Neoadjuvant Hormone Treatmentof Breast Cancer

H.S.A. Oldenburg E.J.Th. Rutgers J.M. Dixon

symposium 29 juni 2005

Neoadjuvante Endocrine therapie

•Waarom geen neoadjuvante chemo?

•Welke endocriene therapie?

•Welke locoregionale behandeling?

•Welke patienten?

Neoadjuvant Endocrine vs Chemotherapy

• 121 Postmenopausal women

• ER + and/or PgR + large operable + LABC

• Randomised to Chemo or Hormone therapy

• Median age: 69y Chemo: 67y Hormones

• Chemo: adriamycin + paclitaxel 3 weekly x 4 n=62

• Anastrozole 1mg or Exemestane 25 mg – 3 months n=59

Semiglasov et al ASCO 2004 Abstract 519

0

20

40

60

80

100

Clinical Mammography pCR

Chemotherapy Anastrozole Exemestane

%

Responses

0

20

40

60

80

Chemotherapy Aromatase Inhibitor

%

Adverse Events

0

10

20

30

40

Rate of Breast ConservingSurgery

Chemotherapy Anastrozole Exemestane

%

Outcomes

p=0.054

0

10

20

30

40

Rate of Breast ConservingSurgery

Local Recurrence Rate

Chemotherapy Anastrozole Exemestane

%

Outcomes

p=0.054

In postmenopausal women with ER + cancersIn postmenopausal women with ER + cancers

Neoadjuvant Hormone Therapy is as least Neoadjuvant Hormone Therapy is as least

effective as Neoadjuvant chemotherapy in effective as Neoadjuvant chemotherapy in

• Response rateResponse rate

• Breast Conservation rateBreast Conservation rate

ANDAND

• Causes much less morbidityCauses much less morbidity

Conclusion

O24 Design

Double-blind, double-dummy, randomized, parallel group,multicentre (55 centres in 16 countries), phase IIb/III trial

Letrozole

2.5 mg o.d.

n=154

Tamoxifen

20 mg o.d.

n=170

Surgery

Follow-up therapy

(investigator driven)

4 months

Patients with 10% ER +veCells and neededMx or had LABC

Outcomes in O24

0

20

40

60

Clinical Mammography Ultrasound BreastConservation

Letrozole Tamoxifen

p<0.001p<0.001

35% 25% 34% 17% 45% 35%

% P

atie

nts

res

po

nd

ing

to

th

erap

y

p=0.042p=0.042 p=0.022p=0.022

55% 36%

p<0.001p<0.001

Outcomes of 83 Inoperable cases in O24

35 3530

13

4642

0

20

40

60

Breast Conservation Mastectomy No Op

Letrozole Tamoxifen

% P

atie

nts

hav

ing

sp

ecif

ied

tre

atm

ent

p = 0.011

Response by ER Allred category

ER Score

% R

esp

on

se

rat

e

7.0 1.5 1.5 3.0 2.2 7.0 21.4 56.5

% in each category

0

20

40

60

80

0 2 3 4 5 6 7 8

tamoxifen

letrozole

Randomise

Anastrozole 113 Tamoxifen 108 Combination 109

Pretreatment surgical assessment

for Mastectomy or BCS*

Surgery

3 months

330 Intent to Treat patients

292 Per Protocol patients

* Breast conserving surgery

Major violations/deviations 34 (10%)

IMIMmediate - mediate - PPreoperative reoperative AArimidex, Tamoxifen, rimidex, Tamoxifen, or or CCombined with ombined with TTamoxifenamoxifen

Outcomes in IMPACT Overall Population (330 Intent to Treat)

0

10

20

30

40

50

Clinical Ultrasound Breast Conservation

Anastrozole Tamoxifen Combination

% P

atie

nts

res

po

nd

ing

to

th

erap

y

NS NS p=0.03

37 36 39 24 20 28 46 22 28

Imp

rove

men

t ra

te (

%)

A v T: OR 2.94 (1.11, 7.81) A v T: OR 2.94 (1.11, 7.81) pp=0.03 *=0.03 *C v T: OR 1.24 (0.44, 3.53) C v T: OR 1.24 (0.44, 3.53) pp=0.68=0.68

26%22%

46%

0

10

20

30

40

50

A T C

21/46 8/36 11/42

*some pts still opted for mastectomy

Conversion to Breast Conserving Surgery (%)

0

20

40

60

80

100

% P

ati

en

ts

Clinical Response Breast ConservingSurgery

Exemestane Tamoxifen

Neoadjuvant Exemestane vs Tamoxifen

n=36 n=37

p>0.05 p<0.05

Semiglasov et al : 73 pts San Antonio Abstract 111; 2003

Neoadjuvant Therapy in Postmenopausal ER + Breast Cancer

• Letrozole superior to Tamoxifen

• Anastrozole possibly superior to Tamoxifen

• Exemestane superior to Tamoxifen (small trial)

• Most impressive data with letrozole

Response to Extended Neoadjuvant Letrozole

% CR

3 months 9.5

6 months 28.6

1 year 36.4

Data from Edinburgh SABCC 2004

Response to Neoadjuvant Chemotherapy

Path CR

Response to Neoadjuvant Chemotherapy

Path CR

40-50%10-20%

12-20%

20%

Response to Neoadjuvant Hormone Therapy

Path CR

70-80%10-20%

2-5%

Hardly Ever

GroupDownstaged to

lumpectomyLumpectomy

proposed initially

No %IBTR No %IBTR

All Patients 69 15 435 7

Age <49 42 17 214 12

>50 27 11 221 2

NSABP 18: Local Recurrence Rates

• 9 year local recurrence rates

Lo

cal

Rec

urr

ence

Fre

e S

urv

ival

Months

XRTNo XRTp<0.0001

Local Recurrence - BCS after Neoadjuvant Endocrine Therapy

27.8%

2.8%

Conclusions

Neoadjuvant aromatase inhibitors in Postmenopausal large operable or LABC

• Response rates up to 80% in selected patients

• Reduces need for mastectomy in over 50%

• As effective as neoadjuvant chemotherapy

• Under utilised in many centres

Surgery following endocrine therapy

relevant factors;

patient preference

tumor criteria, pre- and post-endocrine therapy:• size

• multifocality

• nodal status

• tumor response

Breast-conserving surgery or mastectomy ?

Surgery following endocrine therapyAssessment of tumor response

Clinical assessment is not reliable

Imaging is needed

Local control after downstaging and BCT: current opinion

Increased breast relapse rates do not impact survival

Good assessment with all imaging modalities

Apply standard rules in BCT: WLE and free margins

Standard radiotherapy

Surgery following endocrine therapyIn the clinic

For the surgeon:

See the patient before endocrine therapy

Refer patient to radiation oncologist before endocrine therapy

Monitor patient during endocrine therapy

Assess type of surgery with help of all imaging

Decide together with patient type of surgery: none, BCT, mastectomy, axillary clearance

SN procedure pre or post endocrine therapy?

Surgery following chemotherapyIn the clinic

Patient preferences

• breast-conserving surgery or notTumor criteria

• size, multifocality, stage, localization, nodal statusQuality assurance

• assessment of tumor response• localization of residual tumor• achieving radical margins

This requires excellent collaboration between:

surgeon, medical oncologist, radiotherapist, pathologist, and radiologist (breast clinic)

Surgery following endocrine therapyWhich patients

Older then 55/65 years, and

T2N1

T3, T4

TXN2

Multifocal