Aromatase inhibitor therapy for early breast cancer.

Giorgio Mustacchi

Centro Oncologico

Università di Trieste

LowLow

IntermediateIntermediate

HighHigh

Node –Node –HER2 –HER2 –LVI absentLVI absent

Node –, HER2+ or LVI presentNode + (1-3) and HER2 -

Node + (1-3) and HER2 +Node + 4

G1G1TT22

AGE < 35G2-3 T>2

RRIISSKK

RRIISSKK

ST. GALLEN 2005:ST. GALLEN 2005: DEFINITIONS OF RISK DEFINITIONS OF RISK

2000 Oxford Overview: ER Status is not a prognostic factor

N- N+

EBCTCG, Lancet 2005EBCTCG, Lancet 2005

No Treatment arm

Overall survival ∆:

MA-17 N+ (HR: 0.61, p=0.04), IES (HR: 0.83, p=0.05)

Trial Design F/U N ∆ in DFS

ATAC

(Lancet 2005)A vs T vs AT

(double-blind)~ 5 yr 9366

2.5%-3.0%

BIG 1-98

(ESMO 2006)

T vs Let

(double-blind)~ 4 yr

8028

(4922)~ 3%

ABCSG-8 ARNO95

(Lancet 2005)

T Ana vs T

(open label)~ 3 yr 3224 3%

IES

(ASCO 2006)T Exe vs T (double-blind)

~ 5 yr

(2-3 post-treat)

4724 3.5%

MA.17

(JNCI 2005)L vs Placebo

(double-blind)~ 3 yr 5187 4.6%

Key Aromatase Inhibitors TrialsAll Favor AI Arm

RRIISSKK

TAM or AI or NILTAM or AI or NIL

TAM TAM AI AI or or

ADD CHEMOTHERAPYADD CHEMOTHERAPY

AIAI

Endocrine-responsiveness

AbsentAbsent Uncertain Uncertain SureSure

ST. GALLEN 2005: ST. GALLEN 2005: GUIDELINES FOR ADJ HT GUIDELINES FOR ADJ HT

Neoadjuvant IMPACT:Short Term Predictors for ATAC?

HR 95.2% CI P Value

ANA vs TAM 0.83 0.71-0.96 0.0129Comb vs TAM 1.02 0.88-1.18 0.7718

Anastrozole

Tamoxifen

Combination

Time to event (mo)

Pro

po

rtio

n e

ve

nt-

fre

e (

%)

0

80

85

90

95

100

0 6 12 18 24 30 36 42

ATACn 9366 pts DFS 33 mo

A C

IMPACTn 330 pts Clinical OR 12 wks Biological Ki67 2 wks

T

24%20%

28%

0

10

20

30

40

50

A T C

39%36%37%

0

10

20

30

40

50

A T C

Objective Response (%)Overall Population (330 Intent to Treat)

OR

(%

)

A v T: OR 1.05 (0.61, 1.81) A v T: OR 1.05 (0.61, 1.81) pp=0.87=0.87 C v T: OR 1.15 (0.67, 2.00) C v T: OR 1.15 (0.67, 2.00) pp=0.61 =0.61

OR

(%

)

A v T: OR 1.23 (0.65, 2.32) A v T: OR 1.23 (0.65, 2.32) pp=0.53=0.53C v T: OR 1.48 (0.79, 2.79) C v T: OR 1.48 (0.79, 2.79) pp=0.22=0.22

Clinical Ultrasound

EARLY BREAST CANCER TREATMENT:LESSONS LEARNED FROM CLINICAL TRIALS

An intervention produces, on average, a 50% An intervention produces, on average, a 50% relative risk reduction in relapserelative risk reduction in relapse

Higher risk women will, on Higher risk women will, on average, derive a greater absolute average, derive a greater absolute

benefit

20%20%

10%10%

40%40%

20%20%

Initial riskInitial riskFinal riskFinal risk

N-N- N+N+

There is heterogeneity in the There is heterogeneity in the magnitude of treatment magnitude of treatment

benefit !benefit !

Subset A:70% relative

risk reduction

Subset A:70% relative

risk reduction

Subset B:Subset B:<30% <30% relative risk reductionrisk reduction

Subset B:Subset B:<30% <30% relative risk reductionrisk reduction

# Gene profile = # pCR

Molecular Type % pCR 95% CI

Basal-like 45 24-68

HER2 + 45 24-68

Luminal A & B 6 1 - 21

Rouzier , Clin Cancer Res. 2005

Oncotype DX Recurrence Score

REFERENCEBeta-actinGAPDHRPLPO

GUSTFRC

PROLIFERATIONKi-67

STK15Survivin

Cyclin B1MYBL2

ESTROGENERPR

Bcl2SCUBE2

INVASIONStromolysin 3Cathepsin L2

HER2GRB7HER2

BAG1

GSTM1

CD68

16 Cancer and 5 Reference Genes

0 2 4 6 8 10 12 14 16

Years

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

DR

FS

Low R isk (R S < 18) Intermediate R isk (R S 18 - 30) H igh R isk (RS 31)

NSABP B14-Results: Benefit from Tamoxifen

Paik, NEJM 2005

Tam:High RS

DFS = Placebo

AROMATASE INHIBITORS AND TAMOXIFEN: AROMATASE INHIBITORS AND TAMOXIFEN: HETEROGENEITY IN THE TREATMENT EFFECTHETEROGENEITY IN THE TREATMENT EFFECT

A

B

Subset A : Subset A : 70 % reduction ?70 % reduction ?

Subset B : Subset B : 30 % reduction ?30 % reduction ?

On average :On average :50 % reduction 50 % reduction in the odds of in the odds of

relapserelapse

  molecular signature ?molecular signature ?

PGR ?PGR ? HER-2 ? HER-2 ? Other molecular markers ?Other molecular markers ?

EG

FR

HE

R2

Tam-S Tam-R

Knowlden et al. Endocrinology 144:1032, 2003

10% ‘conversion rate’ to HER2 overexpression in breast cancers that recur (early) on adjuvant tamoxifen (Gutierrez et al. J Clin Oncol 2005; 23:2469)

Tamoxifen-resistant breast tumors acquireErbB receptor overexpression

De Laurentiis et al. Clin. Cancer Res. 11:4741, 2005

ER+/HER2+ BC and endocrine therapy

N=1,925

HER2 + : predictive of resistence to any hormonal treatment ?

0

20

40

60

80

100

% RR

Letrozole Tam

Neoadjuvant Letrozole VS Tamoxifen

HER 2/3+ HER -

Ellis, JCO Sep 2001

020406080

100

% RR

ANA TAM

FISH + Overall

Dowsett, S. Antonio 03Neoadjuvant

Anastrozole VS Tamoxifen

ER+/PR- and hormonal treatment (ATAC trial)

From Cui et al. JCO 23:7721, 2005

Data are HRs and 95% CIs

HR Log Scale

Exemestane

better

Tamoxifen better

0.64 (0.51-0.79)

0.67 (0.39-1.16)

0.58 (0.38-0.90)

0.66 (0.51-0.87)

HR (95% CI)

0.4 0.6 0.8 1.0 1.2

Subgroup (n)

All ER+ (3853)

ER+/PgR unknown (499)

ER+/PgR- (735)

ER+/PgR+ (3853)

Coombes RC, et al. N Engl J Med. 2004;350:1081-1092.

IES 031: DFS According to ER/PgR

*Based on local assessment.

1.00.5 0.75 1.33 2.0

CT given (n = 2024)

CT not given (n = 5986)

0.70

0.85

Node (+) (n = 3311)

Node (-) (n = 4587)

0.71

0.96

ER+/PgR+ (n = 5055)*

ER+/PgR- (n = 1631)*

0.84

0.83

Favors LET Favors TAM

HR (LET:TAM)

Thürlimann BJ, et al. N Engl J Med. 2005;353:2747-2757.

BIG1-98 (Subgroups: DFS)

Viale G, et al. SABCS 2005. Abstract 44.

Disease-Free SurvivalHazard Ratio (95% CI) Letrozole vs Tamoxifen

All patients (N = 4399) 0.71 (0.57-0.88)

ER+/PgR+ (n = 3330) 0.67 (0.51-0.88)

ER+/PgR- (n = 832) 0.88 (0.55-1.41)

ER+/HER2- (n = 3971) 0.72 (0.56-0.91)

ER+/HER2+ (n = 234) 0.68 (0.33-1.41)

• The difference is not significant.

• No tamoxifen resistance observed in ER+/PgR- tumors (??)

BIG 1-98: Central Review of ER, PgR, and HER2

ER/PgR

HER2 &

Tamoxifen

DFS in tamoxifen-

treated patients

Arpino, G. et al. J Natl Cancer Inst 2005;97:1254-1261

ER+/PR+

ER+/PR+

ER+/PR-

ER+/PR-

Need an AI from

start

Cured without therapy

Cured with TAM

only

TRANSLATIONAL RESEARCH MIGHT SHED LIGHT ON THE HETEROGENEITY OF ER+ BC

• who needs an early switch ?

• who does better with a late

switch ?

Best helpedby sequencing

... but :

ER- ER+

AROMATASE INHIBITOR VERSUS TAMOXIFEN AROMATASE INHIBITOR VERSUS TAMOXIFEN WAITING FOR THE FINAL BENEFIT/RISK WAITING FOR THE FINAL BENEFIT/RISK

ASSESSMENTASSESSMENT

Osteoporosis risk Musculo-skeletal events Cost

NeurocognitionSexual function

Lipid metabolismCardiovascular disease

DVT Stroke Endometrial Ca Hot flashes

TAMOXIFENTAMOXIFEN

AROMATASE AROMATASE INHIBITORINHIBITOR

??

Arguments in favour of the switching strategy

• First OS advantage demonstration vs tamoxifen– ITT 15% (-2% – 29%) p = 0.08– ER+/Unknown 17% (0% – 31%) p =

0.05

• To minimize the adverse risk of both agents

• To monitoring the menopausal status in patients with chemo-induced amenorrhea

HR for recurrence in switched adjuvant trials of AIs vs tamoxifen

ABCSG 8 / ARNO 951

(anastrozole)

ITA2

(anastrozole)

IES3

(exemestane)

0.60*

0.35*

0.75†

HRFollow-up (months)

*all patients; †HR+ve patients

28

36

56

1Jakesz R et al. Lancet 20052Boccardo F et al. J Clin Oncol 2005

3Coombes RC et al. Lancet 2007

Trial

MA 17: Postunblinding results(Switch vs Placebo)

EFS ABCSG 8 Trial(Switch vs Sequence)

Arguments in favour of the upfront strategy

• Contraindication to TAM

• Previous therapy with SERMs

• Risk of early relapse (adverse prognostic

factors)

• Biological rationale (PGR-, HER2+)

• Results based on unselected patients

Smoothed event rates for recurrence (HR*-positive population)

0 1 2 3 4 5 6Follow-up time (years)

Annualhazardrates(%)

Anastrozole

Tamoxifen 0.5

1.0

1.5

2.0

2.5

3.03.0

0

*HR=hormone receptor

• Postmenopausal women

• Histologically or cytologically confirmed, receptor-positive, adequately excised, primary breast cancer

N = 6350*5 years

Exemestane 25 mg/day

Anastrozole 1 mg/day

Surgery ± RT ±

chemo-therapy

MA.27: Study Design

Ran

do

miz

atio

n

*Closed to accrual. Primary endpoint: event-free survival

TEAM• Phase III, open-label, randomized trial

of 5 years’ adjuvant exemestane vs adjuvant tamoxifen followed by exemestane

• Postmenopausal women with hormone receptor–positive, early-stage breast cancer

• Sample size = 1240; closed to accrual

Oxford 2006Aromatase Inhibitors vs Tamoxifen

Summary

RR 2p

Death Any Cause 0.89 (# 0.7%) 0.01

BC Deaths 0.80 (# 1%) 0.0002

Non BC Deaths 1.07

(CI very large)

0.4

Fractures 1.48 (# 1.4 %) < 0.00001

Much longer Fup is needed

Patient on day 0 Patient on day 0 of adjuvant ETof adjuvant ET

• High risk• Contra-indication to TAM• Doubt about TAM sensitivity

(e.g. HER2+ and/or PR-)

Anastrozole or Letrozole

Other patientsOther patientsTamoxifen with switch to Ana/Exe at later time

Patient on Patient on adjuvant TAMadjuvant TAM

• Medium to high risk and/or• Doubt about TAM sensitivity

Switch Switch encouraged

Very low risk

Discussion with more Discussion with more weight on known / weight on known /

unknown drug side-unknown drug side-effects profileseffects profiles

Ana/Exeif early switch

(2-3y)

Letrozoleif late switch

(4-6y)

Possible Algorithm for Adj Ht in Postmenopausal pts