1. 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
4/19/2017

2. Early Breast Cancer Trialists’ Collaborative Group
The Oxford Overview
Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG)

3. 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.

4. EBCTCG OVERVIEW Oxford Secretariat Richard Peto Sarah Darby
Mike Clarke
Christina Davies
Paul McGale
Richard Gray
Rory Collins
Jon Godwin

5. 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

6. EBCTCG OVERVIEW Past Chairs I. Craig Henderson William Wood
Current Co-Chairs
Kathy Pritchard
Martine Piccart

7. EBCTCG September 2010. Preliminary results

8. 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

9. EBCTCG OVERVIEW Methodology  Individual patient data
 dates of randomization
 treatment allocation
 age
 menopausal status
 nodes
 ER, PgR

10. EBCTCG OVERVIEW
Methodology
 Data checked for internal consistency
 Data amended and updated by
correspondence

11. 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

12. EBCTCG OVERVIEW Outcomes  Recurrence
 first reappearance of breast cancer
 includes contralateral breast cancer

13. EBCTCG OVERVIEW Outcomes  Deaths
 unknown causes included with deaths from breast cancer unless specifically stated otherwise
 problem of death without recurrence

14.  Breast Cancer Related Deaths  deaths of/with breast cancer
EBCTCG OVERVIEW
Outcomes
 Breast Cancer Related Deaths
 deaths of/with breast cancer

15.  Other Deaths  cardiac  stroke  other cancers EBCTCG OVERVIEW
Outcomes
 Other Deaths
 cardiac
 stroke
 other cancers

16. EBCTCG OVERVIEW 1984  Tamoxifen improved survival
 CMF chemotherapy improved survival
 Ovarian ablation improved survival

17. 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

18. EBCTCG OVERVIEW
1995
 huge magnitude of effect of 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

19. 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?

20. 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

21. 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

22. 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

23.  Locoregional therapy
EBCTCG OVERVIEW
2010
 Tamoxifen
 AI’s
 Chemotherapy
 Locoregional therapy

24. 2010 EBCTCG OVERVIEW TAMOXIFEN
TAMOXIFEN VS NOT
LONGER VS SHORTER TAM
No of women
No of women
1 yr vs not
2 yr vs not
5 yr vs not
9126
23940
21457
2 – 4 vs 1 – 2 y
5 vs y
10 vs 5 y
3200
20000
22000
54523
45200
Median follow-up = 15y
22% are ER- PR-
Median follow-up = 5y
50% are ER ?

26. 2010 EBCTCG OVERVIEW Tamoxifen for 5y vs same management but No Tam
Risks
(all)
Benefits
(ER+)
Death w/o recurrence *
RR 1.05 (+ 0.07) 2p>0.1
Endometrial incidence
RR 2.33 (+ 0.25)
2p<
Absolute gain
at 15y
Proportional risk reductions
Recurrence % (2p< )
BC mortality % (2p< )
All deaths % (2p< )
Contralateral BC 39% (2p< )
13% 9%
* Numerical excess of deaths due to stroke, pulmonary embolus, uterine cancer
(15 vs 13 ; 6 vs 0; 8 vs 1)

27. 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…

28. 2010 EBCTCG OVERVIEW Tamoxifen for 5y : Impact on BC events

29. 2010 EBCTCG OVERVIEW Tamoxifen for 5y: Benefits in subgroups

30. 2010 EBCTCG OVERVIEW Tamoxifen for 5y vs same management but no Tam

31. 2010 EBCTCG OVERVIEW Tamoxifen for 5y : Benefits in subgroups
Nodal
status
AGE
TAM for
5y :
BENEFITS
for whom ?
Tumor
diameter
Tumor
grade
All do benefit !!

32. 2010
EBCTCG
OVERVIEW

33. 2010
EBCTCG
OVERVIEW

34. 2010 EBCTCG OVERVIEW Tamoxifen for 5y: Benefits in subgroups
Yes No
ER levels
(fmol/mg prot)
ER+ PR+
ER- PR-
TAM for
5y :
BENEFITS
for whom ?
ER- PR+
ER+ PR-
Uncertain
Yes

35. 2010 EBCTCG OVERVIEW Tamoxifen for 5y : Benefit over time

37. Duration of adjuvant Tam and outcome
2010 EBCTCG OVERVIEW
Duration of adjuvant Tam and outcome

38. 2010 EBCTCG OVERVIEW Impact of TAM duration
Even 1y only
provides
significant
benefit
10y provide
small benefit
which could ↑
over time

39. 2010 EBCTCG OVERVIEW Tamoxifen for 10y : Benefits vs risks at 10 y Mean follow-up only 5y
Absolute
Xcess
Absolute gain
Proportional risk reductions
Recurrence % (2p=0.03)
BC mortality 10% (2p>0.1)
Contralateral BC
Death w/o recurrence *
+ 1.5% (2p=0.59)
Endometrial cancers
+ 0.7% (2p= )
1% (2p 0.03)
2.9% (2p 0.55)
1.3% (2p 0.03)
*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)

40. 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

41. 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)

42. 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

43. 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

44. Aromatase inhibitors
EBCTCG SEPTEMBER 2010

45. 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

46. 5 years AI vs tamoxifen: life table curve, recurrence
JCO, 2010, 28,

47. 5 years AI vs tamoxifen: subgroup analysis, recurrence
JCO, 2010, 28,

48. 5 years AI vs tamoxifen: life table curves, br ca mortality
JCO, 2010, 28,

49. 2-3yr AI vs tam after 2-3 yrs tam: life table curve, recurrence
JCO, 2010, 28,

50. 2-3yr AI vs tam after 2-3 yrs tam: subgroup analysis, recurrence
JCO, 2010, 28,

51. 2-3yr AI vs tam after 2-3 yrs tam: life table curve,
br ca mortality
JCO, 2010, 28,

52. Message for Clinical Practice in 2010
2010 EBCTCG OVERVIEW
Aromatase Inhibitors
Message for Clinical Practice in 2010
 AIs > tamoxifen
 recurrence
 survival
 good given
 early
 after 2 yrs

53. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
Comparisons between different polychemo- therapy 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: /S (11)
EBCTCG, Lancet 2011

54. 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
EBCTCG, Lancet 2011

55. Trials of chemotherapy vs no adjuvant chemotherapy
- Any anthracycline-based regimen
(eg, standard 4AC) vs nil
- Standard CMF vs nil
EBCTCG, Lancet 2011

56. EBCTCG, Lancet 2011 Chemotherapy vs no adjuvant chemotherapy
L: anthracycline-based regimen (eg, standard 4AC), R: standard CMF
EBCTCG, Lancet 2011

57. EBCTCG, Lancet 2011 Chemotherapy vs no adjuvant chemotherapy
L: anthracycline-based regimen (eg, standard 4AC), R: standard CMF
EBCTCG, Lancet 2011

58. EBCTCG, Lancet 2011 Chemotherapy vs no adjuvant chemotherapy
L: anthracycline-based regimen (eg, standard 4AC), R: standard CMF
EBCTCG, Lancet 2011

59. by TYPE of treatment comparison
Breast cancer mortality ratio: anthracycline-based regimen
(eg, standard 4AC) or standard CMF vs no chemotherapy,
by TYPE of treatment comparison
EBCTCG, Lancet 2011

60. ER+ disease only: by ENTRY AGE
Chemotherapy (anthracycline-based regimen or standard CMF) +
5 year endocrine therapy vs 5 year endocrine therapy only,
ER+ disease only: by ENTRY AGE
EBCTCG, Lancet 2011

61. 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
EBCTCG, Lancet 2011

62. Any anthracycline-based regimen (eg, standard 4AC)
vs no adjuvant chemotherapy,
by ENTRY AGE
EBCTCG, Lancet 2011

63. Any anthracycline-based regimen (eg, standard 4AC)
vs no adjuvant chemotherapy,
by NODAL STATUS
EBCTCG, Lancet 2011

64. EBCTCG, Lancet 2011 by AGE and STAGE
Breast cancer mortality ratio: any anthracycline-based
regimen (eg, standard 4AC) vs no adjuvant chemotherapy,
by AGE and STAGE
EBCTCG, Lancet 2011

65. Any anthracycline-based regimen (eg, standard 4AC)
vs no adjuvant chemotherapy,
by ER STATUS
EBCTCG, Lancet 2011

66. EBCTCG, Lancet 2011 by ER STATUS and subsets of ER+
Breast cancer mortality ratio: any anthracycline-based
regimen (eg, standard 4AC) vs no adjuvant chemotherapy,
by ER STATUS and subsets of ER+
EBCTCG, Lancet 2011

67. EBCTCG, Lancet 2011 ER+ disease only: by ENTRY AGE
Any anthracycline-based regimen (eg, standard 4AC)
vs no adjuvant chemotherapy,
ER+ disease only: by ENTRY AGE
EBCTCG, Lancet 2011

68. Trials of any anthracycline-based regimen. vs standard CMF
Trials of any anthracycline-based regimen* vs standard CMF *Standard 4AC, standard 4EC, or higher-cumulative-dosage regimens (eg, CAF or CEF)
EBCTCG, Lancet 2011

69. Approximate equivalence:
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
EBCTCG, Lancet 2011

70. Standard 4AC vs standard CMF: approximate equivalence
EBCTCG, Lancet 2011

71. 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
EBCTCG, Lancet 2011

72. EBCTCG, Lancet 2011 Anthracycline-based regimens with higher
cumulative dosage (eg CAF/CEF) vs standard CMF
EBCTCG, Lancet 2011

73. EBCTCG, Lancet 2011 by TYPE of treatment comparison
Breast cancer mortality ratio:
anthracycline-based regimen vs standard CMF,
by TYPE of treatment comparison
EBCTCG, Lancet 2011

74. by age, stage and ER status
Trials of any anthracycline-based regimen vs standard CMF:
subgroup analyses
by age, stage and ER status
EBCTCG, Lancet 2011

75. EBCTCG, Lancet 2011 by AGE and STAGE Breast cancer mortality ratio:
anthracycline-based regimen vs standard CMF,
by AGE and STAGE
EBCTCG, Lancet 2011

76. EBCTCG, Lancet 2011 by ER STATUS and subsets of ER+
Breast cancer mortality ratio:
anthracycline-based regimen vs standard CMF,
by ER STATUS and subsets of ER+
EBCTCG, Lancet 2011

77. 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]
EBCTCG, Lancet 2011

78. EBCTCG, Lancet 2011 Taxane-plus-anthracycline-based regimens vs
(L) the SAME, or (R) MORE, non-taxane chemo. 
EBCTCG, Lancet 2011

79. EBCTCG, Lancet 2011 Taxane-plus-anthracycline-based regimens vs
(L) the SAME, or (R) MORE, non-taxane chemo. 
EBCTCG, Lancet 2011

80. EBCTCG, Lancet 2011 Taxane-plus-anthracycline-based regimens vs
(L) the SAME, or (R) MORE, non-taxane chemo. 
EBCTCG, Lancet 2011

81. or whether taxanes are given alone (†).
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 (†).
EBCTCG, Lancet 2011

82. by TYPE of treatment comparison
Breast cancer mortality ratio in taxane trials,
by TYPE of treatment comparison
EBCTCG, Lancet 2011

83. 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
EBCTCG, Lancet 2011

84. EBCTCG, Lancet 2011 by ENTRY AGE
Taxane-plus-anthracycline-based regimen
vs the SAME, or MORE, non-taxane chemo,
by ENTRY AGE
EBCTCG, Lancet 2011

85. EBCTCG, Lancet 2011 by NODAL STATUS before chemotherapy
Taxane-plus-anthracycline-based regimen
vs the SAME, or MORE, non-taxane chemo,
by NODAL STATUS before chemotherapy
EBCTCG, Lancet 2011

86. Breast cancer mortality ratio in taxane trials,
by AGE and STAGE
EBCTCG, Lancet 2011

87. EBCTCG, Lancet 2011 by ER STATUS
Taxane-plus-anthracycline-based regimen
vs the SAME, or MORE, non-taxane chemo,
by ER STATUS
EBCTCG, Lancet 2011

88. by ER STATUS and subsets of ER+
Breast cancer mortality ratio in taxane trials,
by ER STATUS and subsets of ER+
EBCTCG, Lancet 2011

89. 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
EBCTCG, Lancet 2011

90. EBCTCG September 2010. Preliminary results
Effect of Radiotherapy after Breast-conserving Surgery on 10-year Recurrence and 15-year Mortality in Women with Early Breast Cancer
EBCTCG September Preliminary results

91. EBCTCG September 2010. Preliminary results
Proportional effect of radiotherapy after breast-conserving
surgery (BCS ± RT) women, pN0/pN+/pN?
Any recurrence Breast cancer mortality
EBCTCG September Preliminary results

92. EBCTCG September 2010. Preliminary results
Absolute effect of radiotherapy after breast conserving surgery (BCS ± RT): 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 Preliminary results

93. EBCTCG September 2010. Preliminary results
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 Preliminary results

94. EBCTCG September 2010. Preliminary results
Absolute effect of radiotherapy after breast-conserving 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 Preliminary results

95. EBCTCG September 2010. Preliminary results
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 Preliminary results

96. The Oxford Overview: Is it Still Relevant in 2010 ?

97. YES

98. EBCTCG OVERVIEW
Tamoxifen
 5 +/- 5 years
 30% - 40% in recurrence
 in deaths

99. EBCTCG OVERVIEW
AIs
 Better than Tam
 for all subgroups
 % in recurrence
 0 – 25% in BC mortality

100.  ? Stronger effect after two years of tamoxifen
EBCTCG OVERVIEW
AIs
 ? Stronger effect after two
years of tamoxifen

101. EBCTCG OVERVIEW
Chemotherapy vs None
 CMF/AC
 20 – 30% recurrence
 – 30% BC mortality
A vs CMF

102. EBCTCG OVERVIEW
 Adriamycin vs Standard CMF
 10 – 20% recurrence
 – 20% mortality

103. EBCTCG OVERVIEW
Taxanes vs Non-Taxanes
 10 – 20% recurrence
 % BC mortality

104. EBCTCG OVERVIEW
 Natural History of Breast Cancer
 ER/PgR +ve
 ER and PgR -ve

105. EBCTCG OVERVIEW
 By having all data
 avoids publication bias
 gives average effect size
 clarifies time frames of effects
 process / outcomes both useful

106. EBCTCG OVERVIEW  Future – Yes  Publications  2 on radiation results
 one on chemotherapy
2011
 one on tamoxifen
 one on AIs
 Meet Again September 19-22, 2012

111. EBCTCG OVERVIEW  Future – Yes  Publications  2 on radiation results
 one on chemotherapy
2011
 one on tamoxifen
 one on AIs
 Meet Again September 19-22, 2012

112. EBCTCG September 2010. Preliminary results