Third Annual Maria Ricci Lecture Queen’s University and the NCIC CTG Clinical Trials Group Kingston, Ontario Canada

Third Annual Maria Ricci Lecture Queen’s University and the

NCIC CTG Clinical Trials GroupKingston, Ontario

Canada

The Oxford Overview:

Is it Still Relevant in 2010 ?

Presented by

KATHLEEN I. PRITCHARD, MD, FRCPC

Sunnybrook Odette Cancer Centre

University of Toronto

Toronto, Canada

The Oxford Overview

Early Breast Cancer Trialists’ Collaborative Group

(EBCTCG)

EBCTCG OVERVIEWSteering Committee

K. Albain, S. Anderson, R. Arriagada, W. Barlow, J. Bergh, J. Bliss, M. Buyse, D. Cameron, M. Clarke, A. Coates, R. Collins, J. Costantino, J. Cuzick, S. Darby, N. Davidson, C. Davies, A. Di Leo, M. Dowsett, M. Ewertz, R. Gelber, C. Geyer, J. Godwin, A. Goldhirsch, R. Gray, D. Hayes, C. Hill, J. Ingle, R. Jakesz, M. Kaufmann, P. McGale, L. Norton, Y. Ohashi, S. Paik, E. Perez, R. Peto, M. Piccart, L. Pierce, G. Pruneri, K. Pritchard, V. Raina, P. Ravdin, J. Robertson, E. Rutgers, Y. F. Shao, S. Swain, C. Taylor, P. Valagussa, G. Viale, T. Whelan, E. Winer, Y. Wang, W. Wood.

EBCTCG OVERVIEWOxford Secretariat

Richard Peto

Sarah Darby

Mike Clarke

Christina Davies

Paul McGale

Richard Gray

Rory Collins

Jon Godwin

EBCTCG OVERVIEWSteering Committee - Executive

Marc Buyse

Mike Clarke

Rory Collins

Sarah Darby

Christina Davies

Marianne Ewertz

Martine Piccart

Kathy Pritchard

Eric Winer

William Wood

EBCTCG OVERVIEW

Past Chairs

I. Craig Henderson

William Wood

Current Co-Chairs

Kathy Pritchard

Martine Piccart

EBCTCG September 2010. Preliminary results

EBCTCG OVERVIEW1984

First overview process

data sought from all randomized

trials of systemic adjuvant therapy

meta-analysis concept

collaboration sought built

sustained

Trialists

Secretariat

EBCTCG OVERVIEW

Methodology

Individual patient data

dates of randomization

treatment allocation

age

menopausal status

nodes

ER, PgR

EBCTCG OVERVIEW

Methodology

Data checked for internal consistency

Data amended and updated by

correspondence

EBCTCG OVERVIEWMethodology

Each trial analysed separately

Women in one trial are compared directly with only the women in the same trial

One log rank statistic per trial

Stratified by age and nodal status

Combined to give an overall estimate ofthe effect of different treatments

EBCTCG OVERVIEW

Outcomes

Recurrence

first reappearance of breast cancer

includes contralateral breast cancer

EBCTCG OVERVIEW

Outcomes

Deaths

unknown causes included with deaths from breast cancer unless specifically stated otherwise

problem of death without recurrence

EBCTCG OVERVIEW

Outcomes

Breast Cancer Related Deaths

deaths of/with breast cancer

EBCTCG OVERVIEW

Outcomes

Other Deaths

cardiac

stroke

other cancers

EBCTCG OVERVIEW

1984

Tamoxifen improved survival

CMF chemotherapy improved survival

Ovarian ablation improved survival

EBCTCG OVERVIEW

1990

longer tamoxifen seemed better

tamoxifen effects greater in ER+ve

women

tamoxifen reduced rate of contralateral breast cancer

chemo effective in older and younger women

EBCTCG OVERVIEW

1995

huge magnitude of effect of 5 years of tamoxifen

5 years of tamoxifen clearly better than 1 or 2

tamoxifen prevented contralateral

breast cancer only in women with ER+ve disease

anthracycline containing regimens better than CMF

EBCTCG OVERVIEW

2000

15 year effects of chemo sustained in older and younger women

chemo effect appears greater in ER negative

than in ER positive disease

But is this really true?

EBCTCG OVERVIEW

2000

15 year effects of 5 years of tamoxifen sustained and of great magnitude

door opened to question of 5 years versus

longer tamoxifen

ovarian suppression/ablation effective but not significantly so when added to chemotherapy

EBCTG OVERVIEW

2005

2000 Overview: Lancet, 2005 Trialists meet: new Steering Committee

formed Many new trials added More women-years of follow-up for all major

questions But major trials still missing

EBCTCG OVERVIEW2006 Trialists met: new questions

type of anthracycline-based regimen taxane trial status

aromatase inhibitors trastuzumab

chemoendocrine therapy (only in ER+, pre- and postmenopausal subsets) Subcommittees of the SC formed

EBCTCG OVERVIEW2010

Tamoxifen

AI’s

Chemotherapy

Locoregional therapy

2010 EBCTCG OVERVIEWTAMOXIFEN

TAMOXIFEN VS NOT LONGER VS SHORTER TAMNo of women No of women

1 yr vs not2 yr vs not

5 yr vs not

91262394021457

2 – 4 vs 1 – 2 y 5 vs 1 - 2 y

10 vs 5 y

32002000022000

54523 45200

Median follow-up = 15y22% are ER- PR-

Median follow-up = 5y50% are ER ?

2010 EBCTCG OVERVIEWTamoxifen for 5y vs same management but No Tam

Benefits(ER+)

Risks(all)

Proportional risk reductions• Recurrence 38% (2p<0.00001)•BC mortality 30% (2p<0.00001)• All deaths 22% (2p<0.00001)

• Contralateral BC 39% (2p<0.00001)

Death w/o recurrence * RR 1.05 (+ 0.07) 2p>0.1

Endometrial incidence RR 2.33 (+ 0.25)

2p<0.00001

* Numerical excess of deaths due to stroke, pulmonary embolus, uterine cancer(15 vs 13 ; 6 vs 0; 8 vs 1)

Absolute gainat 15y

13%9%

2010 EBCTCG OVERVIEWTamoxifen for 5y vs same management but no Tam

Learning more about Tam benefits

On types of B.C. events…

In subgroups

In relation to chemotherapy administration

Over time…

2010 EBCTCG OVERVIEWTamoxifen for 5y : Impact on BC events

2010 EBCTCG OVERVIEWTamoxifen for 5y: Benefits in subgroups

2010 EBCTCG OVERVIEWTamoxifen for 5y vs same management but no Tam

TAM for5y :

BENEFITSfor whom ?

AGE

Nodal status

Tumor grade

Tumor diameter

2010 EBCTCG OVERVIEWTamoxifen for 5y : Benefits in subgroups

All do benefit !!

2010EBCTCG

OVERVIEW

2010EBCTCG

OVERVIEW

2010 EBCTCG OVERVIEWTamoxifen for 5y: Benefits in subgroups

TAM for5y :

BENEFITSfor whom ?

ER levels(fmol/mg prot)

ER- PR-

ER- PR+

ER+ PR+

ER+ PR-

No

Uncertain

Yes

Yes

2010 EBCTCG OVERVIEWTamoxifen for 5y : Benefit over time

2010 EBCTCG OVERVIEW

Duration of adjuvant Tam and outcome

2010 EBCTCG OVERVIEWImpact of TAM duration

Even 1y onlyprovides

significantbenefit

10y providesmall benefit

which could ↑ over time

2010 EBCTCG OVERVIEWTamoxifen for 10y : Benefits vs risks at 10 y

Mean follow-up only 5y

Benefits Risks

Proportional risk reductions• Recurrence 8% (2p=0.03)• BC mortality 3% (2p>0.1)• Contralateral BC

Death w/o recurrence * + 1,5% (2p=0.59) Endometrial cancers + 0.7% (2p=0.00004)

*Numerical excess of deaths due to cerebrovascular events (42 vs 38 in y0-4; 27 vs 24 in y5-10), thrombo-embolic events (10 vs 56 in y0-4), end. cancers

(8 vs 6 in y0-4, 4 vs 2 in y5-10)

Absolute gain

1% (2p 0.03)2,9% (2p 0.55)1.3% (2p 0.03)

Absolute Xcess


5y in ER+ disease

reduces recurrence by 38%, BC death by 30%

all deaths by 22% contralateral BC by 40%

benefits all women with ER+ disease unclear benefits in ER-PgR+ disease

benefits women with ER very rich tumors more increases endometrial cancer by 2.3 fold


10 yrs vs 5 yrs of adjuvant TAMOXIFEN in ER+/? Disease

absolute reduction in recurrence by 1% (2p=0.03) reduces contralateral BC by 1.3% (2p=0.03) increases endometrial cancer by 0.7% (2p=0.00004) reduces BC mortality by 3% (2p=0.55) increases death without recurrence by 1.5% (2p=0.59)


Messages for clinical practice in 2010

PgR does not predict for benefit of adjuvant TAM For ER-PgR+ patients, the tumor should be retested and if doubt remains, TAM could be offered There is presently little incentive to prescribe more than 5y of TAM, especially in women with an uterus

EBCTCG SEPTEMBER 2010

Aromatase inhibitors

Data from 1st analysis

• No unplanned cross-over

• Cut-off 30 Sept 2006

• Cohort 1: 5yrs AI vs 5yrs tam

• Cohort 2: 2-3 yrs of AI vs 2-3 yrs of tamafter 2-3 yrs tam

JCO, 2010, 28, 509-518

5 years AI vs tamoxifen: trial-specific recurrence data

JCO, 2010, 28, 509-518

5 years AI vs tamoxifen: life table curve, recurrence

JCO, 2010, 28, 509-518

5 years AI vs tamoxifen: life table curves, br ca mortality

JCO, 2010, 28, 509-518

2-3yr AI vs tam after 2-3 yrs tam: life table curve, recurrence

JCO, 2010, 28, 509-518

2-3yr AI vs tam after 2-3 yrs tam: life table curve, br ca mortality

JCO, 2010, 28, 509-518

2-3yr AI vs tam after 2-3 yrs tam: life table curve, mortality(C) without recurrence, (D) all cause

2010 EBCTCG OVERVIEWAromatase Inhibitors

Message for Clinical Practice in 2010

AIs > tamoxifen

recurrence

survival

good given

early

after 2 yrs

N ≈ 10.000N ≈ 14000

2010 EBCTCG OVERVIEWCHEMOTHERAPY

Polychemo vs NOT Anthracycline (A) vs CMF Taxane (+A) vs A

N = 23500 N = 22000 N = 44000

N ≈ 9500N ≈ 18000

N ≈ 23.000

N ≈ 11.000

CMF vs NOT(only 5000 st CMF)

Anthrac vs NOT(only 3000 of Mas strenght)

Anthrac vs st CMF

Tax + A vs lots of ATax + A vs more ATax + A vs same A


Polychemotherapy versus

No chemotherapy

10y results in 23500 women

2010 EBCTCG OVERVIEWPolychemotherapy vs NIL : 10y results

ANTHRACYCLINE

CMF

STANDARDS

2010 EBCTCG OVERVIEWPolychemotherapy vs NO CTX : 10y results

Anthracycline vs No CTX CMF vs No CTX

RR

1.0

0.5

0.680.76 0.720.73

0.82 0.79

RR

1.0

0.5

0.700.80 0.76 0.76

0.88 0.84

Recurrence BC mortality Recurrence BC mortality

A≥60E≥90

Lowerdoses

All A≥60E≥90

Lowerdoses

All St CMF

otherCMF

AllSt

CMFotherCMF

All

2010 EBCTCG OVERVIEWPolychemotherapy vs NIL

Learning more about benefits

• Over time...

• In subgroups

2010 EBCTCG OVERVIEWPolychemotherapy vs NO CTX :

Impact over time

Anthracycline vs No CTX CMF vs No CTX

Strong, early effect... !


Impact on recurrence in subgroups

Anthracycline vs NO CTX Standard CMF vs NO CTX

No indication of reduced benefit !


Tumour

diameter

PolyCTX vsNo CTX

Who benefits ?

Tumour

Grade

AGE

ER poor,

+ or ?

Concurrent

endocrine

therapy

Nodal

Status


Benefits in subgroups

All do benefit !


Anthracycline regimens

vs

standard CMF


AC X4

ANTHRACYCLINE

MORE


0.5

1.0

2010 EBCTCG OVERVIEWAnthracycline vs standard CMF :

10 y results mortality with recurrence Ratio ofannualdeathrates

0.89 0.89

0.780.82

0.980.93

Any Aregimen

CumdoseA 360

E 720-800

CumdoseA 300

E 400-480

Cumdose

A ≤ 360

Dose per cycle< A60, E90

Dose per cycle ≥ A60, E90


Taxane + Anthracycline regimens vs

Anthracycline regimens



T+AVssameA

T+AVsmoreA

0.75

1.0

2010 EBCTCG OVERVIEWTaxane + Anthracycline vs A :5 y results in 44000 women

Recurrence Mortality w/recurrence

Ratio ofannualeventrates

allT+Avs

same AT+Avs

more A

T+Avs

int A

T+Avs

int A

T+Avs

more A

T+Avs

same Aall

2p<0.000012p=0.00012p<0.0001 2pNS 2p=0.000012p=0.001 2p=0.003 2pNS

2010 EBCTCG OVERVIEW:Polychemotherapy :

Impact on recurrence over time

Anthracycline vs st CMF Anthracycline (A) + Taxane vs A

EARLY IMPACT EARLY and LATE IMPACT

2010 EBCTCG OVERVIEWTaxane + Anthracycline vs A :

Impact on recurrence in subgroups


2010 EBCTCG OVERVIEWPOLYCHEMOTHERAPY

Messages for clinical practice in 2010

Taxane-based regimens

Reduced in recurrence (2.8%)

Reduced mortality with recurrence (1.3%) Except when compared to very well dosed (total 2x2) anthracycline-based regimens

Effect seems independent from the recorded tumor characteristics (with lack on information

on HER2)

Effect persists over 5 years

Effect of Radiotherapy after Breast-conserving Surgery on

10-year Recurrence and 15-year Mortality

in Women with Early Breast Cancer



Randomised trials of radiotherapy following breast-conserving surgery (BCS ± RT)

that began before the year 2000

Trial category No of trials

Years trials

started No of women

Lumpectomy 6 1976-86 4500 Sector resection 4 1981-91 2400 Low risk women 7 1989-96 4000 All women 17 11,000 pN0 7300 pN+ 1100 pN ? 2500

50% increase since EBCTCG (2005)


Proportional effect of radiotherapy after breast-conserving surgery (BCS ± RT) 11 000 women, pN0/pN+/pN?

Any recurrence Breast cancer mortality


Absolute effect of radiotherapy after breast conserving surgery (BCS ± RT): 11 000 women pN0/pN+/pN?

Any recurrence Breast cancer mortality Any death


Effect of radiotherapy after breast-conserving surgery (BCS ± RT): 1100 pN+ women


“One-in-four rule” one breast cancer death avoided for every 4 recurrences avoided


Absolute effect of radiotherapy after breast-conserving surgery (BCS ± RT): 7300 pN0 women


“One-in-four rule” one breast cancer death avoided for every 4 recurrences avoided

Conclusions

• Radiotherapy highly effective in reducing recurrence in both pN0 and pN+ women

• Radiotherapy also reduces 15-year breast cancer

• “One-in-four” rule applies for pN0 and pN1 women

• Benefits not substantially reduced by fatal side-effects


The Oxford Overview:

Is it Still Relevant in 2010 ?

YES

EBCTCG OVERVIEW

Tamoxifen

5 +/- 5 years

30% - 40% in recurrence

25 in deaths

EBCTCG OVERVIEW

AIs

Better than Tam

for all subgroups

25% in recurrence

0 – 25% in BC mortality

EBCTCG OVERVIEW

AIs

? Stronger effect after two

years of tamoxifen

EBCTCG OVERVIEW

Chemotherapy vs None

CMF/AC

20 – 30% recurrence

10 – 30% BC mortality

A vs CMF

EBCTCG OVERVIEW

Adriamycin vs Standard CMF


10 – 20% mortality

EBCTCG OVERVIEW

Taxanes vs Non-Taxanes


10% BC mortality

EBCTCG OVERVIEW

Natural History of Breast Cancer

ER/PgR +ve

ER and PgR -ve

EBCTCG OVERVIEW

By having all data

avoids publication bias

gives average effect size

clarifies time frames of effects

process / outcomes both useful

EBCTCG OVERVIEW

Future – Yes

Publications

3 on radiation results

2010 - 2011

one on chemotherapy

2011

one on AIs

2011

Meet Again September 19-22, 2012

EBCTCG OVERVIEW

Future – Yes

Publications

3 on radiation results

2010 - 2011

one on chemotherapy

2011

one on AIs

2011

Meet Again September 19-22, 2012

Documents

Third Annual Maria Ricci Lecture Queen’s University and the NCIC CTG Clinical Trials Group Kingston, Ontario Canada