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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 mortali...
Adjuvant tamoxifen
• 5 years of tamoxifen has been the gold standard for
many years
– Reduction in annual risk of recurren...
Breast cancer recurrence and mortality
after 5 years of tamoxifen
EBCTCG Lancet 2005;365:1687–717
Control
About 5 years of...
Adjuvant tamoxifen
• 5 years of tamoxifen has been the gold standard for
many years
– Reduction in annual risk of death by...
Annual risk of recurrence by nodal status
Saphner et al. J Clin Oncol 1996;14:2738–46
Recurrencehazardrate
0
0.1
0.2
0.3
N...
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
Recurrencehazardrate
ER– (n = 1305...
Years from randomization
0 2 3 4 51
Proportionfailing(%)
LET
TAM
13.6%
10.2%
8.1%
6.2%
5-year difference (LET-TAM): –3.4%
...
Adjuvant tamoxifen
• 5 years of tamoxifen has been the gold standard for
many years
– Reduction in annual risk of death by...
Recurrences Breast cancer deaths
Years
85.2
73.7
0
20
40
60
80
100
0 5 10 15
Tamoxifen
Control
15% 17%
0
20
40
60
80
100
0...
Meta-analysis: risk of recurrence remains
high despite adjuvant tamoxifen therapy
0
5
10
15
20
25
30
35
40
45
50
Tamoxifen...
Reducing late relapses: extending
adjuvant therapy beyond 5 years
• Patients with ER+ breast cancer are at a particularly ...
Randomized trials of extended
adjuvant tamoxifen beyond 5 year
Study Patients N Follow-up
(median)
Outcome
Fisher et al. J...
NSABP B-14: no efficacy benefit of
extending tamoxifen beyond 5 years
Fisher et al. J Natl Cancer Inst 2001;93:684–90
DFS ...
Reducing late relapses: extending
adjuvant therapy beyond 5 years
• Patients with ER+ breast cancer are at a particularly ...
MA.17: trial design
Goss et al. J Natl Cancer Inst 2005;97:1262–
71
Goss et al. N Engl J Med 2003;349:1793–802
Randomizati...
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....
ABCSG-6a: EFS
(Recurrence of BC or new primary BC)
Jakesz et al. J Clin Oncol 2005;23:10s(abstract 527)
Anastrozole is not...
Reducing late relapses: extending
adjuvant therapy beyond 5 years
• Option 1
– Give tamoxifen for longer
 Option 2
– Give...
Long-term toxicities of extended
endocrine therapies
 Menopausal symptoms poorer quality of life
• Vasomotor symptoms (ho...
NSABP B-42: study design
Trial still pending*
Letrozole vs placebo after 5 years of an AI
or sequential tamoxifen / AI
AI ...
MA.17R: design
Primary endpoint: DFS
Secondary endpoints: OS, incidence of contralateral breast cancer,
long-term clinical...
EORTC-BIG MINDACT trial design
6000 women with N– disease
Evaluate clinical-pathological risk and 70-gene signature risk
C...
Summary (1): risk of recurrence
in early breast cancer
• Risk of recurrence highest in first 2–3 years but remains
substan...
Summary (2): risk of recurrence
in early breast cancer
• Extended adjuvant therapy with an AI seems a reasonable
treatment...
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  1. 1. These slides were released by the speaker for internal use by Novartis
  2. 2. Breast cancer recurrence: a continuing problem Tanja Cufer (Institute of Oncology, Ljubljana, Slovenia) ˇ
  3. 3. EBCTCG Lancet 2005;365:1687–717 NODE NEGATIVENODE NEGATIVE NODE NEGATIVENODE NEGATIVE Breast cancer recurrence and mortality without adjuvant medication
  4. 4. 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
  5. 5. Breast cancer recurrence and mortality after 5 years of tamoxifen EBCTCG Lancet 2005;365:1687–717 Control About 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 Breastcancermortality(%) 0 10 20 0 30 40 60 50 10 5 15 Years 11.9 25.7 8.3 17.8 25.6 Recurrence(%) 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
  6. 6. 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;365:1687–717 2. Saphner et al. J Clin Oncol 1996;14:2738–46
  7. 7. Annual risk of recurrence by nodal status Saphner et al. J Clin Oncol 1996;14:2738–46 Recurrencehazardrate 0 0.1 0.2 0.3 N0 N1–3 N4+ 0 1 2 3 4 5 6 7 8 9 10 11 12 Years • Patients receiving adjuvant chemotherapy or endocrine therapy
  8. 8. 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 Recurrencehazardrate 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
  9. 9. Years from randomization 0 2 3 4 51 Proportionfailing(%) 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
  10. 10. 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;365:1687–717 2. Saphner et al. J Clin Oncol 1996;14:2738–46
  11. 11. Recurrences Breast cancer deaths Years 85.2 73.7 0 20 40 60 80 100 0 5 10 15 Tamoxifen Control 15% 17% 0 20 40 60 80 100 0 5 10 15 87.8 Years Tamoxifen Control 9% 18% 91.4 %ofpatients %ofpatients 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
  12. 12. Meta-analysis: risk of recurrence remains high despite adjuvant tamoxifen therapy 0 5 10 15 20 25 30 35 40 45 50 Tamoxifen Control %ofrecurrences 5 years post-diagnosis 10 years post-diagnosis 15 years post-diagnosis EBCTCG Lancet 2005;365:1687–717
  13. 13. 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
  14. 14. 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
  15. 15. 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 Placebo Tamoxifen Years after tamoxifen p = 0.03 100 90 80 70 60 50 %ofpatients 0 5 7 82% 78% 1 2 4 63 0 5 100 90 80 70 60 50 7 %ofpatients Placebo Tamoxifen 94% 91% 1 32 4 6 Years after tamoxifen • Tamoxifen demonstrated higher rates of endometrial cancer and more deaths from ischemic heart disease and cerebrovascular disease
  16. 16. 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
  17. 17. MA.17: trial design Goss et al. J Natl Cancer Inst 2005;97:1262– 71 Goss et al. N Engl J Med 2003;349:1793–802 Randomization (all patients disease-free) Tamoxifen Approx. 5 years’ adjuvant 5 years’ extended adjuvant 0–3 months 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
  18. 18. 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 Hazardrate Months after randomization Letrozole PlaceboPlacebo Letrozole 2583 2531 2425 2060 1555 1110 768 464 244 Placebo 2587 2528 2409 2020 1530 1075 723 436 231
  19. 19. 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 NR 0.64 (0.41–0.99) 0.047 Events 30 56 — —
  20. 20. 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
  21. 21. 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
  22. 22. NSABP B-42: study design Trial still pending* Letrozole vs placebo after 5 years of an AI or sequential tamoxifen / AI AI x 5 years AI x 2–3 yrsTam x 2–3 yrs Letrozole x 5 years Placebo x 5 years 5 years’ further adjuvant Randomization (Disease-free) *n = 5000; primary endpoint = DFS
  23. 23. MA.17R: design Primary endpoint: DFS Secondary 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
  24. 24. EORTC-BIG MINDACT trial design 6000 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 HIGH 70-gene LOW Clin-path LOW 70-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
  25. 25. 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
  26. 26. 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

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