Ospedale S. Cuore Don Calabria
Terapia Ormonale Adiuvante di Lunga Durata
nel Carcinoma Mammario
Marco Venturini
Verona 19 Aprile 2008
Tumore della Mammella
• Il tumore più frequente nella donna in Italia
• Dati del 2005: nuove diagnosi 37.000, casi
prevalenti 416.000, decessi 8500
• Soprevvivenza a 5 anni:
nel 1978  65%
nel 1994  82% (75% al Sud vs 84% al Nord)
• E’ stimata una riduzione di mortalità pari al
30% entro il 2010.
Breast Cancer Mortality by Time
Italy, 1970-2005-10: recent decrease in
breast cancer mortality at ages 35-69
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
0
1970 1980 1990 2000 2010
Berry DA et al. N Engl J Med 2005;353:1784-92.
• Stratificazione dei pazienti in base al
rischio (fattori prognostici)
• Previsione della risposta a diversi
trattamenti (fattori predittivi)
Traditional pathologic prognostic and
predictive factors in breast cancer
St Gallen 2005
Nodal status
T size
Hormonal rec.
Grading
Age
HER2
Vascular
invasion
College Am Path ’99
NIH 2000
(Arch Path Lab Med 124:966,
2000)
(J Natl cancer Inst 93: 979,
2001)
Nodal status
T size
Hormonal rec.
Grading
Histologic type
Mitotic count
Nodal status
T size
Hormonal rec.
Grading
Age
Histologic type
-
Prognosi delle pazienti sulla base dei Recettori per l’
Estrogeno. Dati di mortalità per tumore della mammella
Nodi negativi
Nodi Positivi’
Tamoxifen in ER-poor disease
Tamoxifen
Premenopausal
Ovarian Ablation (LH-RHa)
Adjuvant endocrine
Therapy
Tamoxifen
Postmenopausal
Aromatase Inhibitors
Age.
Similar effects of tamoxifen in under and over 50s
LHRHa in Premenopausal Women


Goserelin available since 1990
Acts on hypothalamic-pituary axix
Hypersecretion of LH following acute
administration of goserelin

Hypersecretion of LH following chronic
administration of goserelin
Results in estradiol decline within 21 days
Mean plasma estradiol levels before and during therapy with the three treatment regimens
Klijn, J. G. M. et al. J Natl Cancer Inst 2000;92:903-911
Copyright restrictions may apply.
Tamoxifen
Premenopausal
Ovarian Ablation (LH-RHa)
Adjuvant endocrine
Therapy
Tamoxifen
Postmenopausal
Aromatase Inhibitors
TAMOXIFENE IN ADIUVANTE
Oxford overview, Lancet: 2005
• 33209 pazienti: TAM 1-2 anni vs no
TAM
• 15017 pazienti: TAM 5 anni vs no TAM
• 32047 pazienti: TAM < 5 anni vs TAM <
10 anni
• Recettori positivi se > 10 fmol/mg di
proteine o se ICH + (con qualsiasi
positività)
TAMOXIFENE IN ADIUVANTE
Oxford overview, Lancet: 2005
• TAM per 5 anni vs no TAM:
• Riduzione di rischio di ricaduta annuale del 41%
• Riduzione del rischio annuale di morte del 34%
• TAM per 5 anni vs TAM per 2 anni:
• Riduzione del rischio di ricaduta annuale: 41% vs
26%
• Riduzione del rischio annuale di morte: 34% vs
18%
More Than Half of Breast Cancer Recurrences
and Deaths Occur Post-Tamoxifen (5 years)
Recurrences
15%
100
Breast Cancer Deaths
17%
9%
100
85.2
18%
91.4
80.9
76.1
80
68.2
68%
73.7
60
55%
62.7
54.9
40
Tamoxifen
Control
20
% of patients
% of patients
80
87.8
73.0
73%
64%
73.2
60
64.0
40
Tamoxifen
Control
20
0
0
0
5
10
Years
15
0
5
10
15
Years
Adapted Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000.
Recurrence Hazard Rates for
Breast Cancer After Primary Therapy
Saphner et al. J Clin Oncol 1996;14:2738-2746.
TAMOXIFENE IN ADIUVANTE
Oxford overview, Lancet: 2005
• TAM per 10 anni vs TAM per 5 anni:
• Nessun ulteriore impatto in DFS e OS e
inoltre:
• Aumenta l’incidenza di effetti collaterali:
tromboembolismo, infarto, cancro
dell’endometrio
10 vs 5 years of tam: ATLAS study
• 11.500 pts treated with tam x 5 yrs
randomized to tam for additional 5 yrs
or no additional tam
• Continuing tam beyond 5 years
associated with lower recurrence rate vs
stopping tam at 5 years
• Effect of longer tam duration on
survival undetermined
Peto R, SABCS 2007
10 vs 5 years of tam: ATLAS study
Annual event rate, % of
patients
Continued Stopped tam Ratio of rates
with continued
tam
vs stopped tam
(SE)
All
recurrences,
per yr
2.9
3.4
0.866 (0.048)
P=.005
Deaths
1.4
1.5
0.895 (0.070)
Peto R, SABCS 2007
Tamoxifen
Premenopausal
Ovarian Ablation (LH-RHa)
Adjuvant endocrine
Therapy
Tamoxifen
Postmenopausal
Aromatase Inhibitors
Anti-Aromatase Agents
Interfere with Estrogen
Biosynthesis
Cholesterol
Cortisol
Pregnenolone
Progesterone
Androstenedione
Testosterone
Anti-Aromatase
Agents
Aldosterone
Estrone
Estradiol
Inhibition of
Estrogen-Dependent Growth
Antiestrogens
Estrogen
biosynthesis
Nucleus
Estrogen
biosynthesis
Inhibition
of growth
Aromatase
Inhibitors
Tumor cell
Aromatasi: distribuzione
• Tessuto adiposo
• Tessuto muscolare
• Tumore mammario
Caratteristiche
dell’aromatasi intratumorale
1. Capacità di produzione AUTONOMA
di estrogeni
2. Potenzialità da parte delle cellule tumorali
di sopravvivere dopo deprivazione
estrogenica periferica
Duration of Initial Endocrine Therapy
TAMOXIFEN
AI
5 years
2 years
3 years
5 years
2 years?
5 years
Trial Design of MA.17
Randomization
(All patients disease-free)
0–3
months
Femara 2.5 mg qd*
n=2575
Tamoxifen
Placebo qd†
n=2582
Approx. 5 years adjuvant
5 years extended adjuvant
Primary end point: DFS
Secondary end points: OS/safety/QOL
Substudies: BMD/bone markers, lipid profile
*n=2575 (efficacy), 2154 (safety); †n=2582 (efficacy), 2145 (safety).
QOL = quality of life; BMD = bone mineral density.
Goss et al. N Engl J Med. 2003;349:1793.
DFS: Letrozole Significantly
Decreased
Risk
of
Recurrence
100
Percent
80
HR= 0.58
(0.45-0.76)
60
P=0.00004
40
20
Femara
Placebo
0
0
10
20
30
40
50
60
Time from randomization (months)
No. at risk (Femara) 2583
2497
1905
1110
541
176
6
No. at risk (Placebo) 2587
2489
1874
1075
519
164
8
Adapted from Goss. ASCO, 2004.
Premenopausal
Complete
5 y TAM
Premenopausal
Premenopausal
TAM for 2-3 y
±LH-RHa
Stop
Postmenopausal
Adjuvant endocrine
Therapy
Postmenopausal
Aromatase Inhibitor for 5 y
Tamoxifen 2-3 y → AI to complete 5 y
Postmenopausal
TAM to 4.5-6 y → AI for 5 y
If AI controindicated, TAM for 5 y
Fig 1. Long-term adherence to adjuvant tamoxifen therapy in eligible patients from 1991 index year
cohort
Partridge, A. H. et al. J Clin Oncol; 21:602-606 2003
Copyright © American Society of Clinical Oncology
Fig 5. Annual proportion of adherent and nonadherent patients with early-stage breast cancer with 36
months of follow-up (anastrozole)
Partridge, A. H. et al. J Clin Oncol; 26:556-562 2008
Copyright © American Society of Clinical Oncology
Safety of Adjuvant Aromatase Inhibitors
M. Venturini et al. Cancer Treatment Reviews (2006) 32, 548– 556
Incidence of AI Musculoskeletal Side
Effects
Anastrozole1
Exemestane2
Letrozole3
Arthralgia
36%
19%
20%
Carpal tunnel
syndrome
3%
3%
NR
Increase in
alkaline
phosphatase
2%
NR
NR
1. Buzdar, ASCO 2006 (abstract 551).
2. Coombes. Lancet 2007; 3. Coates. J Clin Oncol 2007
Statistically significant higher incidence as compared to tam
Trigger finger and Carpal tunnel
syndrome in pts receiving AIs
Morales, Breast Cancer Res Treat, 2007
Shift in BMD status from baseline to 5 years
Status at baseline
Status at 5 years
Anastrozole
(n = 81)
Tamoxifen
(n = 86)
Normal bone
Normal bone
Osteopenic
Osteoporotic
Not recorded
12 (15%)
14 (17%)
0
6 (7%)
16 (19%)
3 (3%)
0
13 (15%)
Osteopenic
Normal bone
Osteopenic
Osteoporotic
Not recorded
1 (1%)
21 (26%)
4 (5%)
21 (26%)
4 (5%)
21 (24%)
1 (1%)
22 (26%)
Coleman et al ASCO06
AI and osteoporosis
• In patients with normal baseline BMD
(T score >-1), development of
osteoporosis in unlikely because bone
loss of more than 12-15% would be
necessary for transition from a healthy
to osteoporotic state, a degree that was
not see with AI
Coleman, Lancet Oncol 2007