CARCINOMA DELLA MAMMELLA

UPDATE FROM AROMATASE INHIBITORS STUDIES AT OCTOBER 2006

ANASTROZOLE (A), LETROZOLE (L), EXEMESTANE (E)

DFS DDFS OS

UPFRONT vs TAM yes no

SWITCH yes yes A yesE noL not mature (2008)

EXTENDED ADJUVANT yes yes yes (MA.17)

What’s really new in endocrine therapy What’s really new in endocrine therapy in breast cancer?in breast cancer?

Jean-Philippe SPANO, MD, PhDJean-Philippe SPANO, MD, PhDGHPS, Paris, FranceGHPS, Paris, France

The Aromatase Inhibitor TrialsThe Aromatase Inhibitor Trials

• ATAC: Tamoxifen ATAC: Tamoxifen vsvs Anastrozole Anastrozole vsvs Combined therapy Combined therapy

• MA17 : Letrozole MA17 : Letrozole vsvs placebo after 5yr Tamoxifen placebo after 5yr Tamoxifen

• IES : Exemestane IES : Exemestane vsvs Tamoxifen after 2-3yr Tamoxifen Tamoxifen after 2-3yr Tamoxifen

• ITA : Anastrozole ITA : Anastrozole vsvs Tamoxifen after 2-3yr Tamoxifen Tamoxifen after 2-3yr Tamoxifen

• ABCSG/ARNO : dittoABCSG/ARNO : ditto

• BIG 1-98 : Letrozole BIG 1-98 : Letrozole vsvs Tamoxifen Tamoxifen

• TEAM: exemestane vs TamoxifenTEAM: exemestane vs Tamoxifen

AI Trials in Early Breast CancerAI Trials in Early Breast CancerUpfrontUpfront ExtendedExtended00 55

ATACATAC

ARNOARNO/ABCSG8/ABCSG8

BIG 1-98BIG 1-98

MA-17MA-17

IESIES

ABCSG-6AABCSG-6A

TamoxifenTamoxifenAnastrozoleAnastrozoleLetrozoleLetrozolePlaceboPlaceboAromasinAromasin

Clemons et al. Cancer Treat Rev. 2004;30:335-332.Clemons et al. Cancer Treat Rev. 2004;30:335-332.

SwitchSwitchYears:Years: 2-32-3 1010

combinationcombination

Upfront StrategyUpfront Strategy

Switch StrategySwitch Strategy

Extended StrategyExtended Strategy

Point of Point of RandomizationRandomization

ATAC ATAC

• Recruitment July 1996 – March 2000• Median follow up 68 months (data cut 31st March 2004)• 8 % of patients remain on trial therapy

Arimidex + Tamoxifen (n=3,125)

Tamoxifen (n=3,116)

Surgery± RT

± Chemo (20 %) Anastrozole (n=3,125)

5 years

• 84 % HR positive• 61 % Node negative

Discontinued following initial analysis as no efficacy or

tolerability benefit compared with tamoxifen arm

Reference

Disease-free survivalDisease-free survivalCurves shown for HR+ patients Curves shown for HR+ patients

DFS includes all deaths as a first event

At risk:A 2618 2540 2448 2355 2268 2014 830T 2598 2516 2398 2304 2189 1932 774

Follow-up time (years)

0

5

10

15

20

25

0 1 2 3 4 5 6

Absolute difference:1.6 % 2.6 % 2.5 % 3.3 %

Pat

ient

s (%

)

Anastrozole (A)Tamoxifen (T)

HR

0.83

0.87

HR+

95 % CI

(0.73–0.94)

(0.78-0.97)

p-value

0.005

0.01ITT

A

424

575

T

497

651

Reference

Overall SurvivalOverall Survival Curves shown for HR+ patients Curves shown for HR+ patients

At risk:A 2618 2566 2505 2437 2377 2117 867T 2598 2549 2502 2430 2333 2080 855

Follow-up time (years)

0

5

10

15

20

25

0 1 2 3 4 5 6

Includes non breast cancer deaths

Pat

ient

s (%

)

Anastrozole (A)Tamoxifen (T)

HR

0.97

0.97

HR+

95 % CI

(0.83–1.14)

(0.85-1.12)

p-value

0.7

0.7ITT

A

296

411

T

301

420

Reference

Efficacy SummaryEfficacy Summary

* Odds Ratio computed instead of Hazard Ratio

Disease-free survival

Time to recurrence

0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0

Time to distant recurrence

Overall survival

Time to breast cancer death

Contralateral breast cancer*

ITT populationHR+ population Anastrozole better Tamoxifen better

Hazard ratio (A : T) and 95 % CIReference

IES: STUDY DESIGNIES: STUDY DESIGN

Diagnosis of breast cancer & treatment for primary disease

RANDOMISE

2-3 yearstamoxifen

2-3 yearsexemestane

years from startof tamoxifen

0

2

3

5

years fromrandomisation

0

2-3

2 to 3 years tamoxifen

Patients followed up

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

Why This Study ?Why This Study ?

• Patients with ER positive metastatic disease Patients with ER positive metastatic disease frequently respond to AI’s after tamoxifenfrequently respond to AI’s after tamoxifen

• Tamoxifen pre-treatment can increase bone densityTamoxifen pre-treatment can increase bone density

• Long-term tamoxifen can cause endometrial cancerLong-term tamoxifen can cause endometrial cancer

• Prior neo-adjuvant tamoxifen studies show that Prior neo-adjuvant tamoxifen studies show that patients frequently relapse after 2-3 yearspatients frequently relapse after 2-3 years

NEJMNEJM SABCS 2004SABCS 2004

DFS eventsDFS events 449449 615615

DeathsDeaths 199199 339339

Median Follow-upMedian Follow-up 30.6 months30.6 months 37.4 months37.4 months

IES: EFFICACY ANALYSISIES: EFFICACY ANALYSIS

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

IES : EVENTS CONTRIBUTING TO DFSIES : EVENTS CONTRIBUTING TO DFS

ExemestaneExemestane TamoxifenTamoxifen TotalTotal

Local recurrence onlyLocal recurrence only†† 4343 5656 9999

Distant recurrenceDistant recurrence 150150 208208 358358

Contralateral breast primaryContralateral breast primary 1212 2626 3838

Intercurrent deaths (without Intercurrent deaths (without recurrence)recurrence)

5757 6363 120120

Total number of patients Total number of patients experiencing an eventexperiencing an event

262262 353353 615615

† Includes 1 ipsilateral breast cancer

IES : DISEASE FREE SURVIVALIES : DISEASE FREE SURVIVAL

Hazard RatioHazard Ratio 95 % CI*95 % CI* P valueP value

Disease free survivalDisease free survival 0.730.73 0.62-0.860.62-0.86 0.00010.0001

Breast cancer free Breast cancer free survivalsurvival

0.700.70 0.58-0.830.58-0.83 0.000050.00005

Time to contralateral Time to contralateral breast cancerbreast cancer

0.500.50 0.26-0.970.26-0.97 0.040.04

* CI denotes confidence interval

Women surviving event-free (%)

Years from randomisation0 1 2 3 4

0

25

50

75

100

No. events/at risk

Hazard ratio=0.73 (95% CI: 0.62-0.86)Log-rank test: p=0.0001

Exemestane

Tamoxifen

0 / 2352 57 / 2233 65 / 2081 75 / 1413 41+24† / 6610 / 2372 82 / 2243 105 / 2062 96 / 1359 47+23† / 650Tamoxifen

Exemestane

† events occurring more than 4 years after randomisation

IES : DISEASE FREE SURVIVALIES : DISEASE FREE SURVIVAL

(262 events)

(353 events)

IES : DISEASE FREE SURVIVALIES : DISEASE FREE SURVIVALSubgroup AnalysisSubgroup Analysis

Data are hazard ratios (HR) and 95% confidence intervals (CI)

Hazard Ratio (Log-Scale)

0.72 (0.62 – 0.85)p=0.00006

0.80 (0.54 – 1.18)

0.78 (0.59 – 1.04)

1.50 (0.71 – 3.15)0.55 (0.35 – 0.88)0.69 (0.48 – 1.01)0.75 (0.59 – 0.94)0.70 (0.58 – 0.83)

HR (95% CI)Subgroup (no. patients)Tamoxifen betterExemestane better

ER+/PgR- (740)ER+/PgR unk (629)

All ER+ (4019)

ER unk (586)

ER+/PgR+ (2650)

Nodes negative (2445)

1-3 Nodes positive (1429)4+ Nodes positive (657)

Previous CT (1531)No previous CT (3171)

All patients (4724) adjusted

0.4 0.6 0.8 1.0 1.2

ER- (119)

0.66 (0.50 – 0.86)0.68 (0.51 – 0.91)

0.68 (0.53 – 0.88)0.76 (0.62 – 0.94)

No. events/at risk

Women alive (%)

Years from randomisation0 1 2 3 4

0

25

50

75

100

Hazard ratio=0.83 (95 % CI : 0.67-1.02)Log-rank test : p = 0.08

Exemestane

Tamoxifen

18 / 2270 41 / 2137 41 / 1469 37+15† / 69023 / 2300 53 / 2165 49 / 1465 41+21† / 701

TamoxifenExemestane

† events occurring more than 4 years after randomisation

(152 deaths)

(187 deaths)

0 / 23520 / 2372

IES : OVERALL SURVIVALIES : OVERALL SURVIVAL

IES : SAFETY PROFILE : IES : SAFETY PROFILE : Musculoskeletal Musculoskeletal

Incidence Case AnalysisIncidence Case Analysis EventsEventsAny GradeAny Grade

ExemestaneExemestanen (%)n (%)

TamoxifenTamoxifenn (%)n (%) PP

Treatment Treatment emergentemergent

PPArthralgiaArthralgia 414177 ( (19.8)19.8) 272755 ( (13.1)13.1) <0.001+<0.001+ ****MyalgiaMyalgia 50 (50 (2.4)2.4) 32 (32 (1.5)1.5) 0.004+0.004+ NSNS

Arthritis / Arthritis / osteoarthritisosteoarthritis

353544 ( (16.8)16.8) 282855 ( (13.5)13.5) 0.000.0033 Osteo NSOsteo NS

Muscle crampMuscle cramp 64 (64 (3.0)3.0) 107 (107 (5.1)5.1) 0.001+0.001+ ****FracturesFracturesOsteoporosisOsteoporosis

80 (3.6)80 (3.6)175(8.3)175(8.3)

60 (2.6)60 (2.6)145(6.9)145(6.9)

NSNSNS NS

**

Carpal tunnelCarpal tunnel 5577 ( (2.7)2.7) 88 ( (0.4)0.4) <0.001<0.001 ****ParaesthesiaeParaesthesiae 6699 ( (3.3)3.3) 2929 ( (1.4)1.4) <<0.001+0.001+ ****

IES SAFETY PROFILE :IES SAFETY PROFILE :Cardiovascular / Thrombo-embolic DiseaseCardiovascular / Thrombo-embolic Disease

Incidence Case AnalysisIncidence Case Analysis

EventsEventsAny GradeAny Grade

ExemestaneExemestanen (%)n (%)

TamoxifenTamoxifenn (%)n (%)

PP Treatment Treatment emergent Pemergent P

Thrombo-embolic diseaseThrombo-embolic disease 4411 ( (1.9)1.9) 6699 ( (3.3)3.3) <<0.001+0.001+ **

Myocardial Infarction (MI)Myocardial Infarction (MI)(Fatal + Non Fatal) (Fatal + Non Fatal)

All MIsAll MIsAge (mean)Age (mean)

On treatment MIsOn treatment MIs

20 (20 (0.9)0.9)68.868.8

14 (0.7)14 (0.7)

88 ( (0.4)0.4)70.970.9

7 (0.3)7 (0.3)

NS (0.02)NS (0.02)

NS (0.13)NS (0.13) NSNS

Tamoxifen: association with MI • Meta-analysis : Braithwaite et al, 2003 : 52,929 patients.• Suggestive of decrease in incidence of MI (HR 0.74 (0.47-1.16))• Decreases death from MI (HR 0.55 (0.36-0.87))

+ trend test ; NS = No-significant (p 0.01), * 0.001 p < 0.01, ** p 0.001 Reference

All patients with MI had 1 predisposing risk factor

IES : EFFICACY CONCLUSIONSIES : EFFICACY CONCLUSIONS

• Switching to exemestane reduces the risk of:Switching to exemestane reduces the risk of:– breast cancer recurrence or death (p=0.0001)breast cancer recurrence or death (p=0.0001)– contralateral breast cancer (p=0.04)contralateral breast cancer (p=0.04)

• Switching to exemestane appears to reduce the Switching to exemestane appears to reduce the chances of dying (p=0.08) but more follow-up is chances of dying (p=0.08) but more follow-up is neededneeded

The ABCSG/ARNO Trial : The ABCSG/ARNO Trial : Switching at 2-3 yearsSwitching at 2-3 years

Jakesz et al, 2005

BIG 1-98 DesignBIG 1-98 Design

Tamoxifen

Letrozole

Tamoxifen Letrozole

Letrozole Tamoxifen

RANDOMIZE

0 2 5YEARS

A

B

C

D

2-Arm Option3/98 to 3/001835 pts

4-Arm Option9/99-5/036193 pts

Primary Core AnalysisPrimary Core Analysis

8028 Randomized

8010 Primary Core Analysis

4007 T4003 L versus

18 withdrew consent (no treatment / FU)

133 (1.66%) ineligible cases included in primary core analysis

Osservazione

STUDIO HERA Qualsiasi CT± RT Tq3sett* x 12 mesi

Tq3sett* per 24 mesi

Paclitaxel q3sett x 4 o qsett x 12

NSABP B-31 AC x 4 Paclitaxel q3sett x 4 o qsett x 12 + T qsett

Paclitaxel qsett x 12

INTERGROUP N9831 AC x 4 Paclitaxel qsett x 12 T qsett

Paclitaxel qsett x 12 + T qsett

AC x 4 Docetaxel q3sett x 4

BCIRG 006 AC x 4 Docetaxel q3sett x 4 +T qsett Tq3sett*

Carboplatino + docetaxel q3sett x 6 + T qsett Tq3sett*

*q3sett alla dose di 6 mg/kg

STUDI HERCEPTIN ADIUVANTE MAMMELLA – AGGIORNATO MARZO 2006