x 4

Surgery

Surgery

Docetaxel x 4

AC x 4 Tam x 5y

AC x 4 Tam x 5y

NSABP B-27: pCR in Breast

9.1

3.7 18.9

7.2

9.9

4.4

0

5

10

15

20

25

30

Grp. I Grp. II Grp. III

DCIS only

No Tumor%

*p<0.001 for test of heterogeneity across groups n=764 n=767

12.8%*

26.1%*

14.3%*

n=775

NSABP B-27 Overall Survival

40

50

60

70

80

90

100

0 1 2 3 4 5

% Surviving

Years after Surgery

TRT N DeathsGroup I 801 150Group II 803 143 HR=0.94 p=0.57Group IIIGroup III 799799 163163 HR=1.07HR=1.07 p=0.53p=0.53

NSABP B-27: RFS

40

50

60

70

80

90

100

0 1 2 3 4 5

% Relapse-free

Years after Surgery

TRT N EventsGroup I 801 247Group II 803 210 HR=0.81 p=0.03Group IIIGroup III 799799 230230 HR=0.91HR=0.91 p=0.32p=0.32

NSABP B-27: DFSpCR vs. non-pCR Patients

40

50

60

70

80

90

100

0 1 2 3 4 5

% Disease-free

Years after Surgery

TRT N EventsNon pCR 1899 638pCR 409 71 HR=0.45 p<0.0001

NSABP B-27: OS pCR vs. non-pCR Patients

40

50

60

70

80

90

100

0 1 2 3 4 5

% Surviving

Years after Surgery

TRT N DeathsNon pCR 1899 396pCR 409 31 HR=0.33p<0.0001

3-31-04

PST with Single Agent Trastuzumab

• Gennari et al. Clin Cancer Res, 5050, 2004

• 11 patients HER2+ POBC • Trastuzumab 4mg/kg, 2mg/kg/we• S by day 21-28 • 1 cCR and 7cPR• No difference in TC proliferation • All tumors showed ly infiltration • TR - ADCC

PST with Trastuzumab and Chemotherapy

Author N Regimen pCR cRR

Burstein 2003 40 PH 18% 75%

Harris 2003 28 NH - 93%

Bines 2003 33 TH 12% 95%

Wenzel 2004 18 TEHw - 86 %

Buzdar 2005 23 P-FEC+H 65% 87%

Hurley 2005 30 TCH 13%

Coudert 2006 33 TH 47% 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; 24:769-777 2006

DCE-MRI and clinical responses in a patient with partial response

Wedam, S. B. et al. J Clin Oncol; 24:769-777 2006

(p-VEGFR2) by immunohistochemistry

PST : Effect of Bevacizumab

Candidate Single Gene Predictive Markers : HR

QuickTime™ en eenTIFF (ongecomprimeerd)-decompressor

zijn vereist om deze afbeelding weer te geven.

Neo-Adjuvant Chemotherapy and pCR

QuickTime™ en eenTIFF (ongecomprimeerd)-decompressor

zijn vereist om deze afbeelding weer te geven.

Neo-Adjuvant Chemotherapy and pCR

Neo-Adjuvant Chemotherapy and pCR

Hess, K. R. et al. J Clin Oncol; 24:4236-4244 2006

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; 24:4236-4244 2006

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)

BCS LNN-

• S-Ax4-CMFx4 38% 35%• ATx4-CMFx4-S 61% 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-)