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These slides were released by the speaker for internal use by Novartis
Breast cancer recurrence: a continuing problem
Tanja Cufer (Institute of Oncology, Ljubljana, Slovenia)
ˇ
EBCTCG Lancet 2005;365:1687–717
NODE NEGATIVENODE NEGATIVE NODE NEGATIVENODE NEGATIVE
Breast cancer recurrence and mortality without adjuvant medication
Adjuvant tamoxifen
• 5 years of tamoxifen has been the gold standard for many years– Reduction in annual risk of recurrence by 41% and
death by 34%
EBCTCG Lancet 2005;365:1687–717
Breast cancer recurrence and mortality after 5 years of tamoxifen
EBCTCG Lancet 2005;365:1687–717
ControlAbout 5 years of tamoxifen
15-year gain 9.2% Logrank 2p < 0.00001
15-year gain 11.8%Logrank 2p < 0.00001
34.8
Breast cancer mortality
Bre
as
t c
an
cer
mo
rta
lity
(%)
0 10
20
0
30
40
60
50
10
5 15
Years
11.9
25.7
8.3
17.8
25.6
Re
cu
rren
ce
(%
)
0 10
20
0
30
40
60
50
10
5 15
Years
Recurrence
45.0
33.2
38.3
24.7
26.5
15.1
Adjuvant tamoxifen
• 5 years of tamoxifen has been the gold standard for many years– Reduction in annual risk of death by 34% and
recurrence by 41%1
• But, the risk of recurrences and breast cancer mortality remain substantial, despite adjuvant therapy2
– Risk of relapse, even while on adjuvant therapy, is highest in the first 2–3 years
1. EBCTCG Lancet 2005;365:1687–7172. Saphner et al. J Clin Oncol 1996;14:2738–46
Annual risk of recurrence by nodal status
Saphner et al. J Clin Oncol 1996;14:2738–46
Re
cu
rren
ce
ha
zard
ra
te
0
0.1
0.2
0.3N0N1–3N4+
0 1 2 3 4 5 6 7 8 9 10 11 12Years
• Patients receiving adjuvant chemotherapy or endocrine therapy
Annual risk of recurrence by ER status
Years
0
0.1
0.2
0.3
0 1 2 3 4 5 6 7 8 9 10 11 12
Rec
urr
ence
haz
ard
rat
e
ER– (n = 1305)
ER+ (n = 2257)
• Over half of breast cancer recurrences occur > 5 years post-surgery
• The annual risk of late recurrence is particularly high in ER+ tumors
Saphner et al. J Clin Oncol 1996;14:2738–46
Years from randomization0 2 3 4 51
Pro
po
rtio
n f
aili
ng
(%
)
LET
TAM
13.6%
10.2%
8.1%
6.2%
5-year difference (LET-TAM): –3.4%p < 0.001
0
5
10
15
20
*Breast cancer event defined as ipsilateral or distant recurrence, or new contralateral breast primary
Thürlimann et al. N Engl J Med 2005;353:2747–57
BIG 1-98: cumulative incidence of breast cancer relapse*
Letrozole is not licensed in all European countries for use in early adjuvant setting
Adjuvant tamoxifen
• 5 years of tamoxifen has been the gold standard for many years– Reduction in annual risk of death by 34% and
recurrence by 41%1
• But, the risk of recurrences and breast cancer mortality remain substantial, despite adjuvant therapy2
– Risk of relapse, even while on adjuvant therapy, is highest in the first 2–3 years
– Over half of all recurrences and deaths occur after completion of 5 years of tamoxifen
1. EBCTCG Lancet 2005;365:1687–7172. Saphner et al. J Clin Oncol 1996;14:2738–46
Recurrences Breast cancer deaths
Years
85.2
73.7
0
20
40
60
80
100
0 5 10 15
TamoxifenControl
15% 17%
0
20
40
60
80
100
0 5 10 15
87.8
Years
TamoxifenControl
9% 18%
91.4
% o
f p
atie
nts
% o
f p
atie
nts
54.9
68.2 73.0
64.0
More than half of all breast cancer recurrences and deaths occur post-
tamoxifen
EBCTCG Lancet 2005;365:1687–717
Meta-analysis: risk of recurrence remains high despite adjuvant tamoxifen therapy
05
101520253035404550
Tamoxifen Control
% o
f re
curr
enc
es
5 yearspost-diagnosis10 yearspost-diagnosis
15 yearspost-diagnosis
EBCTCG Lancet 2005;365:1687–717
Reducing late relapses: extending adjuvant therapy beyond 5 years
• Patients with ER+ breast cancer are at a particularly high risk of late (> 5 years after surgery) relapse*
• Such patients could benefit from further endocrine therapy• Option 1
– Give tamoxifen for longer
*EBCTCG Lancet 2005;365:1687–717
Randomized trials of extended adjuvant tamoxifen beyond 5 year
Study Patients N Follow-up
(median)
Outcome
Fisher et al. JNCI 2001;93:684
N negative
ER+
Premeno = 25%
1152 7.5 years Worse DFS
No difference in OS, RFS
Stewart et al. JCNI 2001;93:456
Mostly N neg.
Mostly ER?
Premeno=25%
342 6 years Suggestion of harm
Tormey et al. JNCI 1996;88:1828
N positive Mostly ER+
Premeno=53%
193 5-6 years Suggestion of benefit
NSABP B-14: no efficacy benefit of extending tamoxifen beyond 5 years
Fisher et al. J Natl Cancer Inst 2001;93:684–90
DFS OS
p = 0.07
PlaceboTamoxifen
Years after tamoxifen
p = 0.03
100
90
80
70
60
50
% o
f pa
tien
ts
0 5 7
82%
78%
1 2 4 63 0 5
100
90
80
70
60
507
% o
f pa
tien
ts
PlaceboTamoxifen
94%
91%
1 32 4 6Years after tamoxifen
• Tamoxifen demonstrated higher rates of endometrial cancer and more deaths from ischemic heart disease and cerebrovascular disease
Reducing late relapses: extending adjuvant therapy beyond 5 years
• Patients with ER+ breast cancer are at a particularly high risk of late (> 5 years after surgery) relapse*
• Such patients could benefit from further endocrine therapy• Option 1
– Give tamoxifen for longer• Option 2
– Give other endocrine therapy after 5 years of tamoxifen
*EBCTCG Lancet 2005;365:1687–717
MA.17: trial design
Goss et al. J Natl Cancer Inst 2005;97:1262–71Goss et al. N Engl J Med 2003;349:1793–802
Randomization(all patients disease-free)
Tamoxifen
Approx. 5 years’ adjuvant 5 years’ extended adjuvant
0–3months
Letrozole 2.5 mg qd (n = 2582)
Placebo qd † (n = 2586)
• Eligibility criteria: postmenopausal, HR+/unknown, recurrence-free, completed 4.5–6 years’ tamoxifen, ECOG PS 0–2
• Primary endpoint: DFS (breast-only events)
• Secondary endpoints: OS, rate of contralateral BC, safety, QoL
• Substudies:Substudies: BMD/bone markers, lipid profile
MA.17: HRs for DFS over follow-up period
Ingle et al. Breast Cancer Res Treat 2006; E-pub 16 March
0.0000
0.0005
0.0010
0.0015
0.0020
0.0025
0.0030
0.0035
0 6 12 18 24 30 36 42 48
Ha
zard
ra
te
Months after randomization
Letrozole
PlaceboPlacebo
Letrozole 2583 2531 2425 2060 1555 1110 768 464244
Placebo 2587 2528 2409 2020 1530 1075 723 436231
ABCSG-6a: EFS(Recurrence of BC or new primary BC)
Jakesz et al. J Clin Oncol 2005;23:10s(abstract 527)Anastrozole is not licensed in this indication
At median follow-up of 5 years:• 3 years of extended adjuvant treatment with anastrozole
reduced the risk of recurrence by 36%• No significant difference in overall survival
Anastrozole (n = 387)
No treatment(n = 409)
Hazard ratio (95% Cl) p value
5-year DFS rate NR NR0.64
(0.41–0.99) 0.047
Events 30 56 — —
Reducing late relapses: extending adjuvant therapy beyond 5 years
• Option 1
– Give tamoxifen for longer Option 2
– Give other endocrine therapy after 5 years of tamoxifen
? Option 3
• Extended treatment with AIs beyond 5 or even 10 years from diagnosis
• Life-long endocrine therapy
Long-term toxicities of extended endocrine therapies
Menopausal symptoms poorer quality of life
• Vasomotor symptoms (hot flushes, sweating)
• Decreased sexual functioning
• Vaginal complaints (dryness, discharge, itching)
• Insomnia
• Fatigue
• Mood disturbances – emotional distress, anxiety
Osteoporosis
? Cardiovascular adverse events
NSABP B-42: study designTrial still pending*
Letrozole vs placebo after 5 years of an AI or sequential tamoxifen / AI
AI x 5 years
AI x 2–3 yrs
Tam x 2–3 yrs
Letrozole x 5 years
Placebo x 5 years
5 years’ further adjuvant
Randomization (Disease-free)
*n = 5000; primary endpoint = DFS
MA.17R: design
Primary endpoint: DFSSecondary endpoints: OS, incidence of contralateral breast cancer, long-term clinical and laboratory safety, overall QoL, menopausal QoL
Rerandomization (Disease-free)
Letrozole
Placebo qd
Letrozole 2.5 mg qd
5 years’ extended adjuvant 5 years’ further extended adjuvant
EORTC-BIG MINDACT trial design6000 women with N– disease
Evaluate clinical-pathological risk and 70-gene signature risk
Clin-path and 70-gene both HIGH
risk
Discordant cases
Clin-path HIGH70-gene LOW
Clin-path LOW70-gene HIGH
Clin-path and 70-gene both LOW
risk
Use Clin-path risk to decide chemo or not
Use 70-gene risk to decide chemo or not
55% 32% 13%
R1
Chemotherapy
n = 3300 n = 780
Endocrine therapy
n = 1920
Tam x 2 y→ Let x 5 y Letrozole x 7 y
Summary (1): risk of recurrence in early breast cancer
• Risk of recurrence highest in first 2–3 years but remains substantial even 5–10 years after diagnosis, particulary in HR+ disease
• Adjuvant tamoxifen substantially reduces risk of recurrence but may be detrimental for > 5 years
• Large proportion of recurrences and > 50% of breast cancer deaths occur after completion of adjuvant tamoxifen
Extended adjuvant treatment with AIs after 5 years of tamoxifen improves DFS, with an OS benefit observed in N+ disease
Summary (2): risk of recurrence in early breast cancer
• Extended adjuvant therapy with an AI seems a reasonable treatment option, but the optimal duration of AI therapy or sequence of AI / tamoxifen is not yet known
• Life-long endocrine therapy is a potential treatment option that should be explored in clinical trials with emphasis on cost:benefit (late side effects) and translational research capable of identifing patients who may benefit most from extended treatment