These slides were released by the speaker
for internal use by Novartis
Risk reduction: why use
adjuvant therapy?
Antonio Llombart Cussac
(Hospital Universitario Arnau de Vilanova, Lérida, Spain)
The need for adjuvant therapy
• In early breast cancer, detectable tumor tissue
can be removed by surgical resection
• BUT
– Micrometastatic deposits of disease may remain
– Untreated micrometastases can develop into
clinical disease recurrence
– Metastatic breast cancer is currently incurable
• Adjuvant therapy protects against recurrence and
improves survival
Outcome is related to
disease stage at diagnosis
• 5-year survival rates
• Stage I disease 95%
• Stage II disease 70%–85%
• Stage III disease 50%–52%
• Stage IV disease 10%–15%
• Even patients with early-stage breast cancer are at
risk of relapse
Fisher et al. J Natl Cancer Inst Monogr 2001;(30):62–6
Parkin et al. Eur J Cancer. 2001;37(Suppl 8):S4–66
Early breast cancer:
common prognostic factors
• Patient-related
– Age
– Menopausal status
– Race
• Tumor-related
– Lymph node involvement: yes/no and number
– Tumor size
– Tumor grade
– ER/PgR status
– Vascular invasion
– HER2/neu expression
Predictors of early recurrence
Nodal status ER status
1.0 1.0
p CMF
– N+ TXN + A/E > AC/CAF
• Endocrine therapy [ER+ and/or PgR+]
– Postmenopausal AI > TAM
– Chemotherapy still effective
• HER2/neu++
– Tamoxifen less effective
– Target EGFR CT + trastuzumab > CT
Benefits of adjuvant chemotherapy
Chemotherapy improves outcomes
in postmenopausal women
Risk of recurrence Risk of mortality
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
Chemotherapy reduces risk of
recurrence in ER– and ER+ disease
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
Risk reduction with chemotherapy
• Risk reductions in recurrence and mortality occur
irrespective of
– Menopausal status
– Additional tamoxifen use
– ER status
– Nodal status
– Other tumor characteristics
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
The future of adjuvant chemotherapy
Annual odds of recurrence
100 No treatment No treatment =
CMF-like 9.0%/year
80
Anthracycline CMF-like =
Recurrence rate
Anthracyclines + taxanes 6.8%/year (risk reduction 24%)
60
40
Anthracycline =
6.0%/year
20 (risk reduction 12%)
0
Anthracycline & taxanes =
5.0%/year
0 1 2 3 4 5 6 7
(risk reduction 17–23%)
Time (years)
Adapted from EBCTCG 1998, CALGB 9344 , BCIRG-001
Benefits of adjuvant
endocrine therapy: tamoxifen
Tamoxifen improves 15-year outcomes
in ER+/unknown breast cancer
60 60
Breast cancer mortality (%)
50 50
45.0
Recurrence (%)
38.3 40
40
34.8
30 26.5 30 25.7
33.2
24.7 20 25.6
20 11.9
17.8
15.1 10
10
8.3
0 0
0 5 10 15 0 5 10 15
Years Control Years
Tamoxifen
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
Tamoxifen reduces recurrence in
ER+ but not ER– disease
ER status Hazard ratio of logrank
annual events*(SE) 2p value
ER-poor 1.04 (0.07)
ER-positive 0.59 (0.03)
ER-unknown 0.69 (0.07)
Subtotal 0.69 (0.03) < 0.00001
*About 5 years’ tamoxifen vs placebo
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
Tamoxifen reduces breast cancer
mortality in ER+ but not ER– disease
ER status Hazard ratio of logrank
annual death rates*(SE) 2p value
ER-poor 1.04 (0.08)
ER+ 0.66 (0.04)
ER-unknown 0.80 (0.09)
Subtotal 0.76 (0.03) < 0.00001
*About 5 years’ tamoxifen vs placebo
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
Greater absolute risk reduction with
tamoxifen in N+ vs N– disease
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
Risk reduction with endocrine therapy
• Tamoxifen highly effective in ER+ breast cancer
• Proportional risk reductions for recurrence and
mortality are unaffected by
– Age
– Use of chemotherapy
– Other tumor characteristics
• Tamoxifen has little effect in ER-poor tumors
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
Trastuzumab in addition to CT reduces
recurrence in HER2+ patients
Trial DFS Hazard
Schema Trastuzumab p
(Median FU) (%) Ratio
B31 – N9831 AC – P 75,4
0,48 < 0.0001
(3 years) AC – PH Simultaneous 87,1
HERA CT 77,4
0,54 < 0.0001
(2 years) CT - H Sequential 85,8
Trastuzumab in addition to CT also
reduces mortality in HER2+ patients
Hazard
Trial Schema Trastuzumab OS p
Ratio
B31 – N9831 AC – P 91,7
0,67 0.015
(FU 3 years) AC – PH Simultaneous 94,3
HERA CT 95,1
0,76 0.26
(FU 2 years) CT - H Sequential 96,0
Survival benefits of adjuvant therapy
• Postmenopausal woman with ER+ disease
– 6 months’ chemotherapy (mortality reduction 20%)
– 5 years’ tamoxifen (mortality reduction 31%)
• Total mortality reduction 45%
• Postmenopausal woman ER– disease
– 6 months’ chemotherapy
• Total mortality reduction 24%
Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
EBCTCG 2005
Summary of adjuvant therapy
• Adjuvant therapy reduces risk of recurrence in
early breast cancer
• Chemotherapy effective regardless of nodal or
tumor status
• Tamoxifen reduces recurrences and mortality in
postmenopausal women with HR+ disease
• 5 years of tamoxifen reduces risk of recurrence for
up to 15 years after surgery
• Tamoxifen is ineffective in ER– tumors
Continuing risk of recurrence
• Adjuvant chemotherapy and endocrine therapy
improve outcomes in patients with early breast cancer
• However
– Not all patients with HR+ tumors respond to
endocrine therapy
– Up to 40% of patients on adjuvant tamoxifen
develop recurrences
– In a study of 105 patients on tamoxifen, 29% developed early
distant recurrences (median time to recurrence 3.8 years)*
• Risk of breast cancer recurrence continues indefinitely
*Update of Loi et al. J Clin Oncol 2005;23(16S):6s(abstract 509)
Considerations for therapy selection
St Gallen 2005
• Fundamental change in algorithm for selecting
adjuvant systemic therapy for early breast cancer
– 1st consideration = endocrine responsiveness
• Endocrine responsive
• Endocrine non-responsive
• Tumors of uncertain endocrine responsiveness
– Divide each category by menopausal status
– THEN divide by risk
• Low, intermediate, high
Goldhirsch et al. Ann Oncol 2005;16:1569–83
Treatment guidelines for adjuvant
therapy for breast cancer
• Patients should be offered
– Chemotherapy for HR– disease
– Endocrine therapy for HR+ disease
• Plus chemotherapy for
– some intermediate-risk groups
– all high-risk groups
– Chemotherapy + endocrine therapy for all patients with
tumors with uncertain hormone responsiveness, except in
low-risk group (endocrine therapy only)
• Premenopausal women with HR+ disease may
benefit from ovarian ablation/suppression before
endocrine therapy
Goldhirsch et al. Ann Oncol 2005;16:1569–83
Trends in breast cancer mortality
USA
EU
30 Japan
Age-adjusted deaths
per 100,000
20
10
0
1975-1979 1980-1984 1985-1989 1990-1994 1995-1997
Years
Levi et al. Eur J Cancer 2001;37:1409–12
SEER Cancer Statistics Review, 1973-1999. At www.seer.cancer.gov
The future of adjuvant therapy
• Need more understanding of resistance
mechanisms, particularly for endocrine agents
• Primary (initial) and secondary (induced)
resistance occurs
• Mechanistic combinations required to target
therapies to block the cross-talk pathways
– New agents
– New combinations/sequences