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Extending adjuvant therapy
beyond 5 years
William Gradishar
(Feinberg School of Medicine, Northwestern University, Chicago, IL, USA)
Thousands of patients currently
completing tamoxifen therapy
• Most women on adjuvant endocrine therapy in
the EU (> 450,000) are on tamoxifen (> 300,000)1
• Estimated 80,000–100,000 patients finish 5 years
of tamoxifen each year in the EU1
• These women exposed to continuing risk of relapse
– Majority of breast cancer deaths and recurrences
occur post-tamoxifen2
• Risk of late recurrence (> 5 years after diagnosis)
particularly high in women with HR+ disease3
1Fletcher-Louis
M, Ireland S. Onkos Study 48: Breast Cancer. Decision Resources Inc., Waltham, MA; 2000
2Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
3Saphner et al. J Clin Oncol 1996;14:2738–46
Most breast cancer recurrences
and deaths occur post-tamoxifen
Recurrences
15%
100
17%
9%
85.2
80
68.2
73.7
60
54.9
40
Tamoxifen
Control
20
% of patients
% of patients
Breast cancer deaths
18%
100
91.4
80
87.8
73.0
60
64.0
40
Tamoxifen
Control
20
0
0
0
5
10
Years
15
0
5
10
15
Years
Adapted with permission. Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
RFS continues to decrease
regardless of ER/PgR status
N+ and N– disease
Proportion disease-free
1.0
0.9
ER/PgR– (n = 430)
0.8
0.7
0.6
ER+ and/or PgR+ (n = 778)
0.5
p < 0.001
0.4
5
•
10
15
Years post-diagnosis
20
Late recurrences (> 5 years) more frequent in ER+ and/or PgR+ tumors
RFS: relapse-free survival
Hortobagyi et al. Proc ASCO 2004;23:23s(abstract 585)
MA.17: trial design
Randomization
(all patients disease-free)
0–3
months
Letrozole 2.5 mg qd (n = 2582)
Tamoxifen
Placebo qd † (n = 2586)
Approx. 5 years adjuvant
5 years extended adjuvant
• Eligibility criteria: postmenopausal, HR+/unknown, recurrence-free,
completed 4.5–6 years’ tamoxifen, ECOG PS 0–2
• Primary endpoint: DFS (ipsilateral, chest wall, local, metastatic, contralateral new)
• Secondary endpoints: OS, rate of contralateral BC, safety, QoL
• Substudies: BMD/bone markers, lipid profile
Goss et al. J Natl Cancer Inst 2005;97:1262–71
Goss et al. N Engl J Med 2003;349:1793–802
MA.17: initial and final analyses
Toxicity Efficacy
2003
March
1998
Aug Oct
2003
2004
Interim analysis1
Final analysis2
DFS events
207
247
Deaths
73
113
No. of patients at 40 months
384
1115
Median follow-up (months)
27.5
30
1Goss
et al. N Engl J Med 2003;349:1793–802; 2Goss et al. J Natl Cancer Inst 2005;97:1262–71
DFS: letrozole significantly
decreased risk of recurrence
% of patients
100
80
60
p = 0.00004
40
20
Letrozole
Placebo
0
0
No. at risk (letrozole) 2583
No. at risk (placebo) 2587
10
20
30
40
50
Time from randomization (months)
2497
2489
1905
1874
1110
1075
541
519
176
164
60
6
8
Goss et al. Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentation
Goss et al. J Natl Cancer Inst 2005;97:1262–71
Distant DFS: letrozole reduced
risk of distant metastases by 40%
All patients
% of patients
100
80
p = 0.002
60
40
Letrozole
Placebo
20
0
0
10
20
30
40
50
60
Time from randomization (months)
No. at risk (letrozole)
No. at risk (placebo)
2583
2587
2497
2489
1905
1874
1110
1075
541
519
176
164
6
8
Goss et al. Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentation
Goss et al. J Natl Cancer Inst 2005;97:1262–71
OS: letrozole reduced mortality
by 39% in patients with N+ disease
100
% Surviving
80
60
Letrozole
p = 0.04
Placebo
40
20
0
0
10
20
30
40
50
Months from randomization
60
• No significant increase in OS in total study population or N– disease
• Similar reduction in breast cancer events occurred in N– and N+ disease
Goss et al. J Natl Cancer Inst 2005;97:1262–71
MA.17: summary of key efficacy results
N+
disease
N–
disease
HR 0.61*
(95% CI 0.45–0.84)
HR 0.53*
(95% CI 0.36–0.78)
HR 0.61*
(95% CI 0.38–0.98)
DFS*
Distant
DFS*
OS
HR 0.45*
(95% CI 0.27–0.75)
HR 0.63
(95% CI 0.31–1.27)
HR 1.52
(95% CI 0.76–3.06)
*Statistically significant benefit of letrozole
 A similar reduction in local recurrences, new primaries, and distant
recurrences occurred in patients with N+ and N– disease
Goss et al. Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentation
Goss et al. J Natl Cancer Inst 2005;97:1262–71
MA.17 safety profile
Letrozole is comparable to placebo
% of patients
Letrozole
Placebo
p value
Hot flashes
58
54
0.003
Arthritis/arthralgia
25
21
< 0.0001
Muscle pain
15
12
0.04
Vaginal bleeding
6
8
0.005
Hypercholesterolemia
16
16
0.79
Cardiovascular events
6
6
0.76
Osteoporosis
8
6
0.003
Discontinuations due to AEs
5
4
0.02
Discontinuations for other reasons
4
5
0.1
*90% of AEs grade 1or 2
Goss et al. J Natl Cancer Inst 2005;97:1262–71
ABSCG-6a extended adjuvant trial
• Postmenopausal women completing 5 years’ tamoxifen
(n = 450) or tamoxifen plus aminoglutethimide (n = 409)
• Re-randomized to anastrozole or no treatment for
3 years (no placebo control)
• Median follow-up 5 years
• Anastrozole significantly reduced recurrence:
HR = 0.64, 95% CI 0.41–0.99, p = 0.047
• No significant difference in OS
• No safety data reported
Jakesz et al. J Clin Oncol 2005;23:10S(abstract 527)
NCIC CTG MA.17 update
• Duration of therapy
• Ingle et al. Breast Cancer Res Treat
March 2006 published online
• Post-unblinding analysis
• Update of Goss et al. Breast Cancer Res Treat
2005;94:S10(abstract 16)
Increasing benefit of letrozole with
longer duration of treatment
• Purpose
•
To assess impact of duration of treatment on outcomes for
extended adjuvant letrozole vs placebo in MA.17 as
measured by hazard ratios over 48 months
• End points: DFS (primary), distant DFS, OS
• Cohorts evaluated
•
•
•
All randomized patients (n = 5170)
N+ (n = 2360)
N– (n = 2568)
Ingle et al. Breast Cancer Res Treat Mar 2006 published online
Hazard rates for DFS over 48 months
(letrozole vs placebo)
0.0035
Placebo
Hazard rate
0.0030
0.0025
0.0020
0.0015
Letrozole
0.0010
0.0005
Hazard
ratio
0.52
0.35
0.45
0.19
0.0000
0
6
12
18
24
30
36
42
48
464
436
244
231
Months after randomization
Letrozole
Placebo
2583
2587
2531
2528
2425
2409
2060
2020
1555
1530
1110
1075
768
723
Ingle et al. Breast Cancer Res Treat Mar 2006 published online
Increasing benefit of letrozole with
longer duration of treatment: DFS
0.8
Upper 95%
confidence limit
Ratio
estimate
Hazard ratio
0.6
0.52
I
0.4
Lower 95%
confidence limit
0.19
I
0.2
p < 0.0001 for HR trends based on
time-dependent Cox model
0.0
0
6
12
18
24
30
36
Months after randomization
42
48
Ingle et al. Breast Cancer Res Treat Mar 2006 published online
Increasing benefit of letrozole with
longer duration of treatment: summary
N+
disease
N–
disease
HR ~0.6–~0.25
p = 0.0004
HR ~0.35–~0.25
p = 0.0005
HR ~0.55–~0.4
p = 0.038
DFS
Distant DFS
OS
HR 0.52–0.19
p < 0.0001
HR 0.43–0.21
p = 0.0013
HR 0.87–0.79
p = NS
HR ~0.7–~0.5
p = 0.027
HR ~0.25–~0.2
p = NS
HR ~2.0–~2.25
p = NS
*Statistically significant benefit of letrozole
• Significant improvements in HR between 12 and 48 months of letrozole vs
placebo for DFS and distant DFS overall, for all three endpoints in N+ disease
and for DFS in N– disease
Ingle et al. Breast Cancer Res Treat Mar 2006 published online
Increasing benefit of letrozole with
longer duration of treatment: conclusions
• Recent guidelines recommend
• ASCO 2004: a minimum of 2.5 years of extended letrozole
consistent with median follow-up of MA.17
• NCCN 2006: 5 years of letrozole following 5 years of tamoxifen
• St Gallen: switch to AI (letrozole) after 5 years of tamoxifen
• Ingle et al. study shows that, at least to about 48 months,
longer duration of letrozole is associated with greater benefit
• Based on these data* extended adjuvant letrozole therapy
should be for at least 4 years
Winer et al. J Clin Oncol 2005;23:1609–10; Goldhirsch et al. Ann Oncol 2005;16:1569–83; National Comprehensive Cancer
Network. Clinical Practice Guidelines in Oncology – v.2.2006, Breast Cancer. At:
www.nccn.org/professionals/physician_gls/PDF/breast.pdf;
*Ingle et al. Breast Cancer Res Treat Mar 2006 published online
Late extended adjuvant therapy
Analysis post-unblinding
Tamoxifen
n = 5187
Letrozole n = 2593
Letrozole (Let) n = 2457
Placebo n = 2594
No Letrozole (Plac) n = 613
Letrozole (Plac–Let) n = 1655
5 years
0–3
mo
Median F/U
(months)
30
Unblinding
54
Purpose: compare placebo–letrozole vs placebo to determine
benefits/safety of starting letrozole after prolonged periods (1–5 years)
off tamoxifen
Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)
Significantly different baseline
characteristics (all p < 0.01)
Plac–Let
Plac
120
Per cent
100
80
92
96
80
66
57
60
49
40
49
33
20
0
Age < 70 years
ECOG = 0
N–
Prior CTx
Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)
Late extended adjuvant therapy
analysis post-unblinding: DFS
Percentage disease-free
100
80
Plac–Let
Plac
60
40
DFS
Adjusted HR: 0.31 (0.18–0.55); p < 0.0001
20
0
0
20
40
60
Time from randomization (months)
80
Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)
Late extended adjuvant therapy
analysis post-unblinding
Hazard ratio
(placebo–letrozole vs placebo)
Summary of efficacy
0.6
0.53
0.5
p = 0.05
0.4
0.31
0.3
0.28
p < 0.0001
0.23
p = 0.002
0.2
p = 0.012
0.1
0
DFS
Distant DFS
OS
CBC
Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)
Late extended adjuvant therapy
analysis post-unblinding
Adverse events
p = 0.007
4.5
Incidence (%)
4.0
p = 0.60
p = 0.84
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Fracture
New osteoporosis
Plac–Let
CV disease
Plac
Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)
MA.17: updated analysis safety conclusions
• Letrozole associated with low-grade estrogen
depletion symptoms
• Overall QoL unaffected (in ~3600 women)
• No changes in CV events or lipid profiles
• Mild decreases in bone density, but no significant
increase in fracture risk
• Bone density changes can be easily monitored
and corrected
• AEs with letrozole after unblinding similar to those in
the main trial for osteoporosis, fractures, and CV disease
MA.17: updated analysis efficacy conclusions
• Letrozole significantly increased DFS and distant DFS
(all patients) and OS (patients with N+ disease)
• Benefit with letrozole increased with treatment duration
• Late extended adjuvant letrozole (after prolonged treatment-free
interval) significantly improved all outcomes
• Women with long tamoxifen-free periods should be
considered for letrozole therapy
• International guidelines*: based on MA.17 findings
postmenopausal women with HR+ EBC finishing
5 years of tamoxifen should consider treatment with letrozole
• Updated analysis suggests extended adjuvant letrozole therapy
should be for at least 4 years
*Winer et al. J Clin Oncol 2005;23:1609–10; Goldhirsch et al. Ann Oncol 2005;16:1569–83; National Comprehensive Cancer
Network. Clinical Practice Guidelines in Oncology – v.2.2006, Breast Cancer. At:
www.nccn.org/professionals/physician_gls/PDF/breast.pdf
MA.17R re-randomization study
n= 800
MA.17
Placebo
n = 900
Tamoxifen
Letrozole*
Non-study patients
MA.17
+
Non-study patients
0
5
10
n = 900
MA.17R
15
Years post-surgery
*Women remaining disease-free
Goss et al. Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentation

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