Aromatase Inhibitors in Breast Cancer

Aromatase Inhibitors in Breast Cancer

Aromatase Inhibitors in Breast Cancer

First generationFirst generationFirst generationFirst generation

Second generationSecond generationSecond generationSecond generation

Third generationThird generationThird generationThird generation

- Aminoglutethimide*- Aminoglutethimide*

- Fadrozole

- 4-OHA

- Fadrozole

- 4-OHA

- Anastrozole

- Exemestane

- Letrozole

- Anastrozole

- Exemestane

- Letrozole

Development of Aromatase Inhibitors: Activity Profiles

Development of Aromatase Inhibitors: Activity Profiles

ToxicityToxicity SpecificitySpecificity PotencyPotency

Rash,etc.

Rash,etc.

No adrenalinsufficiency,

etc.

No adrenalinsufficiency,

etc.

500to

10,000

500to

10,000

100100

11

*No approved indication for breast cancer in the United States.

Case #1 Case #1

Clinical presentation

– 63 year-old postmenopausal woman

– 3 cm. lump detected in upper outer quadrant of left breast

– Ipsilateral axilla clinically negative

– Remainder of physical exam normal / ECOG 0

– No significant co-morbidities Risk factors

– HRT x 9 years

– No family history

– No prior breast abnormalities



– 3 cm. lump detected in upper outer quadrant of left breast

– Ipsilateral axilla clinically negative

– Remainder of physical exam normal / ECOG 0

– No significant co-morbidities Risk factors

– HRT x 9 years

– No family history

– No prior breast abnormalities

Work UpWork Up

Lumpectomy + ALND 3.2 cm Grade 3/3 infiltrating ductal carcinoma Resection margins clear 4/12 nodes positive ER+, PgR–, and HER2– CXR, bone scan, Abdominal CT negative Laboratory profile is normal

Lumpectomy + ALND 3.2 cm Grade 3/3 infiltrating ductal carcinoma Resection margins clear 4/12 nodes positive ER+, PgR–, and HER2– CXR, bone scan, Abdominal CT negative Laboratory profile is normal

PrognosisPrognosis

32.5% probability of living @ 10 yrs

– 60% probability of cancer death

– 7.5% probability of non cancer death Absolute benefit of chemotherapy 10% Absolute benefit of hormonal therapy 11% Absolute benefit of combined therapy 21%

32.5% probability of living @ 10 yrs


– 7.5% probability of non cancer death Absolute benefit of chemotherapy 10% Absolute benefit of hormonal therapy 11% Absolute benefit of combined therapy 21%

Post-operative ManagementPost-operative ManagementStop HRT

CA X 4 Paclitaxel X 4

Local Radiation Therapy

Adjuvant Endocrine Therapy

Stop HRT

CA X 4 Paclitaxel X 4


Adjuvant Endocrine Therapy? Tamoxifen

? Aromatase Inhibitor

how long

which inhibitor

Case #2 Case #2



– Mammographically-detected right-sided suspicious calcifications

– Physical exam normal / ECOG 1

Risk factors

– Past history of postmenopausal vaginal bleeding

– Endometrial polyp with atypia



– Mammographically-detected right-sided suspicious calcifications

– Physical exam normal / ECOG 1

Risk factors

– Past history of postmenopausal vaginal bleeding

– Endometrial polyp with atypia

Work UpWork Up

Core biopsy reveals infiltrating lobular carcinoma

Wire localization excision + SLND 1.2 cm grade 2/3 tumor with clear margins 0 nodes positive ER+, PgR+, and HER2– CXR negative Laboratory profile negative

Core biopsy reveals infiltrating lobular carcinoma

Wire localization excision + SLND 1.2 cm grade 2/3 tumor with clear margins 0 nodes positive ER+, PgR+, and HER2– CXR negative Laboratory profile negative

PrognosisPrognosis

65% probability of living @ 10 yrs


– 28% probability of non cancer death Absolute benefit of chemotherapy 1% Absolute benefit of hormonal therapy 2% Absolute benefit of combined therapy 3%

65% probability of living @ 10 yrs


– 28% probability of non cancer death Absolute benefit of chemotherapy 1% Absolute benefit of hormonal therapy 2% Absolute benefit of combined therapy 3%

Post-operative ManagementPost-operative Management





Tamoxifen

? Aromatase Inhibitor

how long

which inhibitor

1998 Overview: Effectiveness Of Adjuvant Therapy On Breast Cancer Mortality

Tam Chemo Combined< 50 ER+ 25% 25% 45% ER- 0% 35% --

> 50 ER+ 25% 10% 35% ER- 0% 20% --

Risk Reduction in Early Breast Cancer in Estrogen ReceptorPositive Patients Risk Reduction in Early Breast Cancer in Estrogen ReceptorPositive Patients

Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451.

100

% R

ecu

rren

ce-f

ree

90

80

60

40

20

05 10+0

Node -ve: 14.9% SD 1.4: 2P<0.00001Node +ve: 15.2% SD 2.5: 2P<0.00001

Node -ve

Node +ve

87.4

79.274.9

75.6 64.3

59.758.3

44.5

100

90

80

60

40

20

05 10+0

Node -ve: 5.6% SD 1.3: 2P<0.00001Node +ve: 10.9% SD 2.5: 2P<0.00001

Node -ve

Node +ve

91.8

78.989.3

74.2

73.3

50.5

80.1

61.470

50

30

10

70

50

30

10

Absolute Recurrence Reduction Absolute Mortality Reduction

Years Years

% A

live

Tamoxifen (~5 y)

Control

Control

Tamoxifen (~5 y)

Tamoxifen (~5 y)

Control

Control

Tamoxifen (~5 y)

Recurrence as First Event Mortality From Any Cause

NSABP B-14 Trial: 10 Years of Tamoxifen vs Stopping

NSABP B-14 Trial: 10 Years of Tamoxifen vs Stopping

Fisher et al. J Natl Cancer Inst. 2001;93:684.

TAM 570 560 433 250 176Stop 583 567 411 251 163

Dis

eas

e-fr

ee s

urv

ival

(%

) 100

80

60

400 1 2 3 4

P=0.03

Placebo

Tamoxifen

Year after second randomizationNumber at Risk

Patients re-randomized after 5 years of tamoxifen

Rationale for Aromatase Inhibitors in Adjuvant Therapy

Rationale for Aromatase Inhibitors in Adjuvant Therapy

Mortality is reduced by only ~ 1/4 by Tamoxifen

Aromatase inhibitors

– Effective after Tamoxifen

– May be superior to Tamoxifen first-line

– Well tolerated

– Low risk of endometrial carcinoma, thromboembolic events

Mortality is reduced by only ~ 1/4 by Tamoxifen

Aromatase inhibitors

– Effective after Tamoxifen

– May be superior to Tamoxifen first-line

– Well tolerated

– Low risk of endometrial carcinoma, thromboembolic events

Potential Considerations in Evaluating Aromatase Inhibitors in the Adjuvant Setting

Potential Considerations in Evaluating Aromatase Inhibitors in the Adjuvant Setting

Potential Risks:• Vasomotor

• Urogenital

• Bone

• Lipid

• Cognitive

• ? Other

Potential Risks:• Vasomotor

• Urogenital

• Bone

• Lipid

• Cognitive

• ? Other

Potential Benefits:• Inhibit breast cancer

• Fewer endometrial cancers

• Less thromboembolism

Potential Benefits:• Inhibit breast cancer

• Fewer endometrial cancers

• Less thromboembolism

Clinical Trial Strategies in Adjuvant Therapy with Aromatase

Inhibitors

Clinical Trial Strategies in Adjuvant Therapy with Aromatase

Inhibitors

ATAC

BIG 1-98(BIG FEMTA)

TAMOXIFEN

ANASTROZOLE

PLACEBO

ARNO

MA-17

LETROZOLE

EXEMESTANE

ICCG Study 96

TEAM

NSABP B33

* Surgery + radiotherapy + chemotherapy(Patients may start trial therapy while still receiving radiotherapy)

+

Postmenopausal women with invasive breast cancer

Completion of primary therapy*

Randomization 1:1:1 for 5 years

Anastrozole 1mg od+

Tamoxifen placebo

Anastrozole placebo+

Tamoxifen 20mg od

Anastrozole 1mg od+

Tamoxifen 20mg od

Regular follow-up monitoring adverse events

Trial endpoints

ATAC Trial DesignATAC Trial Design

ATAC Update SABCS 2002ATAC Update SABCS 2002

Median follow up: 47 months Median duration of therapy: 37 months Number of events: 1373 Patients receiving >3 yrs of Rx: ~50% Breast cancer event rate (%):

– Yr. 1: A=2.49 T=2.30 HR=1.08

– Yr. 2: A=2.61 T=4.28 HR=0.61

– Yr. 3: A=2.94 T=3.72 HR=0.77

Bianco, et al. SABCS 2002,#632

Median follow up: 47 months Median duration of therapy: 37 months Number of events: 1373 Patients receiving >3 yrs of Rx: ~50% Breast cancer event rate (%):

– Yr. 1: A=2.49 T=2.30 HR=1.08

– Yr. 2: A=2.61 T=4.28 HR=0.61

– Yr. 3: A=2.94 T=3.72 HR=0.77

Bianco, et al. SABCS 2002,#632

First Events in Overall PopulationFirst Events in Overall Population

First event 413 (13.2) 472 (15.1)

Locoregional recurrence 84 (2.7) 101 (3.2)

Distant recurrence 195 (6.2) 222 (7.1)

Contralateral (invasive) 20 (0.6) 35 (1.1)

Contralateral (DCIS) 5 (0.2) 5 (0.2)

Death (non-breast cancer) 109 (3.5) 109 (3.5)

Tamoxifenn=3116 (%)

Anastrozolen=3125 (%)

Probability of Recurrence inReceptor-positive PopulationProbability of Recurrence inReceptor-positive Population

Pro

po

rtio

n w

ith

rec

urr

ence

(%

)

00 6 12 18 24 30 36 42 48 54

HR 95% CI p-value

AN vs TAM 0.78 0.65–0.93 0.007

* Censoring non-BC deaths before recurrence

Time to event (months)No. ofPts. at riskANTAM

AbsoluteDifference 1.8%

AbsoluteDifference 2.6%

AnastrozoleTamoxifen

26172598

25332516

24362386

22432180

12581210

602574

0

5

10

15

20

Comparison of ATAC data with EBCTCG 1995 Overview1: Receptor-positive Patients >50 Years

Comparison of ATAC data with EBCTCG 1995 Overview1: Receptor-positive Patients >50 Years100

80

00 1 2 3 4 5+ years

Est

imat

ed %

wit

ho

ut

recu

rren

ce

Control (EBCTCG)

Tamoxifen (EBCTCG)

90

70

1Lancet 1998;351: 1451–1467Anastrozole (ATAC)

Tamoxifen (ATAC)

92.2%

4-yearrecurrence-free rate:

89.6%

Time to Recurrence by SubgroupsTime to Recurrence by Subgroups

0.30 0.40 0.60 0.80 1.00 1.25 1.50 2.00

+veReceptor status

–ve

0Nodal status

4+

1–3

Previous chemo noyes

Hazard ratio (AN/TAM)In favour of Anastrozole In favour of Tamoxifen

ATAC Trial:Adverse EventsATAC Trial:Adverse Events

-10 -5 0 5 10Difference between anastrozole and tamoxifen AEs (%)

-5.4%

-1.8%

-3.6%

-8.6%

-1.1%

-1.4%

-0.7%

Fractures of hip,spine, wrist

Fractures

MSK disorders

-0.4%

In favor of In favor of anastrozoleanastrozole

Hot flushes

Weight gain*

Vag. bleeding

6.6%

2.1%

0.8%

Endo ca

ICVA

VTE

DVT

Vag. discharge

In favor of In favor of tamoxifentamoxifen

*Proportion with 10% gain in body weight from baseline to year 2. Baum et al. San Antonio Breast Cancer Symposium. 2001.

ATAC Trial: Bone Mineral DensityATAC Trial: Bone Mineral Density

A (80) T(87) Comb.(82) Cont.(39)

% change @ 1 yr

LS Spine -2.59 1.01 0.21 -.36

Femur -1.68 0.48 0.78 -.13

A (80) T(87) Comb.(82) Cont.(39)

% change @ 1 yr

LS Spine -2.59 1.01 0.21 -.36

Femur -1.68 0.48 0.78 -.13

Eastell R. ESMO. 2002

Lipid Effects of Aromatase InhibitorsLipid Effects of Aromatase Inhibitors

Anastrazole (n=1,021)

LDL Letrozole (n=20)

TC, LDL,

HDL Exemestane (n=76)

TG

TC, HDL,TC/HDL ratio unchanged

Anastrazole (n=1,021)

LDL Letrozole (n=20)

TC, LDL,

HDL Exemestane (n=76)

TG

TC, HDL,TC/HDL ratio unchanged

Summary of ASCO Panel Consensus

Summary of ASCO Panel Consensus

Results of ATAC are preliminary 5 years of Tamoxifen remains standard There is no reported survival advantage with

anastrozole All 3 AI’s are generally comparable in MBC, the

only data in adjuvant setting is with Arimidex Use Arimidex if Tamoxifen contraindicated,

have already received Tamoxifen (?raloxifene) or significant side effects with Tamoxifen

Results of ATAC are preliminary 5 years of Tamoxifen remains standard There is no reported survival advantage with

anastrozole All 3 AI’s are generally comparable in MBC, the

only data in adjuvant setting is with Arimidex Use Arimidex if Tamoxifen contraindicated,

have already received Tamoxifen (?raloxifene) or significant side effects with Tamoxifen

Case #3Case #3

70 years old with performance status 0 Presents with 7 cm mass in right breast that

has been present for > one year Biopsy reveals ER+, PgR+, HER2– breast

cancer CT reveals a single liver metastasis Bone scan + with several areas of uptake

70 years old with performance status 0 Presents with 7 cm mass in right breast that

has been present for > one year Biopsy reveals ER+, PgR+, HER2– breast

cancer CT reveals a single liver metastasis Bone scan + with several areas of uptake

Treatment OptionsTreatment Options

Tamoxifen Anastrozole Letrozole Exemestane Chemotherapy

Tamoxifen Anastrozole Letrozole Exemestane Chemotherapy

Third-Generation AIs in First-Line Studies

Third-Generation AIs in First-Line Studies

Tamoxifen 20 mg RANDOMIZE

Third-generation AIs Anastrozole 1 mg

or

Letrozole 2.5 mg

or

Exemestane 25 mg

Indirect Comparison of AI’s and Tamoxifen Phase III First-Line Data

Indirect Comparison of AI’s and Tamoxifen Phase III First-Line Data

Letr. Tam. Anast. Tam. Exem.Tam

Patients(n) 294 305 305 306 31 32

TTP(mo) 9.7 6.0 10.7 6.4 8.9 5.2

Survival(mo) 34 30 NR NR NRNR

Letr. Tam. Anast. Tam. Exem.Tam

Patients(n) 294 305 305 306 31 32

TTP(mo) 9.7 6.0 10.7 6.4 8.9 5.2

Survival(mo) 34 30 NR NR NRNR

Letrozole vs Tamoxifen Overall Survival

Letrozole vs Tamoxifen Overall Survival

100

90

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 1 2 4 5

Kap

lan

-Mei

er E

stim

ate

(%)

Years

Letrozole TamoxifenInitial therapy:

1-yr. survivalrate

Letrozole

83% 64%

Tamoxifen 75% 58%

P (log-rank test) 0.004 0.02

3

99% of patients crossed over by 36 months

Overall Survival

35 mo

2 yr. survivalrate

32 mo

0.514

Mouridsen et al. J Clin Oncol. 21:2101-2109, 2003.

Letrozole vs Tamoxifen: Time to Chemotherapy

Letrozole vs Tamoxifen: Time to Chemotherapy

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 12 18 24 30 36 42 48 54 606

Median time to chemotherapy Letrozole 16 moTamoxifen 9 moP=0.005 (log-rank test)

Ka

pla

n-M

eie

r es

tim

ate

MonthsLetrozole (n=453) Tamoxifen (n=454)Initial therapy:

Mouridsen et al. J Clin Oncol. 21:2101-2109, 2003.

Anastrazole v Tamoxifen as First Line Therapy in MBC. (#255 SABCS 2002. Thuerlimann et al, Switzerland)

Anastrazole v Tamoxifen as First Line Therapy in MBC. (#255 SABCS 2002. Thuerlimann et al, Switzerland)

Swiss patients enrolled in protocol 027 60 pts: ER/Pr +: 56, 4 unknown

A (31) T (29)

TTP 1st line 11.3 mo 8.3 mo

TTP 2nd line 6mo 6mo

Total TTP 28.2mo 19.5 mo*

*p=.36

Swiss patients enrolled in protocol 027 60 pts: ER/Pr +: 56, 4 unknown

A (31) T (29)

TTP 1st line 11.3 mo 8.3 mo

TTP 2nd line 6mo 6mo

Total TTP 28.2mo 19.5 mo*

*p=.36

(18) (19)

Exemestane After Failure of Nonsteroidal AI’s


Phase II trial N= 241 Prior therapies

– aminoglutethimide, letrozole, anastrazole, vorozole

Rx: Exemestane 25 mg daily

Phase II trial N= 241 Prior therapies

– aminoglutethimide, letrozole, anastrazole, vorozole

Rx: Exemestane 25 mg daily

Lonning et al. JCO.11:2234, 2000



OR n (%) 16 (6.6) CR n (%) 3 (1.2) PR n (%) 13 (5.4) SD (>6mo) (%) 42 (17.4) Clinical benefit 74 (24.3)

OR n (%) 16 (6.6) CR n (%) 3 (1.2) PR n (%) 13 (5.4) SD (>6mo) (%) 42 (17.4) Clinical benefit 74 (24.3)

Lonning et al. JCO.11:2234, 2000

GONO-MIG 8: Sequential Use of AI’s in Metastatice Breast Cancer


A

B

C

No Prior AI

Prior Exemestane

Prior letrozole oranastrazole

Exemestane

Exemestane

Letrozole oranastrazole

Letrozole oranastrazole

Bertelli, ASCO 2002.238



EL/A L/AE

A (32) B(10) C(24)

PR n (%) 6 (18.4) 1(10) 1(4.2)

SD>6mo 9 (28.1) 3(30) 5(20.8)

Clin. Benefit 15(46.9) 4(40) 6(25)

EL/A L/AE

A (32) B(10) C(24)

PR n (%) 6 (18.4) 1(10) 1(4.2)

SD>6mo 9 (28.1) 3(30) 5(20.8)

Clin. Benefit 15(46.9) 4(40) 6(25)

Bertelli, ASCO 2002.238

Randomized Trials of AIs in First Line Setting : Conclusions

Randomized Trials of AIs in First Line Setting : Conclusions

The aromatase inhibitors (anastrazole, letrozole, exemestane) are at least as effective as tamoxifen

TTP favors AI in all trials Survival data reported only for letrozole No direct comparisons available Optimal sequence not clear

The aromatase inhibitors (anastrazole, letrozole, exemestane) are at least as effective as tamoxifen

TTP favors AI in all trials Survival data reported only for letrozole No direct comparisons available Optimal sequence not clear

Ellis MJ et al. J Clin Oncol. 19:3808-3816, 2001.

0.0781.7(0.9-2.9)

42/100(42%)

55/101(54%)

ErbB1/2–ER+

Neoadjuvant Femara vs. Tamoxifen: Response by ErbB1+ and ErbB2+ Category

Neoadjuvant Femara vs. Tamoxifen: Response by ErbB1+ and ErbB2+ Category

0.000428(4.5-177)

4/19(21%)

15/17(88%)

ErbB1/2+ER+

P ValueOdds Ratio Let vs Tam

TamoxifenLetrozoleCategory

Analysis on ER positive and/or PgR positive cancers only

RREESSIISSTTAANNCCEE

RREESSIISSTTAANNCCEEFirst line

Nonsteroidal

AI or

SERD or Tam

First line

Nonsteroidal

AI or

SERD or Tam

Breast Cancer-2003Sequential Use of Hormones

Breast Cancer-2003Sequential Use of Hormones

PPRREEVVEENNTTIIOONN

PPRREEVVEENNTTIIOONN

TamoxifenTamoxifen

Second line

SERD

Or

Steroidal AI

Second line

SERD

Or

Steroidal AI

Third line

Steroidal AI

Or

MA

Third line

Steroidal AI

Or

MA

Adjuvant

Tamoxifen

Or

Anastrazole

Adjuvant

Tamoxifen

Or

Anastrazole

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Aromatase Inhibitors in Breast Cancer