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These slides were released by the speaker for internal use by Novartis

These slides were released by the speaker for internal use by Novartis. Breast cancer recurrence: a continuing problem. ˇ. Tanja Cufer (Institute of Oncology, Ljubljana, Slovenia). Breast cancer recurrence and mortality without adjuvant medication. NODE NEGATIVE. NODE NEGATIVE.

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These slides were released by the speaker for internal use by Novartis

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  1. These slides were released by the speaker for internal use by Novartis

  2. Breast cancer recurrence: a continuing problem ˇ • Tanja Cufer • (Institute of Oncology, Ljubljana, Slovenia)

  3. Breast cancer recurrence and mortality without adjuvant medication NODE NEGATIVE NODE NEGATIVE EBCTCG Lancet 2005;365:1687–717

  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. Recurrence Breast cancer mortality 60 60 50 50 45.0 38.3 40 40 34.8 26.5 30 30 33.2 Breast cancer mortality (%) Recurrence (%) 25.7 25.6 24.7 20 20 11.9 17.8 15.1 10 10 8.3 0 0 0 5 10 15 0 5 10 15 Years Years Breast cancer recurrence and mortality after 5 years of tamoxifen 15-year gain 11.8% Logrank 2p < 0.00001 15-year gain 9.2% Logrank 2p < 0.00001 Control About 5 years of tamoxifen EBCTCG Lancet 2005;365:1687–717

  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. Annual risk of recurrence by nodal status 0.3 N0 N1–3 N4+ 0.2 Recurrence hazard rate 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years • Patients receiving adjuvant chemotherapy or endocrine therapy Saphner et al. J Clin Oncol 1996;14:2738–46

  8. 0.3 ER+ (n = 2257) ER– (n = 1305) 0.2 Recurrence hazard rate 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years Annual risk of recurrence by ER status • 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. 20 5-year difference (LET-TAM): –3.4% p < 0.001 13.6% 15 TAM 8.1% LET Proportion failing (%) 10 10.2% 5 6.2% 0 0 1 2 3 4 5 Years from randomization BIG 1-98: cumulative incidence of breast cancer relapse* *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 Letrozole is not licensed in all European countries for use in early adjuvant setting

  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. Recurrences Breast cancer deaths 15% 17% 9% 18% 100 100 91.4 85.2 73.0 80 80 87.8 68.2 73.7 60 60 64.0 % of patients % of patients 54.9 40 40 Tamoxifen Control Tamoxifen Control 20 20 0 0 0 5 10 15 0 5 10 15 Years Years More than half of all breast cancer recurrences and deaths occur post-tamoxifen EBCTCG Lancet 2005;365:1687–717

  12. 5 years post-diagnosis 15 years 10 years post-diagnosis post-diagnosis Meta-analysis: risk of recurrence remains high despite adjuvant tamoxifen therapy 50 45 40 35 30 25 % of recurrences 20 15 10 5 0 Tamoxifen Control EBCTCG Lancet 2005;365:1687–717

  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. Randomized trials of extended adjuvant tamoxifen beyond 5 year

  15. 100 94% 100 90 91% 90 80 82% % of patients 80 70 78% % of patients 70 60 Placebo Tamoxifen Placebo Tamoxifen 60 50 0 1 2 3 4 5 6 7 50 Years after tamoxifen 0 1 2 3 4 5 6 7 NSABP B-14: no efficacy benefit of extending tamoxifen beyond 5 years DFS OS p = 0.03 p = 0.07 Years after tamoxifen • Tamoxifen demonstrated higher rates of endometrial cancer and more deaths from ischemic heart disease and cerebrovascular disease Fisher et al.J Natl Cancer Inst 2001;93:684–90

  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. Randomization (all patients disease-free) 0–3months Letrozole 2.5 mg qd (n = 2582) Tamoxifen Placebo qd † (n = 2586) Approx. 5 years’ adjuvant 5 years’ extended adjuvant MA.17: trial design • 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: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

  18. MA.17: HRs for DFS over follow-up period Placebo Hazard rate Letrozole Months after randomization Letrozole 2583 2531 2425 2060 1555 1110 768 464 244 Placebo 2587 2528 2409 2020 1530 1075 723 436 231 Ingle et al. Breast Cancer Res Treat 2006; E-pub 16 March

  19. ABCSG-6a: EFS(Recurrence of BC or new primary BC) At median follow-up of5 years: • 3 years of extended adjuvant treatment with anastrozole reduced the risk of recurrence by 36% • No significant difference in overall survival Jakesz et al.J Clin Oncol 2005;23:10s(abstract 527) Anastrozole is not licensed in this indication

  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. 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. NSABP B-42: study designTrial still pending* Letrozole vs placebo after 5 years of an AI or sequential tamoxifen / AI Randomization (Disease-free) Letrozole x 5 years AI x 5 years Placebo x 5 years Tam x 2–3 yrs AI x 2–3 yrs 5 years’ further adjuvant *n = 5000; primary endpoint = DFS

  23. MA.17R: design Rerandomization (Disease-free) Letrozole 2.5 mg qd Letrozole Placebo qd 5 years’ extended adjuvant 5 years’ further extended adjuvant Primary endpoint: DFS Secondary endpoints: OS, incidence of contralateral breast cancer, long-term clinical and laboratory safety, overall QoL, menopausal QoL

  24. EORTC-BIG MINDACT trial design6000 women with N– disease Evaluate clinical-pathological risk and 70-gene signature risk 13% 55% 32% n = 780 n = 3300 Discordant cases Clin-path and 70-gene both LOW risk Clin-path and 70-gene both HIGH risk Clin-path HIGH 70-gene LOW Clin-path LOW 70-gene HIGH R1 n = 1920 Use Clin-path risk to decide chemo or not Use 70-gene risk to decide chemo or not Chemotherapy Endocrine therapy Tam x 2y→ Let x 5 y Letrozole x 7 y

  25. Summary (1): risk of recurrence in early breast cancer • Risk of recurrence highest in first 2–3 years butremains substantial even 5–10 years after diagnosis, particulary in HR+ disease • Adjuvant tamoxifen substantially reduces risk of recurrencebut 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. 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 sideeffects) and translational research capable of identifing patientswho may benefit most from extended treatment

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