Download Tamoxifen

Recent advances in endocrine therapy for
postmenopausal women with early breast cancer:
implications for treatment and prevention
Meyerstein Institute of Oncology, Middlesex Hospital, London, UK
Annals of Oncology, 2004: 15; 1738–1747
BACKGROUND
Hansoo Kim, M.D.
Introduction
Endocrine therapy for breast cancer

important systemic treatment for hormone-receptor-positive beast cancer (BC)

Tamoxifen

selective estrogen receptor modulator (SERM)

improvement in overall survival, disease-free survival (DFS)

estrogen, progesterone receptor status should be determined

endocrine therapy only for receptor-positive case

adjuvant endocrine therapy: increase chance of curing early breast cancer
w/ low level of adverse side-effect
Hansoo Kim, M.D.
Introduction
Tamoxifen

gold standard in postmenopausal women

more effective in women > 50Y w/ receptor-positive

50% reduction in new tumor

limitations

increased risk of endometrial cancer, sarcoma

thromboembolic disorders
Lancet, 1992
J Natl Cancer Inst 1998
new agent w/ equal or improved efficacy and fewer side effects ?
Hansoo Kim, M.D.
OBEJCTIVES &
DESIGN
Hansoo Kim, M.D.
Objectives
To review the recent advances made in endocrine therapy
and their subsequent impact on treatment strategies
Hansoo Kim, M.D.
Design
PubMed search
Hansoo Kim, M.D.
ADVACED BREAST CANCER
Hansoo Kim, M.D.
Aromatase Inhibitors (AIs)
General considerations

for ceased ovarian function treatment

aromatase: cytochrome P450 enzyme


catalyze conversion (androgen to estrogen) in peripheral tissues

reduce synthesis, output of estrogen in postmenopausal
in premenopausal setting:

estrogen primarily made in ovaries: non-complete blocking

tamoxifen; initial endocrine option

further endocrine therapy; oophorectomy or megestrol acetate
Hansoo Kim, M.D.
Aromatase Inhibitors (AIs)
Prescriptions


aminoglutethimide

widely, successfully used 1st AIs

toxicity, lack of aromatase selectivity
formestane

2nd-generation AIs: increased selectivity, fewer side-effects

injection every 2 W: compliance ↓
Hansoo Kim, M.D.
Aromatase Inhibitors (AIs)
Prescriptions

anastrozole (Arimidex), letrozole, exemestane (steroidal)

3rd-generation AIs

for postmenopausal w/ metastatic hormone-response breast cancer

orally administered, highly selective for aromatase
Anastrozole highly selective, no effect on cortisol/ aldosterone
Exemestane no effect on adrenal steroidogenesis (up to 800 mg)
Letrozole
alter cortisol/ aldosterone level (0.5-2.5 mg)
Buzdar, 2001
Evans, 1992
Bisagni, 1996
Hansoo Kim, M.D.
Aromatase Inhibitors (AIs)
Megestrol vs. 3rd generation AIs

3rd generation AIs: more efficacy, tolerability over megestrol acetate

2 phase III trial: anastrozole (1 mg QD)


survival advantages

lower death rate (57.4% vs. 67.6%, P<0.025)

longer median time to death (26.7M vs. 22.5M)
Buzdar, 1998
phase III trial: exemestane

longer survival at median follow-up of 11 M
Hansoo Kim, M.D.
Aromatase Inhibitors (AIs)
Megestrol vs. 3rd generation AIs


phase III trial: letrozole (0.5 mg QD, 2.5 mg QD)

no significant survival advantages over megestrol

2.5 mg: longer survival than 0.5 mg (P=0.03)
phase III trial: letrozole

no survival advantages over megestrol

design factors, statistical powers?
Dombernowsky, 1998
Buzdar, 2001
Hansoo Kim, M.D.
Aromatase Inhibitors (AIs)
Anastrozole vs. Tamoxifen

TARGET (Tamoxifen and Arimidex Randomized Group Efficacy and Tolerability), North American

superior efficacy in TTP (time to progression), tolerability benefits
Letrozole vs. Tamoxifen

single phase III trial

superiority in a number of end points

66 % patients were receptor-positive: adjustment done
Mouridsen, 2001
no data for Exemestane available
Hansoo Kim, M.D.
Estrogen Receptor Antagonist
Fulvestrant

competitively bind to estrogen receptor (affinity: > tamoxifen)


phase I, II clinical trial


down-regulation of estrogen-regulated gene
Howell, 1996
lack of cross-resistance between fulvestrant & tamoxifen
prospective analysis of 2 multicenter trials (n=851)
Pippen, 2003

fulvestrant: effective as anastrozole in overall survival, similar side-effects

additional treatment options for receptor-positive advance breast cancer
following prior anti-estrogen therapy
Hansoo Kim, M.D.
Estrogen Receptor Antagonist
Fulvestrant as 1st-line therapy

similar efficacy to tamoxifen

median follow-up of 14.5 M

fulvestrant (250 mg IM monthly) & tamoxifen (20 mg QD)

for TTP, clinical benefits, objective response: no differences
Robertson, 2002

fulvestrant in 1st, 2nd line treatment of postmenopausal advanced breast cancer

earlier fulvestrant injection in treatment sequence

early data showing good efficacy, better response

ongoing data
Hansoo Kim, M.D.
ADJUVANT THERAPY
Hansoo Kim, M.D.
General Considerations
Adjuvant therapies

3rd generation AIs: being evaluated for adjuvant therapy

treatment sequences

initially tamoxifen: switch to AIs

extend therapy beyond 5Y
Hansoo Kim, M.D.
ATAC Trial
General considerations

randomized, double-blind, multicenter in postmenopausal invasive early BC

completed primary therapy, eligible for adjuvant therapy


anastrozole (1 mg QD), tamoxifen (20 mg QD), combination

primary end point: DFS, safety/ tolerability
follow-up: 33.3 M, 47 M, 36.9 M
Hansoo Kim, M.D.
ATAC Trial
1st analysis (median follow-up for DFS of 33.3 M)

anastrozole: more effective than tamoxifen

longer DFS (HR 0.83; 95% confidence interval 0.71 – 0.96; P=0.013)

superior TTR (HR 0.79; 95% CI 0.67 – 0.94; P=0.008)

reduced odds of contralateral breast cancer (OR 0.42; 95%
CI 0.22 – 0.79; P=0.007)
Hansoo Kim, M.D.
ATAC Trial
2nd analysis (median follow-up of 47 M)

benefits seen w/ DFS in anastrozole-treated group

sustained in overall population; attenuated in receptor-positive group

relapses: 413 for anastrozole, 472 for tamoxifen

DFS at 4Y: 86.9% for anastrozole, 84.5% for tamoxifen

TTR: longer in anastrozole group ( larger in HR+)

deaths w/ no recurrence: 109 in both

reduction in contralateral BC: 25 for anastrozole, 40 for tamoxifen
Hansoo Kim, M.D.
Incidence of Adverse Events of ATAC Trial
A: anastrozole
T: tamoxifen
Relative risk (RR): <1 favors anastrozole, >1 favors tamoxifen
Hansoo Kim, M.D.
Switching Adjuvant Endocrine Treatment Trials
Italian Tamoxifen Arimidex
Boccardo, 2003
426 HR+ receiving 2-3Y of tamoxifen
218 for tamoxifen
208 for anastrozole
24M follow-up
Decreased risk of relapse (HR 0.36; 95% CI 0.17-0.75; P=0.006)
Fewer serious side effects
(14 vs. 29)
Hansoo Kim, M.D.
Extending Adjuvant Endocrine Treatment Trials
MA.17 trial
Goss, 2003

double-blind, placebo-controlled

objectives: benefit from additional 5Y of letrozole after completed 5Y of
tamoxifen adjuvant therapy in postmenopausal HR+ early breast cancer?

5187 patients for 2.4Y of follow-up

differences in DFS (P<0.001)


75 recurrences or new primary BC in letrozole, 132 in placebo

higher estimated 4Y DFS in letrozole group, 43% reduction in risk
early discontinuation
Hansoo Kim, M.D.
IMPACT on CURRENT
TREATMENT STRATEGIES
Hansoo Kim, M.D.
Anastrozole
Overviews

only form of primary or initial endocrine therapy: effective adjuvant therapy
for postmenopausal w/ early breast cancer

preferred choice for early-stage breast cancer: more effective adjuvant

recurrent BC w/ previous successful anastrozole adjuvant

most likely no respond to other non-steroidal AIs

limited data regarding alternative treatment

theoretical arguments
Hansoo Kim, M.D.
Other Regimens
Fulvestrant, exemestane, tamoxifen
valid treatment option for progression on anastrozole

tamoxifen: effective 2nd line after anastrozole

exemestane


Thurlimann, 2004
Lonning, 2000
effective in patients progressing on non-steroidal AIs
fulvestrant
Perey, 2002

preliminary data: benefits following progression after non-steroidal AIs

more effective option in recurring on or after adjuvant anastrozole?
Hansoo Kim, M.D.
CHEMOPREVENTION
Hansoo Kim, M.D.
Tamoxifen
Preventive therapy for breast cancer


women a high risk of invasive carcinoma

previous in situ (non-invasive) tumors confined duct (DCIS)

confined to lobules (lobular carcinoma in situ)
NSABP (National Surgical Adjuvant Breast and bowel Project)

tamoxifen after lumpectomy and RTx: decrease rate of breast cancer

NSABP-P1 prevention trial: 5Y tamoxifen reduces risk of invasive BC

no prevention on frequency of breast cancer
Powels, 1998/ Veronesi, 1998
Increased incidence of adverse effects: endometrial cancer, thromboembolism
Hansoo Kim, M.D.
Tamoxifen
Preventive therapy for breast cancer

IBIS-I (International
Breast Intervention
Study Study
I)
Recommendations
by IBIS
chairman

significantly reduce s breast cancer over 10Y

endometrial cancer: no significant differences

thromboembolism: significant higher in tamoxifen group

death from all causes: much higher in tamoxifen group
no longer tamoxifen for prevention of breast cancer

UKCCCR (UK Coordinating Committee on Cancer Research) DCIS Working Party

1701 patients w/ completed excised DCIS: RTx vs. tamoxifen

RTx recommended, little support for tamoxifen
Hansoo Kim, M.D.
AIs
Anastrozole for chemoprevention

endometrial cancer & thromboembolism

low incidence of contralateral breast cancer w/ anastrozole

IBIS-II in postmenopausal DCIS or increased risk of BC


large, multicenter, randomized, double-blind, controlled

normal women at increased risk: anastrozole (1 mg QD) or placebo

completely excised DCIS: anastrozole (1 mg QD) or tamoxifen (20 mg QD)

recruitment: February, 2003
no proven data for letrozole, exemestane
Hansoo Kim, M.D.
CONCLUSIONS
Hansoo Kim, M.D.
Conclusions
Adjuvant therapy

anastrozole

ATAC trial: more effective than tamoxifen for adjuvant therapy of early
HR+ breast cancer in postmenopausal


maybe replacing tamoxifen?
switching adjuvant endocrine treatment

initially 2-3Y of tamoxifen, switch to anastrozole or exemestane

preliminary: further follow-up required
Hansoo Kim, M.D.
Conclusions
Chemoprevention


tamoxifen

only current available endocrine options for chemoprevention

reduce risk of invasive cancer DCIS

high risk of adverse events
alternative options: anastrozole

significantly lower incidence of contralateral breast cancer

tolerability benefits
Hansoo Kim, M.D.