SABCS 2005

Central review of ER, PgR and HER-2 in BIG 1-98 evaluating letrozole vs. tamoxifen

as adjuvant endocrine therapy for postmenopausal women with receptor-

positive breast cancer

IBCSG 18-98/BIG 1-98

Giuseppe Viale and Meredith Reganfor the BIG 1-98 Collaborative

Coordinated by the International Breast Cancer Study

Group

SABCS 2005

BIG 1-98TamoxifenLetrozole

Letrozole

Letrozole Tamoxifen

RANDOMIZE

0 2 5

ABCD

Tamoxifen

YEARS

• Compares Letrozole versus Tamoxifen• Letrozole: Arms B and D (n=4003)• Tamoxifen: Arms A and C (n=4007)• Excludes events and FU beyond switch for C & D

SABCS 2005

Disease-Free Survival25.8 mos. median follow-up

100

T

L

0

20

40

60

80

0 1 2 3 4 5

Perc

ent A

live

and

Dis

ease

-Fre

e

EventsN HR (95% CI) p

7798010 0.81 (.70-.93) 0.003

Years from RandomizationNo. at Risk

40034007

38923896

892866

567544

29642926

12611238

SABCS 2005

BIG 1-98 DFS by Local Pathological Assessment

0.81 All patients (n=8010)

0.84 ER+ / PgR+ (n=5055)

0.83 ER+ / PgR- (n=1631)

0.72 ER+ / PgR unk (n=1154)

0.5 0.75 1.0 1.25 1.5

Favors L Favors T

Hazard Ratio (L:T)

SABCS 2005

BIG 1-98 Central Review Project

• ER and PgR by IHC– ER (1D5 monoclonal antibody; Dako) – PgR (636 monoclonal antibody; Dako)– Positive is ≥10% stained cells

• HER2 – IHC for all cases (HercepTest; Dako)– FISH for all IHC 2+, 3+; also for IHC 1+ with ≥50% stained cells (Pathvision kit; Vysis)

– Positive is a positive result by FISH, or in a few cases IHC=3+ with unevaluable FISH

SABCS 2005

BIG 1-98 Central Review Project

• Assessable material for 4,399 patients• Compared to patients without centrally

reviewed material, the analysis cohort of 4399 patients had:– Slightly better prognostic features– Shorter follow-up (25.4 months)– Fewer events

SABCS 2005

ER / PgR by Type of AssessmentLocal CentralN %

3124 71.021.9

5.01.80.1

0<0.1

0<0.1

965220

8050203

N %ER+ / PgR+ 3330 75.7

ER+ / PgR? 48 1.1ER- / PgR+ 13 0.3ER- / PgR- 103 2.3ER- / PgR? 1 < 0.1ER? / PgR+ 23 0.5ER? / PgR- 7 0.2ER? / PgR? 42 1.0

ER+ / PgR- 832 18.9

SABCS 2005

0 1 2 3 4

020

4060

8010

0

Years

Per

cent

Aliv

e an

d D

isea

se-F

ree

DFS according to Treatment

ER+ (n=4089)

TamoxifenLetrozole

ER- / PgR- (n=103)

SABCS 2005

Research Questions: PgR

• Is there evidence of tamoxifen resistance in ER+ / PgR- tumors?

• Is the benefit of letrozole vs. tamoxifen greater in patients with ER+ / PgR-tumors than with ER+ / PgR+ tumors?

SABCS 2005

0 1 2 3 4

020

4060

8010

0

Years

Per

cent

Aliv

e an

d D

isea

se-F

ree

0 1 2 3 4

020

4060

8010

0

Years

DFS: ER+ / PgR by TreatmentTamoxifen Letrozole

ER+/PgR- (N=415)ER+/PgR+ (N=1682)

ER+/PgR- (N=417)ER+/PgR+ (N=1648)

SABCS 2005

0 1 2 3 4

020

4060

8010

0

Years

Per

cent

Aliv

e an

d D

isea

se-F

ree

0 1 2 3 4

020

4060

8010

0

Years

Interaction p-value=0.32

DFS: ER+ according to PgRER+ / PgR+ ER+ / PgR-

TamoxifenLetrozole

N HR (95% CI)

3330 0.67 (.51-.88)

Events

215

N HR (95% CI)

832 0.88 (.55-1.41)

Events

70

SABCS 2005

BIG 1-98 DFS by Central Pathological Assessment

0.71 All patients (n=4399)

0.67 ER+ / PgR+ (n=3330)

0.88 ER+ / PgR- (n=832)

0.5 0.75 1.0 1.25 1.5

Favors L Favors T

Hazard Ratio (L:T)

SABCS 2005

0 10 30 40 50 65 75 90 99

020

4060

8010

0

LT

4-yr

DFS

(%)

PgR% [pars=450,400]

DFS by level of PgR expressionin ER+ patients

Subpopulation Median PgR (%)

Letrozole Tamoxifen

SABCS 2005

Research Questions: HER2

• Is there evidence of tamoxifen resistance in ER+/HER2+ tumors?

• Is the benefit of letrozole vs. tamoxifen greater for patients with ER+ / HER2+ tumors than with ER+ / HER2- tumors?

SABCS 2005

HER2 Positivity by ER/PgR Status

HER2+Subgroup N % of subgroup

5%10%32%

Other 14 10%All patients 279 6%

ER+ / PgR- 79ER- / PgR- 33

ER+ / PgR+ 153

SABCS 2005

0 1 2 3 4

020

4060

8010

0

Years

Per

cent

Aliv

e an

d D

isea

se-F

ree

0 1 2 3 4

020

4060

8010

0

Years

DFS: ER+ / HER2 by TreatmentTamoxifen Letrozole

ER+/HER2- (N=1986)ER+/HER2+ (N=107)

ER+/HER2- (N=1985)ER+/HER2+ (N=127)

HR=0.52 (0.31, 0.88) HR=0.56 (0.31, 0.98)

SABCS 2005

0 1 2 3 4

020

4060

8010

0

Years

Per

cent

Aliv

e an

d D

isea

se-F

ree

0 1 2 3 4

020

4060

8010

0

Years

DFS: ER+ according to HER2ER+ / HER2- ER+ / HER2+

Interaction p-value=0.90

TamoxifenLetrozole

N HR (95% CI)

3971 0.72 (.56-.91)

Events

263

N HR (95% CI)

234 0.68 (.33-1.41)

Events

29

SABCS 2005

BIG 1-98 DFSby Central Pathological Assessment

0.71 All patients (n=4399)

Favors L Favors T

1.00.5 0.75 1.25 1.5

Hazard Ratio (L:T)

ER+ / HER2+ (n=234)

ER+ / HER2- (n=3971)

0.68

0.72

SABCS 2005

Conclusions

• Benefit of letrozole vs. tamoxifen is maintained irrespective of PgR status in patients with ER+ tumors

• Tamoxifen resistance for ER+ / PgR-tumors was not observed

• Resistance to endocrine treatments for ER+/HER2+ tumors requires further evaluation

SABCS 2005

The IBCSG Central Pathology Team

Bern Milano Buffalo

Rosita KammlerAdriana AeschbacherHans-Rudolf PauliStephan OelhafenRegula StuderAnita Hiltbrunner

Tara ScoleseSusan FischerDanita HarrisonLois UhtegJohn GouldLynette Blacher

Giulia PeruzzottiRaffaella GhisiniEloise ScaranoPatrizia Dell’OrtoBarbara Del CurtoMauro MastropasquaStefania Andrighetto

SABCS 2005

BIG 1-98 Contributing Pathologists

W P Olszewski I Peter Z Orosz F Knox

D Larsimont E Mery M Lacroix A ParmaM Lazzarotto-Rumpler T Perin A Gloghini HJ AltermattC Oehlschlegel JF Mosnier C Metcalf G SingerJM Picquenot S Laberge I Bulucheva P RinaldiE Bajetta P Grigolato I Tan-Go OF ChepikG MacGrogan A Nerurkar P Tricomi L LuciniJ Sanchez Lihon CA Purdie S Cordovi R BrayeR Brown P Figueiredo K Jaskiewicz C WrightM Fiche J Kiesler B Coudert L Arnould

…and another 300…

SABCS 2005

Thanks to…

• The patients participating in the trial• The pathologists who submitted material• The IBCSG Pathology Office• The IBCSG Data Management Center• The principal investigators• The co-investigators, data managers, nurses,

study coordinators• BIG 1-98 Steering Committee• Novartis