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