Department of Surgery, United Christian Hospital

Aromatase InhibitorsCurrent Use in Breast Cancer

JHGR 16 Jan 2005JHGR 16 Jan 2005Dr. Sharon ChanDr. Sharon ChanDepartment of Surgery, UCHDepartment of Surgery, UCH

Estrogen and breast cancer growth

EstrogenEstrogen – main – main hormone involved in hormone involved in pathogenesis of pathogenesis of breast tumorsbreast tumors

ER & PR statusER & PR status are are the most important the most important biomarkersbiomarkers

Anti-estrogen in breast cancer

Tamoxifen in Breast Cancer

Used in treatment of MBC since 70’sUsed in treatment of MBC since 70’s Golden standardGolden standard for adjuvant therapy in 90’s for adjuvant therapy in 90’s

Improve 10 yr survival Improve 10 yr survival 10.9% 10.9% in 75000 node in 75000 node +ve+ve

Increase 10 yr survival Increase 10 yr survival 5.6% 5.6% in 2644 node -in 2644 node -veve

EBCTCG. Systemic treatment of early breast cancer….Lancet EBCTCG. Systemic treatment of early breast cancer….Lancet 1992; 339: 71-851992; 339: 71-85

Limitation of tamoxifen

Partial agonist effectPartial agonist effect

Increase risk ofIncrease risk of uterine canceruterine cancer ThromboembolismThromboembolism

Tumor cell resistanceTumor cell resistance Eastern Cooperative Eastern Cooperative

Oncology Group (J NCI Oncology Group (J NCI 1996)1996)

Scotish Cancer Trials Scotish Cancer Trials Breast Group (BJC 1996)Breast Group (BJC 1996)

NSABP B14 (J NCI 2001)NSABP B14 (J NCI 2001)

Aromatase Inhibitors IntroductionIntroduction

Mechanism of actionMechanism of action Current UseCurrent Use

Advanced breast cancerAdvanced breast cancer Adjuvant therapyAdjuvant therapy Neo-adjuvantNeo-adjuvant ChemopreventionChemoprevention

Aromatase Inhibitor -Introduction

Aromatase - biosynthesis of oestrogen

Potency of Aromatase Inhibitors

% suppresion total body aromatase% suppresion total body aromatase

11stst generation 2 generation 2ndnd generation 3 generation 3rdrd generation generation 1x 10-100x 100-2000x1x 10-100x 100-2000x

Types of Aromatase inhibitors

Mechanism of action

ANDROGENS OESTROGENS

P-450 Aromatase+ NADPH-cytochrome P-450 reductase

(Testosterone, androstenedione,

16-OH-testosterone)

(Oestradiol, oestrone)

Aromatase Inhibitors

tumourgrowth

Postmenopausal Woman peripheral aromatisation

Breasttumour

Muscle Fat Liver

Intra-tumoral aromatase activity

AI in pre-menopausal woman

Aromatase Inhibitor in advanced breast cancer

Aromatase inhibitor in advanced disease as second line therapy

Aromatase inhibitor in advanced disease as first line therapy

Aromatase Inhibitorsin adjuvant therapy

Major Adjuvant studies of AI Direct comparisonDirect comparison

ATAC, TEAM, MA 27ATAC, TEAM, MA 27 Sequencing therapySequencing therapy

IES, ABCSG, ARNO (after 2-3 yrs TAM)IES, ABCSG, ARNO (after 2-3 yrs TAM) MA 17, NSABP B-33 (after 5 yrs TAM)MA 17, NSABP B-33 (after 5 yrs TAM)

Combination with ovarian suppressionCombination with ovarian suppression SOFTSOFT TEXTTEXT

ATAC (Arimidex, Tamoxifen Alone or in Combination)

ATAC – result at median 33m FU

Disease free survival (3y) Disease free survival (3y) Ana 89.4% vs Tam 87.4% Ana 89.4% vs Tam 87.4% (HR 0.83, p=0.013)(HR 0.83, p=0.013) Combination 87.2% vs Tam 87.4% (HR 1.02, Combination 87.2% vs Tam 87.4% (HR 1.02,

p=0.8)p=0.8) Incidence of contralateral breast cancerIncidence of contralateral breast cancer

Ana vs Tam 0.3% vs 1% Ana vs Tam 0.3% vs 1% (OR 0.42, p=0.007)(OR 0.42, p=0.007) Combination 0.7% vs Tam 1% (OR 0.84, p=0.51)Combination 0.7% vs Tam 1% (OR 0.84, p=0.51)

ATAC Trialist’s Gp. Anastrozole alone or in combination….LancetATAC Trialist’s Gp. Anastrozole alone or in combination….Lancet . .

359(9324):2131-9, 2002 Jun 22359(9324):2131-9, 2002 Jun 22

ATAC, completed treatment analysis-based on a median FU of 5 years Disease free survival (HR +ve pt)Disease free survival (HR +ve pt)

Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

ATAC, completed treatment analysis-based on a median FU of 5 years Time to Recurrence (HR +ve pt)Time to Recurrence (HR +ve pt)

Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

ATAC, completed treatment analysis-based on a median FU of 5 years Incidence of contralateral breast cancer (HR +ve pt)Incidence of contralateral breast cancer (HR +ve pt)

Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

ATAC, completed treatment analysis-based on a median FU of 5 years Time to distant recurrence (HR +ve pt)Time to distant recurrence (HR +ve pt)

Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

ATAC, completed treatment analysis-based on a median FU of 5 years Overall survival (HR +ve pt)Overall survival (HR +ve pt)

Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

ATAC, completed treatment analysis-based on a median FU of 5 years Overview of adverse eventsOverview of adverse events

Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

ATAC, completed treatment analysis-based on a median FU of 5 years

Pre-specified adverse events %Pre-specified adverse events %

Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

IES – Exem after 2-3 yr Tam

4742 patients4742 patients Swtiching Tam 2-3y + Exem vs Tam 5ySwtiching Tam 2-3y + Exem vs Tam 5y 183 vs 266 new events183 vs 266 new events Unadjusted Unadjusted HR 0.68HR 0.68 (0.56-0.82, p<0.001) (0.56-0.82, p<0.001)

R Coombes RCT of exemestane after 2-3 yrs of R Coombes RCT of exemestane after 2-3 yrs of Tam..NEJM 350(11): Mar 04: 1081-1092Tam..NEJM 350(11): Mar 04: 1081-1092

MA 17 –Letrozole after 5yr TAM

5187 patients5187 patients Let reduced recurrence (42%), Distant disease Let reduced recurrence (42%), Distant disease

recurrence (40%)recurrence (40%) Let reduced new contralateral breast cancer (37.5%)Let reduced new contralateral breast cancer (37.5%) Est 4y survivalEst 4y survival Let Let 93%93% vs placebo vs placebo 87%87% (p<0.001) (p<0.001) SE (hot flushes, osteoporosis) more frequent, but NSSE (hot flushes, osteoporosis) more frequent, but NS Stopped after interim analysis (median FU 2.4 y)Stopped after interim analysis (median FU 2.4 y)

Goss E NEJM 349 (19); Nov 03: 1793-1802Goss E NEJM 349 (19); Nov 03: 1793-1802

ASCO Technology Assessment 2005

Optimal adjuvant hormonal therapy for a Optimal adjuvant hormonal therapy for a postmenopausal woman with receptor +ve postmenopausal woman with receptor +ve breast cancer included an AI as initial breast cancer included an AI as initial therapy or after treatment with tamoxifentherapy or after treatment with tamoxifen

Winter E et al J Clin Onc 23; 3 Jan 2005Winter E et al J Clin Onc 23; 3 Jan 2005

Aromatase InhibitorOther roles

AI – neoadjuvant therapy

Higher rate of regression than tamoxifenHigher rate of regression than tamoxifen OR Let 55% vs Tam 36% (p<0.001)OR Let 55% vs Tam 36% (p<0.001) BCT possible Let 45% vs Tam 36% BCT possible Let 45% vs Tam 36%

(p=0.022)(p=0.022)

Ellis MJ et alLetrozole is more effective neoadjuvant…Clin Oncol 2001 Sep 15;19(18):3808-16    

AI - chemoprevention

ChemopreventionChemoprevention Tamoxifen dec contralateral CA breast Tamoxifen dec contralateral CA breast

by 50%by 50% AI further dec contralateral CA breast AI further dec contralateral CA breast

by 26%by 26%

Conclusion

AI as first line and second line therapy for AI as first line and second line therapy for advanced CA breastadvanced CA breast

Included as initial and subsequent therapy in Included as initial and subsequent therapy in adjuvant settingadjuvant setting

Potential use in chemoprevention and neo-Potential use in chemoprevention and neo-adjuvant therapyadjuvant therapy

Unresolved issue

Which is the ideal agentWhich is the ideal agent Mono vs sequential vs combination endocrine Mono vs sequential vs combination endocrine

therapytherapy What is the optimal durationWhat is the optimal duration Long term toxicityLong term toxicity Identification of at risk gp of osteoporotic bone Identification of at risk gp of osteoporotic bone

loss and prevention of fractureloss and prevention of fracture Cost benefit issue ( 38/tab vs 0.2/tab )Cost benefit issue ( 38/tab vs 0.2/tab )

Department of Surgery, United Christian Hospital

Thank YouThank You