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Early Breast Cancer Trialists Collaborative Groupe. Tamoxifen for early breast
cancer: an overwiew of the randomised trials. Lancet. 1998;351:1451-1467.

Categories of endocrine
responsiveness


Highly endocrine responsive (previously


referred to as endocrine responsive)


Incompletely endocrine responsive (previously


referred to as endocrine response uncertain)


in which the tumors express high levels of both steroid


hormone receptors in a majority of cells (identified with proper
immunohistological methods)

some expression of steroid hormone receptors but at lower


levels or lacking either ER or PgR

Endocrine non-responsive



tumors having no detectable expression of steroid hormone


receptors
While this group is clearly defined in terms of lack of
responsiveness to endocrine therapies, it includes tumors of
*Goldhirsch et al: submitted for publication
diverse phenotype

,
HER2-

.
Pergam MD, Pauletti G, Slamon DJ. HER-2/neu as a predictive marker of
response to breast cancer therapy. Breast Cancer Res Treat. 1998;52:65-77.
De Laurentiis M, Arpino G, Massarelli E, et al. A meta-analysis on the
interaction between HER-2 expression and response to endocrine treatment
in advanced breast cancer. Clin Cancer Res. 2005;11:4741-4748.




 ,
Arimidex,
Tamoxifen, Alone or in Combination (ATAC)
, HER2

.
Dowsett M, Allred DC on Behalf of the TransATAC Investigators. Relationship
between quantitative ER and PgR expression and HER2 statuswith recurrence
in the ATAC trial. San Antonio Breast Cancer Symposium. 2006; Abstract 48.


NCCN


1:
,

2:
,
.
2: ( )
,

.
3:
.




-
, ,
HER2- ,


0,5 0,6 1
,

.



- .
ER-
39%
31% ,
, ,
.

,
5 .

NSABP B-14 Study






Patients had Finished 5 Years of Tamoxifen


All Patients had Node-Negative Cancer
Random Assignment to Tamoxifen vs Placebo
for 5 More Years
Endpoints: OS, DFS, DDFS

Fisher,B. JNCI 1996:88;1529

NSABP B-14 Findings


DFS*

DDFS

OS

Tam-5

92%

96%

96%

Tam-10

86%

90%

94%

*p=.003
p=.01

Fisher,B. JNCI 1996:88;1529



,
.
Albain K, Barlow W, OMalley F, et al. Concurrent (CAFT) versus sequential (CAF-T)
chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen)
versus T alone for postmenopausal node positive estrogen (ER) and/or progesterone
(PgR) receptor-positive breast cancer: mature outcomes and new biologic correlates on
phase III Intergroup trial 0100 (meeting abstract). Presented at the San Antonio breast
cancer symposium, San Antonio, TX, December 8-11, 2004;Abstract LBA37.

Adjuvant endocrine therapy for


HR+ early breast cancer


5 years of tamoxifen has been the gold standard for


many years
41% reduction in annual risk of recurrence
 34% reduction in annual risk of death1


But


A substantial number of relapses are not prevented by


adjuvant tamoxifen


Risk of relapse peaks at 23 years after surgery

Resistance to tamoxifen is common


 Associated with potentially life-threatening AEs


1. EBCTCG Lancet 2005;365:1687717; 2. Saphner et al. J Clin Oncol 1996;14:273846




.


, 2-3

(extended) 4,5-6 .







,

.





,

,
, .
Coombes RC, Paridaens R, Jassem J, et al. First mature analysis of the Intergroup
exemestane study (meeting abstract). J Clin Oncol. 2006;24:18s(June 20 suppl).
Abstract LBA527.
Kaufmann M, Jonat W, Hilfrich J, et al. Survival benefit of switching to anastrozole
after 2 years treatment with tamoxifen versus continued tamoxifen therapy: The
ARNO 95 study (meeting abstract). J Clin Oncol. 2006;24:18s(june 20 suppl). Abstract
547.


, -17
(NCIC
CTG)
(extended)
, ER
(
).
Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following
tamoxifen as extended adjuvant therapy in receptor-positive breast cancer:
updated findings from NCCN CTG MA 17. JNatl Cancer Inst. 2005;97:1262-1271.



.
,
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- ,
,

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.
,


,
- .
Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen
versus tamoxifen alone for adjuvant treatment of postmenopausal women with early
breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359:2131-2139.
Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone
or in Combination) trial after completion of 5 years adjuvant treatment for breast cancer.
Lancet. 2005;365:60-62.

ATAC Trial Design


Postmenopausal women with invasive breast cancer


Surgery radiotherapy chemotherapy

Randomization 1:1:1 for 5 years

Anastrozole 1mg od

Anastrozole placebo

Anastrozole 1mg od

Tamoxifen placebo

Tamoxifen 20mg od

Tamoxifen 20mg od


Regular follow-up


Primary trial endpoints
Disease-free survival
Safety/tolerability

Secondary trial endpoints


Incidence of contralateral breast cancer
Time to distant recurrence
Survival

Key Patient Characteristics


All treatment groups well balanced


34% patients node-positive

84% patients receptor-positive

8% receptor-negative

8% receptor-unknown

Mean age 64 years

Lancet 2002

Absolute Benefits in Favour of Arimidex


3 Years
(%)

4 Years
(%)

Overall Population
Disease Free Survival

1.5

2.4

Recurrences

1.7

2.3

Disease Free Survival

1.7

2.9

Recurrences

1.8

2.6

Receptor Positive Population


68
-
9366 ,
,
(
0,87; 95% CI 0,78-0,97; =0,01)
.
-

( 0,83; 95% CI 0,73-0,94;
=0,005).


(
0,97; 95% CI 0,85-1,12; =0,7). ,
,
, .

( ) ,

(
),
,


.


Breast International Group (BIG) 1-98
,
5- ,
5- ,
2-
3-
2-
3- .




 BIG 1-98:

,

2- .
Thurlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and
tamoxifen in postmenopausal women with early breast cancer. N Engl J Med.
2005;353:2747-2757.

BIG 1-98: 8010 ,

,
,
( 0,81; 95% CI
0,70-0,93; log rank =0,003).
PgR
.
.

4-
2-3-
3-
.
Italian Tamoxifen Anastrozole (ITA)
426
,
2-3-

5- .


ITA:
,
( 0,35; 95% CI 0,18-0,68;
=0,001),
(=0,10).
Boccardo F, Rubagotti A, Puntoni M, et al. Switching to anastrozole versus
continued tamoxifen of early breast cancer: preliminary results of the Italian
Tamoxifen Anastrozole Trial. J Clin Oncol. 2005;23:5138-5147.




 Intergroup Exemestane Study
(IES) 4742

, 23-

5-
.


IES: 30,6 .



. ,
, ER-
PgR-

( 0,58).


IES 58 .
,
,

( 0,74 95% CI 0,64-0,85;
0,0001) (
0,83).
Coombes RC, Paridaens R, Jassem J, et al. First mature analysis of the
Intergroup exemestane study (meeting abstract). J Clin Oncol. 2006;24:18s(June
20 suppl). Abstract LBA527.


3224
8

(ABCSG)
Arimidex Nolvadex (ARNO 95)
2-
,
5- , ,
3- .




 ABCSG trial 8/ARNO 95: 28 .


( 0,60; 95% CI 0,44-0,81;
= 0,0009).
.



ARNO 95 30,1 . ,


( 0,61; 95% CI 0,400,93; =0,023),
( 0,48; 95% CI 0,25-0,91; =0,025).
Kaufmann M, Jonat W, Hilfrich J, et al. Survival benefit of switching to anastrozole
after 2 years treatment with tamoxifen versus continued tamoxifen therapy: The
ARNO 95 study (meeting abstract). J Clin Oncol. 2006;24:18s(june 20 suppl).
Abstract 547.


-17, 5187
, (exteded)
4,5-6-

.
Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in
postmenopausal women after five yearrs of tamoxifen therapy for early-stage
breast cancer. N Engl J Med. 2003;349:1793-1802.
Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following
tamoxifen as extended adjuvant therapy in receptor-positive breast cancer:
updated findings from NCCN CTG MA 17. JNatl Cancer Inst. 2005;97:12621271

Letrozole after Tamoxifen









Randomized, Placebo-Controlled Trial


5187 Women; 4.5-6 Years of Tamoxifen
Enrolled Within 3 Months after Tamoxifen
Primary End Point was DFS
About Half of Patients had Positive Nodes
Study Halted after Median 2.4 Years F\U

Goss,P.E. NEJM 2003:349;1


MA-17: 2,5



(exteded)
( 0,58; 95% CI 0,45-0,76;
0,001).
( 0,82; 95% CI
0,57-1,19; =0,3).


MA-17:

( 0,61; 95% CI 0,38-0,98;
=0,04).

,
.
Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in MA.17: a randomized,
placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin
Oncol. 2005; 23:6931-6940.
Perez EA, Josse RG, Pritchard KI, et al. Effect of letrozole versus placebo on bone mineral
dencity in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a
companion study to NCIC CTG MA.17. J Clin Oncol. 2006;24:3629-36-35.

Overall Conclusions
Letrozole reduced the overall risk of recurrence by 42%
Letrozole significantly reduced the risk of distant metastases by
40% compared with placebo
Letrozole demonstrated a statistically significant survival advantage
in women with node-positive tumors
Benefit from extended adjuvant letrozole increases with duration of
therapy
For those patients who did not start on letrozole within 3 months
post-tamoxifen, the MA.17 post-unblinding results demonstrate that
there is still a benefit to initiating letrozole for up to 5 years
following discontinuation of TAM

Goss et al. J Natl Cancer Inst. 2005;97:1262.


Ingle JN, et al, Breast Cancer Res Treat. 2006 Oct;99(3):295-300 Update of Goss et al. Breast
Cancer Res Treat. 2005;94(suppl 1):S10. Abstract 16.
Update of Robert et al. J Clin Oncol. 2006;24(18S):15s. Abstract 550.

Selection of neoadjuvant therapy: endocrine therapy vs


chemotherapy


Chemotherapy less effective in ER+ than ER disease


 Significantly lower pCR rate with neoadjuvant chemotherapy
in ER+ tumors than in ER tumors (5.0% vs 20.6%, p <
0.001)1
Patients with ER+ tumors are candidates for neoadjuvant
endocrine therapy2
Increasing evidence that patients with ER+ tumors may derive
minimal or no benefit from neoadjuvant chemotherapy3

pCR = pathologic complete response


1. Buzdar et al. Breast Cancer Res Treat 2003;82(Suppl 1):S69(abstract 302); 2. Dixon et al. Eur J Cancer
2002;38:221421; 3. Gianni et al. J Clin Oncol 2005; 23:726577


,
ER- .

,
, , ,
. ,

, , ,
.
Ellis MJ, Coop A, Singh B, et al. Letrozole ist more effective neoadjuvant endocrine
therapy than tamoxifen for ErbB-1- and ErbB-2-positive, estrogen receptor-positive
primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol.
2001;19:3808-3816.

Phase IIb/III study of neoadjuvant


tamoxifen vs letrozole (P024)



Double-blind, randomized study


55 centers in 16 countries

ER+ and/or PgR+


Postmenopausal
Not eligible for
BCS

R
A
N
D
O
M
I
Z
E

Tamoxifen
20 mg o.d.
n = 170

Letrozole
2.5 mg o.d.

S
U
R
G
E
R
Y

Adjuvant
therapy at
investigators
discretion

n = 154

4 months
o.d. = once daily
Eiermann et al. Ann Oncol 2001;12:152732

Neoadjuvant letrozole superior


to tamoxifen (P024)
Clinical response
p < 0.001

60
50
40
30
20

60% 37%

51% 34%

55% 36%

10
0

T2
> T2
Tumor stage

Letrozole

Overall

60
Patients having BCS (%)

Clinical response rate (%)

70

Conversion to BCS
p = 0.022

40

20

45%

35%

Tamoxifen
Eiermann et al. Ann Oncol 2001;12:152732

Letrozole superior to tamoxifen in


tumors with low ER expression
(P024)
Objective response rate (%)

Tamoxifen

Letrozole

70
60
50
40
30
20
10
0
3

ER expression (Allred)
Ellis et al. Clin Oncol 2001;19:380816

Objective response rate (%)

Letrozole is superior to tamoxifen


irrespective of HER2/neu status
80

p = 0.506

70

p = 0.045

HER2/neu+
HER2/neu

60
50
40

69%

53%

30
20
10

17%

40%

0
Letrozole

Tamoxifen

Letrozole achieves responses in HER2+ tumors, in which tamoxifen is


relatively ineffective
Ellis et al. Clin Oncol 2001;19:380816

Are all AIs equivalent in the


neoadjuvant setting?


Compared with tamoxifen, AIs achieve





Letrozole demonstrates superiority over tamoxifen in






Overall RR
Rate of BCS
HER2+ tumors and tumors with low ER expression

Anastrozole did not achieve superior RR but




Equivalent or superior RR
Higher rates of conversion from mastectomy to BCS

More patients became eligible for BCS with anastrozole than


with tamoxifen

Exemestane appears more effective than tamoxifen in the


neoadjuvant setting

Optimum duration of neoadjuvant


letrozole therapy


Continuing tumor shrinkage for up to 2 years

Higher partial and complete response rates can be


achieved with prolonged therapy

Optimum duration of neoadjuvant letrozole therapy


may be > 34 months

Neoadjuvant letrozole vs anastrozole


in ER+ tumors: effects on
biomarkers
 Letrozole and anastrozole significantly reduced ER,
PgR and Ki67 expression


Only letrozole significantly reduced Ki67 in tumors


with low ER expression (Allred score 25)


Letrozole p = 0.024

Anastrozole p = 0.061

Similar reduction in proliferation and PgR


expression with anastrozole and letrozole in HER2+
and HER2 tumors
Murray et al. Breast Cancer Res Treat 2004;88:S37(abstract 406)




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Buzdar A, Douma J, Davidson N, et al. phase III, multicenter,
double-blind, randomized study of letrozole, an aromatase
inhibitor, for advanced breast cancer versus megestrol acetate. J
Clin Oncol. 2001; 19:3357-3366.



,


,
.

Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus


tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer:
results of a phase IIIstudy of the International Letrozole Breast Cancer Group. J Clin
Oncol. 2001; 19:2596-2606.





 ,

,

,
LHRH
.



,
,

LHRH .
Klijn JG, Blamey RW, Boccardo F, et al. Combined tamoxifen and luteinizing
hormone-releasing hormonr (LHRH) agonist versus LHRH agonist alone in
premenopausal advanced breast cancer: a meta-analysis of four randomized
trials. J Clin Oncol. 2001;19:343-353.





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Robertson JF, Osborne CK, Howell A, et al. Fulvestrant versus anastrozole for the
treatment of advancedbreast carcinoma in postmenopausal women: a prospective
combined analysis of two multicenter trials. Cancer. 2003; 98:229-238.




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