University of Toronto Province-Wide
Oncology Rounds
May 18, 2012
The EBCTCG Overview: Is it still relevant
in 2012?
By
Dr. Kathleen I. Pritchard
Department Division Director, Medical Oncology
Professor, Department of Medicine
Faculty of Medicine, University of Toronto
Medical Oncology
4/8/2015
The Oxford Overview
Early Breast Cancer Trialists’
Collaborative Group
(EBCTCG)
Medical Oncology
EBCTCG OVERVIEW
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.
Medical Oncology
EBCTCG OVERVIEW
Oxford Secretariat
Richard Peto
Sarah Darby
Mike Clarke
Christina Davies
Paul McGale
Richard Gray
Rory Collins
Jon Godwin
Medical Oncology
EBCTCG OVERVIEW
Steering Committee - Executive
Marc Buyse
Mike Clarke
Rory Collins
Sarah Darby
Christina Davies
Marianne Ewertz
Martine Piccart
Kathy Pritchard
Eric Winer
William Wood
Medical Oncology
EBCTCG OVERVIEW
Past Chairs
I. Craig Henderson
William Wood
Current Co-Chairs
Kathy Pritchard
Martine Piccart
Medical Oncology
EBCTCG September 2010.
Preliminary results
Medical Oncology
EBCTCG OVERVIEW
1984

First overview process





data sought from all randomized
trials of systemic adjuvant
therapy
meta-analysis concept
collaboration sought built
sustained
Trialists
Secretariat
Medical Oncology
EBCTCG OVERVIEW
Methodology

Individual patient data

dates of randomization

treatment allocation

age

menopausal status

nodes

ER, PgR
Medical Oncology
EBCTCG OVERVIEW
Methodology

Data checked for internal
consistency

Data amended and updated by
correspondence
Medical Oncology
EBCTCG OVERVIEW
Methodology

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 of
the effect of different treatments
Medical Oncology
EBCTCG OVERVIEW
Outcomes

Recurrence

first reappearance of breast cancer

includes contralateral breast
cancer
Medical Oncology
EBCTCG OVERVIEW
Outcomes

Deaths

unknown causes included with
deaths from breast cancer unless
specifically stated otherwise

problem of death without
recurrence
Medical Oncology
EBCTCG OVERVIEW
Outcomes

Breast Cancer Related Deaths

deaths of/with breast
cancer
Medical Oncology
EBCTCG OVERVIEW
Outcomes
 Other Deaths



cardiac
stroke
other cancers
Medical Oncology
EBCTCG OVERVIEW
1984

Tamoxifen improved survival

CMF chemotherapy improved
survival

Ovarian ablation improved survival
Medical Oncology
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
Medical Oncology
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
Medical Oncology
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?
Medical Oncology
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
Medical Oncology
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
Medical Oncology
EBCTCG OVERVIEW
2006
 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
Medical Oncology
EBCTCG OVERVIEW
2010
 Tamoxifen
 AI’s
 Chemotherapy
 Locoregional therapy
Medical Oncology
2010 EBCTCG OVERVIEW
TAMOXIFEN
TAMOXIFEN VS NOT
No of women
1 yr vs not
2 yr vs not
5 yr vs not
LONGER VS SHORTER TAM
No of women
9126
23940
21457
2 – 4 vs 1 – 2 y 3200
5 vs 1 - 2 y 20000
10 vs 5 y
22000
54523
45200
Median follow-up = 15y
22% are ER- PR-
Median follow-up = 5y
50% are ER ?
Medical Oncology
Medical Oncology
2010 EBCTCG OVERVIEW
Tamoxifen for 5y vs same management but No
Tam
Risks
Benefits
(all)
(ER+)
Death w/o recurrence *
RR 1.05 (+ 0.07) 2p>0.1
Endometrial incidence
Absolute gain
RR 2.33 (+ 0.25)
at 15y
Proportional risk reductions
2p<0.00001
• Recurrence
38% (2p<0.00001) 13%
•BC mortality
30% (2p<0.00001) 9%
• All deaths
22% (2p<0.00001)
• Contralateral BC 39% (2p<0.00001)
* Numerical excess of deaths due to stroke, pulmonary embolus, uterine cancer
(15 vs 13 ; 6 vs 0; 8 vs 1)
Medical Oncology
2010 EBCTCG OVERVIEW
Tamoxifen 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…
Medical Oncology
2010 EBCTCG OVERVIEW
Tamoxifen for 5y : Impact on BC events
Medical Oncology
2010 EBCTCG OVERVIEW
Tamoxifen for 5y: Benefits in subgroups
Medical Oncology
2010 EBCTCG OVERVIEW
Tamoxifen for 5y vs same management but no
Tam
Medical Oncology
2010 EBCTCG OVERVIEW
Tamoxifen for 5y : Benefits in subgroups
AGE
Tumor
grade
Nodal
status
TAM for
5y :
Tumor
diameter
BENEFITS
for whom ?
All do benefit !!
Medical Oncology
2010
EBCTCG
OVERVIEW
Medical Oncology
2010
EBCTCG
OVERVIEW
Medical Oncology
2010 EBCTCG OVERVIEW
Tamoxifen for 5y: Benefits in subgroups
Yes
No
ER- PR-
ER- PR+
Uncertain
ER levels
(fmol/mg prot)
ER+ PR+
TAM for
5y :
BENEFITS
for whom ?
ER+ PR-
Yes
Medical Oncology
2010 EBCTCG OVERVIEW
Tamoxifen for 5y : Benefit over time
Medical Oncology
Medical Oncology
2010 EBCTCG OVERVIEW
Duration of adjuvant Tam
and outcome
Medical Oncology
2010 EBCTCG OVERVIEW
Impact of TAM duration
Even 1y only
provides
significant
benefit
10y provide
small benefit
which could ↑
Medical Oncology
over time
2010 EBCTCG OVERVIEW
Tamoxifen for 10y : Benefits vs risks at 10 y
Mean follow-up only 5y
Risks
Benefits
Absolute
Xcess
Absolute gain
Proportional risk reductions
Death w/o recurrence *
• Recurrence
8% (2p=0.03) 1% (2p 0.03)
+ 1.5% (2p=0.59)
• BC mortality 10% (2p>0.1) 2.9% (2p 0.55)
Endometrial cancers
• Contralateral
1.3% (2p 0.03)
+ 0.7% (2p=0.00004)
BC
*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)
Medical Oncology
2010 EBCTCG OVERVIEW
TAMOXIFEN
 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
Medical Oncology
2010 EBCTCG OVERVIEW
TAMOXIFEN
10 yrs vs 5 yrs of adjuvant TAMOXIFEN in ER+/?
Disease





absolute reduction in recurrence by 8% (2p=0.03)
reduces contralateral BC by 10% (2p=0.03)
increases endometrial cancer by 4 fold
reduces BC mortality by 3% (2p=0.55)
increases death without recurrence by 1.5% (2p=0.59)
Medical Oncology
2010 EBCTCG OVERVIEW
TAMOXIFEN
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
Medical Oncology
2010 EBCTCG OVERVIEW
TAMOXIFEN
Messages for clinical practice in 2010


There is presently little incentive to
prescribe more than 5y of TAM, in
postmenopausal women
More than 5y of TAM may be useful at
least for DFS in premenopausal women
especially those without a uterus
Medical Oncology
Aromatase inhibitors
EBCTCG
Medical Oncology
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 tam
after 2-3 yrs tam
Medical Oncology
5 years AI vs tamoxifen: life table curve, recurrence
Medical Oncology
JCO, 2010, 28, 509-5
5 years AI vs tamoxifen: subgroup analysis, recurrence
Medical Oncology
JCO, 2010, 28, 509-5
5 years AI vs tamoxifen: life table curves, br ca mortality
Medical Oncology
JCO, 2010, 28, 509-5
2-3yr AI vs tam after 2-3 yrs tam: life table curve, recurrence
Medical Oncology
JCO, 2010, 28, 509-5
2-3yr AI vs tam after 2-3 yrs tam:
subgroup analysis, recurrence
Medical Oncology
JCO, 2010, 28, 509-5
2-3yr AI vs tam after 2-3 yrs tam: life table curve,
br ca mortality
Medical Oncology
JCO, 2010, 28, 509-5
2010 EBCTCG OVERVIEW
Aromatase Inhibitors
Message for Clinical Practice in 2010
 AIs > tamoxifen
 recurrence
 survival
 good given
 early
 after 2 yrs
Medical Oncology
Comparisons between different polychemotherapy regimens for early breast cancer:
meta-analyses of long-term outcome among
100,000 women in 123 randomised trials
Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG)
Published online December 6, 2011 in The Lancet
DOI:10.1016/S0140-6736(11)61625-5
Medical Oncology
EBCTCG, Lancet 2011
Direct and indirect comparisons between
different polychemotherapy regimens,
based on ~100,000 randomised women
45,000 taxane vs no taxane*
(44,000 with anthracycline in both arms)
22,000 anthracycline vs CMF
(18,000 vs “standard” CMF)
5,000 more vs less anthracycline
(2000 comparing currently relevant doses)
31,000 polychemotherapy vs no adjuvant chemo
(13,000 CMF vs Nil; 10,000 anthr.-based regimen vs Nil)
* Excludes trials of one taxane regimen vs another
Medical Oncology
EBCTCG, Lancet 2011
Trials of chemotherapy vs
no adjuvant chemotherapy
- Any anthracycline-based regimen
(eg, standard 4AC) vs nil
- Standard CMF vs nil
Medical Oncology
EBCTCG, Lancet
Chemotherapy vs no adjuvant chemotherapy
L: anthracycline-based regimen (eg, standard 4AC), R: standard CMF
Medical Oncology
EBCTCG, Lancet
Chemotherapy vs no adjuvant chemotherapy
L: anthracycline-based regimen (eg, standard 4AC), R: standard CMF
Medical Oncology
EBCTCG, Lancet 2011
Chemotherapy vs no adjuvant chemotherapy
L: anthracycline-based regimen (eg, standard 4AC), R: standard CMF
Medical Oncology
EBCTCG, Lancet 2011
Breast cancer mortality ratio: anthracycline-based regimen
(eg, standard 4AC) or standard CMF vs no chemotherapy,
by TYPE of treatment comparison
Medical Oncology
EBCTCG, Lancet 2011
Chemotherapy (anthracycline-based regimen or standard CMF) +
5 year endocrine therapy vs 5 year endocrine therapy only,
ER+ disease only: by ENTRY AGE
Medical Oncology
EBCTCG, Lancet 2011
Trials of any anthracycline-based
regimen (eg, standard 4AC) vs
no adjuvant chemotherapy:
Subgroup analyses by
age, stage and ER status,
and by subsets of ER+ disease
Medical Oncology
EBCTCG, Lancet 2011
Any anthracycline-based regimen (eg, standard 4AC)
vs no adjuvant chemotherapy,
by ENTRY AGE
Medical Oncology
EBCTCG, Lancet 2011
Any anthracycline-based regimen (eg, standard 4AC)
vs no adjuvant chemotherapy,
by NODAL STATUS
Medical Oncology
EBCTCG, Lancet 2011
Breast cancer mortality ratio: any anthracycline-based
regimen (eg, standard 4AC) vs no adjuvant chemotherapy,
by AGE and STAGE
Medical Oncology
EBCTCG, Lancet 2011
Any anthracycline-based regimen (eg, standard 4AC)
vs no adjuvant chemotherapy,
by ER STATUS
Medical Oncology
EBCTCG, Lancet 2011
Breast cancer mortality ratio: any anthracycline-based
regimen (eg, standard 4AC) vs no adjuvant chemotherapy,
by ER STATUS and subsets of ER+
Medical Oncology
EBCTCG, Lancet 2011
Any anthracycline-based regimen (eg, standard 4AC)
vs no adjuvant chemotherapy,
ER+ disease only: by ENTRY AGE
Medical Oncology
EBCTCG, Lancet 2011
Trials of any anthracycline-based
regimen* vs standard CMF
*Standard 4AC, standard 4EC,
or higher-cumulative-dosage
regimens (eg, CAF or CEF)
Medical Oncology
EBCTCG, Lancet 2011
Definitions of “standard” CMF and 4AC
(mg/m2 x frequency/cycle)
Standard CMF:
Six 4-weekly cycles of C100x14 oral M40x2 iv F600x2 iv
Standard 4AC:
Four 3-weekly cycles of A60 iv C600 iv
Approximate equivalence:
in the trials of standard AC vs standard CMF,
both appeared to be of comparable efficacy
Medical Oncology
EBCTCG, Lancet 2011
Standard 4AC vs standard CMF: approximate equivalence
Medical Oncology
EBCTCG, Lancet 2011
Examples of higher-cumulative-dosage*
anthracycline-based regimens
(mg/m2 x frequency/cycle)
CAF:
Six 4-weekly cycles of C100x14 oral A40x2 iv F500x2 iv
CEF:
Six 4-weekly cycles of C75x14 oral E60x2 iv F500x2 iv
* Higher dosage than standard 4AC not only of
anthracycline but also of other cytotoxic drugs;
scheduled dosages could be reduced for toxicity
Medical Oncology
EBCTCG, Lancet 2011
Anthracycline-based regimens with higher
cumulative dosage (eg CAF/CEF) vs standard CMF
Medical Oncology
EBCTCG, Lancet 2011
Breast cancer mortality ratio:
anthracycline-based regimen vs standard CMF,
by TYPE of treatment comparison
Medical Oncology
EBCTCG, Lancet 2011
Trials of any anthracycline-based
regimen vs standard CMF:
subgroup analyses
by age, stage and ER status
Medical Oncology
EBCTCG, Lancet 2011
Breast cancer mortality ratio:
anthracycline-based regimen vs standard CMF,
by AGE and STAGE
Medical Oncology
EBCTCG, Lancet 2011
Breast cancer mortality ratio:
anthracycline-based regimen vs standard CMF,
by ER STATUS and subsets of ER+
Medical Oncology
EBCTCG, Lancet 2011
Taxane trials
Data on 44,000 women in randomised trials of a
taxane-plus-anthracycline-based regimen vs the
SAME, or MORE, non-taxane chemotherapy
11,000 in trials where the non-taxane regimen was
the SAME, and 33,000 in trials where it was MORE
[15% node-negative; mean follow-up only 5 years;
mean recurrence rate about 5% per year]
Medical Oncology
EBCTCG, Lancet 2011
Taxane-plus-anthracycline-based regimens vs
(L) the SAME, or (R) MORE, non-taxane chemo.
Medical Oncology
EBCTCG, Lancet 2011
Taxane-plus-anthracycline-based regimens vs
(L) the SAME, or (R) MORE, non-taxane chemo.
Medical Oncology
EBCTCG, Lancet 2011
Taxane-plus-anthracycline-based regimens vs
(L) the SAME, or (R) MORE, non-taxane chemo.
Medical Oncology
EBCTCG, Lancet 2011
Taxane comparisons,
subdivided according to:
(a) how the non-taxane treatments compare
(active = control, active = ½ control,
or an intermediate ratio), and
(b) whether the cycles of taxane are given
concurrently (©) with the anthracycline,
or whether taxanes are given alone (†).
Medical Oncology
EBCTCG, Lancet 2011
Breast cancer mortality ratio in taxane trials,
by TYPE of treatment comparison
Medical Oncology
EBCTCG, Lancet 2011
Taxane trials: subgroup analyses
by age, stage and ER status
Taxane-plus-anthracycline-based regimen
vs
an anthracycline-based control regimen
with the SAME, or MORE, of each
non-taxane cytotoxic drug
Medical Oncology
EBCTCG, Lancet 2011
Taxane-plus-anthracycline-based regimen
vs the SAME, or MORE, non-taxane chemo,
by ENTRY AGE
Medical Oncology
EBCTCG, Lancet 2011
Taxane-plus-anthracycline-based regimen
vs the SAME, or MORE, non-taxane chemo,
by NODAL STATUS before chemotherapy
Medical Oncology
EBCTCG, Lancet 2011
Breast cancer mortality ratio in taxane trials,
by AGE and STAGE
Medical Oncology
EBCTCG, Lancet 2011
Taxane-plus-anthracycline-based regimen
vs the SAME, or MORE, non-taxane chemo,
by ER STATUS
Medical Oncology
EBCTCG, Lancet 2011
Breast cancer mortality ratio in taxane trials,
by ER STATUS and subsets of ER+
Medical Oncology
EBCTCG, Lancet 2011
Halving big risks and halving
small risks by chemotherapy
• Proportional risk reduction does not
depend much on age, ER status or nodal
status (or on tumour grade or tumour
diameter)
• Absolute risk reduction, however,
depends on the prognosis – and, for ER+
disease, this is the prognosis with
endocrine therapy
• Information lacking on tumour gene
expression and on quantitative
immunohistochemistry
Medical Oncology
EBCTCG, Lancet 2011
Effect of Radiotherapy after
Breast-conserving Surgery on
10-year Recurrence and 15-year
Mortality
in Women with Early Breast Cancer
EBCTCG September
2010. Preliminary
results
Medical Oncology
Proportional effect of radiotherapy after breast-conserving
surgery (BCS ± RT) 11 000 women, pN0/pN+/pN?
Any recurrence
Breast cancer mortality
EBCTCG September
2010. Preliminary results
Medical Oncology
Absolute effect of radiotherapy after breast conserving
surgery (BCS ± RT): 11 000 women pN0/pN+/pN?
Any recurrence
Breast cancer mortality
Any death
“One-in-four rule” one breast cancer death avoided for every
4 recurrences avoided
EBCTCG September
2010. Preliminary results
Medical Oncology
Effect of radiotherapy after breast-conserving
surgery (BCS ± RT): 1100 pN+ women
Any recurrence
Breast cancer mortality
“One-in-four rule” one breast cancer death avoided for every
4 recurrences avoided
EBCTCG September
2010. Preliminary results
Medical Oncology
Absolute effect of radiotherapy after breastconserving surgery (BCS ± RT): 7300 pN0 women
Any recurrence
Breast cancer mortality
“One-in-four rule” one breast cancer death avoided for every 4
recurrences avoided
EBCTCG September 2010. Preliminary
results
Medical Oncology
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
EBCTCG September
2010. Preliminary results
Medical Oncology
The Oxford Overview:
Is it Still Relevant in 2010 ?
Medical Oncology
YES
Medical Oncology
EBCTCG OVERVIEW
Tamoxifen

5 +/- 5 years


30% - 40% in recurrence
25 in deaths
Medical Oncology
EBCTCG OVERVIEW
AIs

Better than Tam



mortality
for all subgroups
25%
in recurrence
0 – 25%
in BC
Medical Oncology
EBCTCG OVERVIEW
AIs
 ? Stronger effect after two
years of tamoxifen
Medical Oncology
EBCTCG OVERVIEW
Chemotherapy vs None

CMF/AC


20 – 30%
10 – 30%
recurrence
BC mortality
A vs CMF
Medical Oncology
EBCTCG OVERVIEW
 Adriamycin vs Standard CMF

10 – 20%
recurrence

10 – 20%
mortality
Medical Oncology
EBCTCG OVERVIEW
Taxanes vs Non-Taxanes

10 – 20%

10%
recurrence
BC mortality
Medical Oncology
EBCTCG OVERVIEW
 Natural History of Breast Cancer

ER/PgR +ve

ER and PgR -ve
Medical Oncology
EBCTCG OVERVIEW
 By having all data




avoids publication bias
gives average effect size
clarifies time frames of effects
process / outcomes both
useful
Medical Oncology
EBCTCG OVERVIEW



Future – Yes
Publications

2 on radiation results
2010 - 2011
 one on chemotherapy
2011

one on tamoxifen
2011

one on AIs
2011
Meet Again September 19-22, 2012
Medical Oncology
Medical Oncology
Medical Oncology
Medical Oncology
Medical Oncology
EBCTCG OVERVIEW



Future – Yes
Publications

2 on radiation results
2010 - 2011
 one on chemotherapy
2011

one on tamoxifen
2011

one on AIs
2011
Meet Again September 19-22, 2012
Medical Oncology
EBCTCG September 2010.
Preliminary results
Medical Oncology