1. Endocrinoterapia adiuvante del carcinoma nel 2008
Ritmi circadiani e qualità di vita: actigrafia e uovi orizzonti nel carcinoma della mammella
Mediterranean Scholl of Oncology
Endocrinoterapia adiuvante del carcinoma nel 2008
Cecilia Nisticò
Dipartimento di Oncologia Medica
Oncologia Medica C
Direttore: Prof. E. Terzoli
IRE - Istituto Nazionale Tumori
Regina Elena
Roma
Roma, 28 Novembre 2008

2. Breast Cancer Treatment
Final Outcomes:
Adjuvant setting
Treatment Goal: to Cure
Advanced Disease
Treatment Goal: to Care

3. Adjuvant Therapy - Early Breast Cancer -
Chemotherapy
Endocrine therapy
Biologic targeted therapy
Bisphosphonates
Organ specific therapy

4. Recent decrease in UK and USA breast cancer mortality at ages 35­69 years
Adj CTX
Adj HT
Screening
Modified from Peto et al. Lancet 355:1822, 2000

6. 13%
18%
25%
30%
12%
15% !

8. Benefits from Adjuvant Systemic Therapy
It is estimated that
Optimal chemotherapy would reduce annual odds of recurrence by about 50%-60%
Optimal endocrine therapy would reduce annual odds of recurrence by about 60%-70%
Trastuzumab would reduce annual odds of recurrence by 45%-55%
Zoledronic acid would reduce odds of recurrence by about 36%
Reductions in odds of mortality are somewhat more modest because of competing causes of death

9. Benefits from Adjuvant Systemic Therapy
Benefits of endocrine therapy are restricted to ER +/or PgR+ tumors
Can we predict response to individual endocrine agents?
Optimal endocrine therapy would reduce annual odds of recurrence by about 60%-70%
Sequential administration of chemotherapy followed by endocrine therapy provides optimal benefit for the overall group
Can we identify patients in this group who do not benefit from the addition of chemotherapy?

10. Davidson N, ASCO 2007

11. Breast Cancer Recurrence, % Breast Cancer Mortality, %
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 15-Year Reductions in Recurrence and Disease-Specific Mortality
Meta-analysis of 194 randomized trials
Meta-analysis of 144,939 women
Treatment Comparison
Breast Cancer Recurrence, %
Log Rank 2P
Breast Cancer Mortality, %
Tamoxifen 5 yrs vs none, ER-positive women
11.8
<
9.2
EBCTCG. Lancet. 2005;365:

12. EFFICACY OF ADJUVANT TAM Relative reduction in odds of
5 YEARS, ER +/UNKNOWN
Relative reduction in odds of
AGE
RECURRENCE
DEATH
< 50
34%(+6%)
24%(+7%)
50-59
35%(+6%)
20%(+7%)
60-69
50%(+5%)
27%(+5%)
> 70
38%(+18%)
p=.00001
26%(+15%) p=.00001
EBCTCG, Lancet 2005;365:

13. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
Polychemotherapy versus tamoxifen-treated ER+ disease, for entry age <50:
5-year probabilities of recurrence (ER+ includes 12% ER unknown)
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
Lancet 2005; 365: 1687–1717
EBCTCG Overview (2005)

14. Davidson N, ASCO 2007

15. Davidson N, ASCO 2007

16. Davidson N, ASCO 2007

17. Davidson N, ASCO 2007

18. 5 yrs

19. Davidson N, ASCO 2007

20. Breast Cancer Recurrence, % Breast Cancer Mortality, %
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 15-Year Reductions in Recurrence and Disease-Specific Mortality
Meta-analysis of 194 randomized trials
Meta-analysis of 144,939 women
Treatment Comparison
Breast Cancer Recurrence, %
Log Rank 2P
Breast Cancer Mortality, %
Ovarian ablation or suppression
vs none
4.3
.00001
3.2
.004
EBCTCG. Lancet. 2005;365:

21. Breast Cancer Recurrence, % Breast Cancer Mortality, %
EBCTCG. Lancet. 2005;365:
Treatment Comparison
Breast Cancer Recurrence, %
Log Rank 2P
Breast Cancer Mortality, %
Ovarian ablation or suppression vs none
4.3
.00001
3.2
.004
EBCTCG Overview (2005)

23. Ovarian function suppression (OFS) was accepted as an alternative where tamoxifen was contraindicated.
Retrospective subset analysis suggests that women younger than 40 years seemed to benefit from the addition of goserelin to CMF.

25. Retrospective subset analysis suggests that women younger than 40 years seemed to benefit from the addition of goserelin to CAF.
J Clin Oncol 2005;23:

28. Davidson N, ASCO 2007

30. TAM standard all pts
TAM for 5 yrs
Chemo + TAM better than whatever alone
OS beneficial in youger pts continuing to menstruate after chemo or TAM
Optimal LHRH duration uncertain
AIs in Meno after chemo: caution!
No data of AIs + LHRH vs TAM (RCTs ongoing)

31. AIs & TAM: mechanism of action

37. Hormonal Adjuvant Treatment Strategies in Early Breast Cancer
“Up-Front” R
Tamoxifen
Aromatase Inhibitors
5 years
“Extended Switch”
Placebo R
Tamoxifen
Aromatase Inhibitors
10 years
“Early Switch”
Tamoxifen R
Tamox.
Arom. Inhibitors
2-3 years
3-2 years

38. RCTs – AIs Adjuvant BC DFS/EFS OS Strategy RCTs Pts Update
Median FU (mo.) AI
Efficacy [HR, p]
DFS/EFS OS
Up-Front
ATAC
6186
Lancet 2006 68
ANA
0.87 (0.01)
0.85 (0.7)
BIG-1-98
4922
JCO 2007 51
LET
0.82 (0.007)
0.91 (>0.05)
“Early” Switch
ITA-1
380
JCO 2001 61
AGT
NR (0.6)
NR (0.005)
ITA-2
448
Ann Oncol 2006 64
0.57 (0.005)
0.56 (0.1)
IES
4742
Lancet 2007 56
EXE
0.76 (0.0001)
0.85 (0.08)
ABCSG8/ARNO
3224
Lancet 2005 28
0.60 (0.0009)
NR (0.16)
“Late” Switch
MA.17
5157
JNCI 2005 30
0.58 (0.001)
0.82 (0.3)
ABCSG 6a
856
JNCI 2007 60
0.64 (0.047) NR
NSABP B-33
1598
SABCS 2006
0.68 (0.07)
1.20 (0.63)

39. Adjuvant Aromatase Inhibitors
Study
therapy
f.u. HR
Abs d
ATAC 03
upfront 4
0.82 3%
ITA 04
switch 3
0.36
5.3%
IES 04
2.7
0.68
4.7%
MA17 04
extended
2.5
0.58
5 %
ARNO -ABCSG 04
0.6
BIG 05
2.4
0.81
2.6%

40. Aromatase Inhibitors Adjuvant Trials. Distant metastases
Study
Reduction in distant metastases p
ATAC Lancet 05
14%
.01
BIG 1-98 NEJM 05
27%
.0012
IES NEJM 04
34%
.0004
ARNO/ABCSG Lancet 05
39%
.0067
ITA JCO 05
51%
.06
MA 17 JNCI 05
40%
.002

41. ATAC: recurrences* before 2.5 years (HR+ patients)25
HR+ A
282 T
370 HR
0.74
95% CI
(0.64–0.87)
p-value
0.0002
Patients (%) 20 15
‘Arimidex’ (A) 10
Tamoxifen (T) 5
In agreement with the 1998 EBCTCG overview of adjuvant tamoxifen trials, the endpoint of Time to Recurrence excludes death prior to recurrence
There was a significantly greater benefit with respect to recurrence for the anastrozole group than for the tamoxifen group.
As with disease-free survival, the absolute difference between treatment arms with respect to recurrence increased out beyond completion of treatment to 6 years. 1 2 3 4 5 6
Follow-up time (years)
At risk: A
2618
2540
2448
2355
2268
2014
830 T
2598
2516
2398
2304
2189
1932
774
Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:
* Censoring non-BC deaths before recurrence

42. Pre-defined adverse events*: ATAC Median follow-up 68 months
Hot flushes
p<0.0001
Vaginal bleeding
p<0.0001
Vaginal discharge
p<0.0001
Anastrozole
Endometrial cancer
p=0.02
Tamoxifen
Ischemic cerebrovascular events
p=0.03
Venous thromboembolic events
p=0.0004
Deep venous thromboembolic events
p=0.02
Joint symptoms
p<0.0001
Total fractures
p<0.0001 10 20 30 40 50
Incidence (%)
* Other Pre-defined AE’s with NO significant differences seen between groups:
Ischemic Cardiovascular Disease, Cataracts, Nausea & Vomiting, Mood Disturbances, Fatigue
ATAC Trialists’ Group. Lancet 2005;365:60-62

43. ATAC 100 mo.: SAEs: on and off treatment (Number – safety population)
On treatment
Off treatment
Serious adverse event
Anastrozole
Tamoxifen
Anastrozole
Tamoxifen
Treatment-related
153
284 49 57
Endometrial cancer 4 12 1
Myocardial infarction 34 33 26 28
Key point: The occurrence of any serious adverse events were similar in both arms but treatment-related serious adverse events were significantly* lower with anastrozole compared with tamoxifen during treatment. * Need to check if 153 vs. 284 is statistically significant
After treatment completion, treatment-related serious adverse events were similar leading to a lower overall prevalence for treatment-related serious adverse events for anastrozole in this study.
Endometrial cancer – The difference in endometrial cancer was statistically significantly lower with anastrozole compared with tamoxifen (5 vs 24 events, p=0.0004). MI – similar in both arms during treatment and after treatment completion. Cerebrovascular accidents – Lower number seen with anastrozole during treatment for those reported as serious compared with tamoxifen. Previously, for all AEs on treatment there is a significantly larger number of cerebrovascular accidents on tamoxifen and this is still the case in the final analysis of all AEs on treatment (see pre-specified table in back up)
Back-up slide information:
All adverse events occurring on treatment were recorded. After treatment (or up to 14 days after treatment termination) all fractures and serious adverse events continued to be recorded blindly up to the time of recurrence or death.
Cerebrovascular accident 20 34 22 20
Fracture episodes*
375
234
146
143
*A fracture episode comprised one or more fractures on the same day based on adverse events and serious adverse event reports 43

44. Predefined adverse events at any time on treatment or any severity
Anastrozole
(N = 3092)
Tamoxifen
(N = 3094)
Hot flushes
Nausea and vomiting
Fatigue / tiredness (asthenia)
Mood disturbances
Musculo-skeletal disorders
Vaginal bleeding
Vaginal discharge
Ischaemic cardiovascular disease
Ischaemic cerebrovascular event
Venous thromboembolic events
Deep venous thromboembolic events
Cataracts Carpal tunnel syndrome†
1102 (35.6)
394 (12.7)
578 (18.7)
599 (19.4)
1104 (35.7)
167 (5.4)
110 (3.6)
130 (4.2)
64 (2.1)
87 (2.8)
48 (1.6)
189 (6.1) 79 (2.5)
1263 (40.8)
358 (12.4)
544 (17.6)
555 (17.9)
915 (29.6)
319 (10.3)
409 (13.2)
106 (3.4)
91 (2.9)
141 (4.6)
75 (2.4)
218 (7.0)
22 (0.7)
Predefined side effects during treatment (or within 14 days of cessation) were very similar to those previously published,1 as 92% of patients had completed treatment by that time.
No new safety concerns were identified with longer follow-up.
Reference
1The ATAC Trialists' Group. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol 2006;7:
†included as a non-predefined adverse event of interest

45. Deaths according to treatment group (ITT population)
No. patients (%)
Cause of death
Total deaths
Deaths after recurrence
Deaths without recurrence
Cardiovascular
Cerebrovascular
Second primary non-breast cancer
Other
Anastrozole (n = 3125)
629 (20)
350 (11)
279 (9)
67 (2)
25 (1)
84 (3)
103 (3)
Tamoxifen (n = 3116)
624 (20)
382 (12)
242 (8)
66 (2)
29 (1)
60 (2)
87 (3)
No differences were seen in overall survival between treatment groups.
This may be partly because there was a non-statistically significant excess of deaths from other causes without a previous recurrence, which were a major component of overall survival (approximately 44% and 39% of the total deaths in the anastrozole and tamoxifen arms, respectively, were non-breast cancer deaths).

46. Fracture episode rates throughout the study
Annual fracture episode rates (%) 4
Anastrozole (A) Tamoxifen (T) 3 2 1
Key point: The increase in fracture rates appears to only be associated with the active treatment period and does not continue after treatment completion.
Q: Why is the carryover effect not seen with bones ?
Q: Were any of these patients receiving bisphosphonates or other relevant medications ? Q: How do these fracture rates compare with an age-matched population ? Q: Wouldn’t you expect the tamoxifen patients to begin to do worse with respect to fractures as they come off treatment and the protective effect of tamoxifen is lost ? 1 2 3 4 5 6 7 8 9
Time since randomization (years)
At risk: A T
2984
2976
2859
2824
2745
2699
2640
2572
2496
2419
2306
2208
2077
2000
1713
1645
702
659 46

47. ATAC 100: benefits continue and detrimental effects decline after treatment cessation
Time to recurrence
Fracture episode rates
Patients (%) 30
Annual fracture episode rates (%) 4
Tamoxifen (T)
Anastrozole (A)
Tamoxifen (T)
Anastrozole (A) 25
21.8% 3 20 15
12.5% 2
17.0% 10
The carryover effect seen for the efficacy endpoints is a reflection of the patients who have been “cured” plus those for whom the hormonal treatment prevents recurrences during therapy.
The likely mechanism of the increased fracture risk during the active phase of AI treatment is an increase in bone turnover and an acceleration of bone loss due to suppression of oestrogen (Eastell 2005).
There is evidence suggesting that the residual levels of oestrogen during menopause are important in maintaining bone health. Therefore when anastrozole treatment is completed and oestrogen levels rise, it is not surprising that the increased fracture risk disappears.
References
Eastell R, Hannon R. Long-term effects of aromatase inhibitors on bone. J Steroid Biochem Mol Biol. 2005;95: 1
9.7% 5
Absolute difference
2.8%
4.8% 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9
Follow-up time (years)
Time since randomisation (years)

48. BIG 1-98: cumulative incidence of breast cancer relapse
Proportion
failing (%) 20
5-year difference (L-T) = -3.4% (SE 1.2)
Cuminc p=0.0002 15
13.6%
Tamoxifen (T)
Letrozole (L) 10
8.1%
10.2% 5
6.2% 1 2 3 4 5
Time since randomisation (years)
SE = standard error
Thürlimann B et al. The Breast 2005;14:S3, abs S4

49. 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)

50. “Endometrial events” : Tamoxifen vs Aromatase Inhibitor
Hysterectomy
Endometrial
biopsies
ATAC
5% vs 1%
BIG 1
7.2% vs 1.9%

51. Trial Design RANDOMIZE Exemestane 5162* Post Treatment Follow-up
10335*
Tamoxifen
Tamoxifen
5294*
2-3 years study treatment
2-3 years
Start of study
Diagnosis
Total 5 years endocrine therapy
* Total women years

52. Results-event- and recurrence-free survival
Results-survival
Results-secondary outcomes
Cancer Treatment Reviews (2006) 32, 325– 332

53. TAM
AIs

54. Aromatase Inhibitors: Tox Issues
Bone Fractures
Cardiovascular Disease

55. Bone Health: Issues Protective Effects of TAM
Steroidal vs Non-Steroidal
Predictive role of BMD on fracture
Other fracture risk factors:
Patient’ characteristics
Bone turnover
Steroid use (abuse?)
What about bisphosphonates?

57. Fracture incidence

58. Incidence of fracture reported in different adjuvant aromatase inhibitor trials

59. CV Disease - Background References: 1Howell JSBMB 2005
The earliest publications of the RCTs using AIs provided conflicting results about the supposed higher risk of ischaemic cardiovascular toxicity
The pathogenesis of cardiac damage induced by AIs is still definitively unclear, while some pathways seem to be involved1:
The reduction of circulating estradiol
The unbalanced lipid metabolism
References: 1Howell JSBMB 2005

61. Lipid effects
Increase of:
Colestherol TG
LpA
LDL-C
Decrease of:
HDL-C

63. End-Points Primary Secondary Grade 3-4 as defined by NCIC
Cardiovascular Adverse Events Rate (CVAE)
Grade 3-4 as defined by NCIC
Secondary
Thromboembolic Adverse Events Rate (TEAE)
Cerebrovascular Adverse Events Rate (CBVAE)
In order to reduce heterogeneity across AIs, the analysis has been carried on considering:
all AIs (Overall analysis)
only 3rd generation AIs (CVAE-New)
Cuppone F, Cancer 2008

64. Selected RCTs
Cuppone F, Cancer 2008

65. Results – CVAE Rate (Cardiovascular Adverse Events)
Cuppone F, Cancer 2008

66. Results – CVAE Rate (Cardiovascular Adverse Events)
Cuppone F, Cancer 2008

67. Results - CVAE Rate-3rd Generation AIs (Cardiovascular Adverse Events)
Cuppone F, Cancer 2008

68. Results - CVAE Rate-3rd Generation AIs (Cardiovascular Adverse Events)
Cuppone F, Cancer 2008

69. Results – TEAE Rate (Thromboembolic Adverse Events)
Cuppone F, Cancer 2008

70. Results – CBVAE Rate (Cerebrovascular Adverse Events)
Cuppone F, Cancer 2008

71. …..free for lack of evidences
‘Trial’ Verdict
Controversial ‘Motive’ (not clear background)
Overestimated risk (0.5%) when AI vs TAM
No difference AIs vs placebo
Protective effect of TAM really ‘guilty’
…..free for lack of evidences

72. Cardio-protective effect of tamoxifen Metanalysis
32 trials comparing tamoxifen against a control group (metastatic, adjuvant, and prevention settings)
12 reported on myocardial infarction death
> 52,000 patients; 66% postmenopausal; mean age 54.8 yrs; mean treatment duration: 4.3 yrs; mean FU: 5.6 yrs
Relative risk ratio for fatal MIs (tamoxifen / control): 0.62 (95% CI: )
Risk ratio without the Scottish trial: 0.81 (95% CI: )
Braithwaite et al JGIM 2003;18:937-47

73. Myocardial Infarction

74. Cognitive Function, Fatigue and Menopausal Symptoms
HSCS*
(impairment)
FACT-F
FACT-ES
FACT-G
Adjuvant CT
16% 31 58 77
Control 4% 46 64 93
0.008
0.0001
* High Sensitivity Cognitive Screen
N Tchen, JCO 2005

75. LONG TERM TREATMENT WITH A.I.
POTENTIAL
BENEFIT
RISK
SUPERIOR EFFICACY
LOSS SEVER LONG TERM EFFECTS
Endometrial cancer
Thromboembolism
FEWER HYSTERECTOMIES
INCREASED FRACTURE RATE
TREATMENT-INDUCED BMD LOSS
ARTHROMYALGIA
LIPID DISTURBANCES
COGNITIVE DISTURBANCES
VASOMOTOR SIDE EFFECTS

76. Tailoring the treatment on the basis of the clinical histories?
Which patients should we deny the advantage linked to AI treatment on the basis of their characteristics?