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

2. Breast cancer recurrence: a continuing problemˇ
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. Breast cancer recurrence and mortality after 5 years of tamoxifen10 20 30 40 60 50 5 15
Years
Recurrence
45.0
33.2
38.3
24.7
26.5
15.1
34.8
Breast cancer mortality
Breast cancer mortality (%) 10 20 30 40 60 50 5 15
Years
11.9
25.7
8.3
17.8
25.6
15-year gain 11.8%
Logrank 2p <
15-year gain 9.2%
Logrank 2p <
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 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. Annual risk of recurrence by ER status
Years
0.1
0.2
0.3 1 2 3 4 5 6 7 8 9 10 11 12
Recurrence hazard rate
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. BIG 1-98: cumulative incidence of breast cancer relapse*
Years from randomization 2 3 4 5 1
Proportion failing (%)
LET
TAM
13.6%
10.2%
8.1%
6.2%
5-year difference (LET-TAM): –3.4%
p < 0.001 10 15 20
LET, letrozole; TAM, tamoxifen.
In looking at the cumulative incidence of breast cancer events, letrozole reduced the 5‑year incidence from 13.6% to 10.2%, which was virtually identical to the reduction seen in the ATAC trial.
This slide shows cumulative breast cancer events: ipsilateral recurrence, contralateral breast cancer, and metastatic events on the y axis against time in years on the x axis. The data demonstrate significantly fewer relapses over time with letrozole, with the 2 curves starting to separate 1 year postrandomization and continuing to diverge, indicating an ongoing and increasing benefit with letrozole over tamoxifen (P = .0002).
*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
Thurlimann et al. J Clin Oncol. 2005;23(16S):6s. Abstract 511; and oral presentation at ASCO, 2005.

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

12. Meta-analysis: risk of recurrence remains high despite adjuvant tamoxifen therapy50
5 years
post-diagnosis 45 40
10 years
post-diagnosis 35 30
15 years
post-diagnosis 25
% of recurrences 20 15 10 5
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
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. NSABP B-14: no efficacy benefit of extending tamoxifen beyond 5 years
DFS OS
100 90 80 70 60 50
% of patients 5 7
82%
78% 1 2 4 6 3 5
100 90 80 70 60 50 7
% of patients
Placebo
Tamoxifen
94%
91% 1 3 2 4 6
Years after tamoxifen
p = 0.03
p = 0.07
Placebo
Tamoxifen
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. MA.17: trial design 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: 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
Placebo
Ingle et al. Breast Cancer Res Treat 2006; E-pub 16 March

19. ABCSG-6a: EFS (Recurrence of BC or new primary BC)
Anastrozole (n = 387)
No treatment (n = 409)
Hazard ratio (95% Cl)
p value
5-year DFS rate NR
0.64 (0.41–0.99)
0.047
Events 30 56 —
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
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 design Trial 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
Tam x 2–3 yrs
AI x 2–3 yrs
Placebo x 5 years
5 years’ further adjuvant
*n = 5000; primary endpoint = DFS

23. 5 years’ extended adjuvant
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 design 6000 women with N– disease
Evaluate clinical-pathological risk and 70-gene signature risk
n = 3300
55%
32%
13%
n = 780
Clin-path and 70-gene both HIGH risk
Discordant cases
Clin-path and 70-gene both LOW risk
Clin-path HIGH
70-gene LOW
Clin-path LOW
70-gene HIGH
n = 1920 R1
Use Clin-path risk to decide chemo or not
Use 70-gene risk to decide chemo or not
Chemotherapy
Endocrine therapy
Tam x 2 y→ 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 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. 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