Perfil de paciente para estratégia switch de hormonioterapia

Perfil de paciente para estratégia switch de hormonioterapia

30/05/2016
Perfil de paciente para estratégia
switch de hormonioterapia
Daniele Assad
Oncologista Clínica - Centro de Oncologia
do Hospital Sírio Libanês
Tratamento endócrino do câncer de mama
Declaração de conflito de interesses
Resolução CFM no 1595/2000, 18/05/2000
RDC ANVISA no 102, 30/11/2000
Speaker Roche
Speaker Pfizer
Benefício de tamoxifen por 5 anos
• Em até 75% dos casos de câncer de mama, a
sinalização de ER é um dos principais causadores
da
proliferação
tumoral
• O tratamento endócrino adjuvante melhora
significativamente os resultados do câncer de
mama precoce com ER+
Cleator SJ et al. Clin Breast Cancer. 2009;9(Suppl 1):S6–S17.
EBCTCG 2005 Lancet 2005
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Opções de terapia hormonal
Mecanismo
Exemplos de modalidades terapêuticas
Bloqueio do ER
Moduladores seletivos dos receptores de
estrogênio (SERMs)
Down-regulators seletivos dos receptores
de estrogênio (SERDs)
Supressão da síntese de
estrogênio (mulheres na pósmenopausa)
Inibidor / inativador da aromatase (AI)
Ablação hormonal
(mulheres na prémenopausa)
Análogos de LHRH, radiação, cirurgia
Outros
Andrógenos, progesterona
Mecanismos de ação
Hayes DF et al. In: Robertson et al., eds. Endocrine Therapy of Breast Cancer. 2002:3–10.
Robertson JF. Clin Ther. 2002;24(suppl A):A17–A30.
Metanálise de IA x TAM
Estudos com IA
1. Aromatase inhibitors as initial therapy
a. postmenopausal
•
ATAC: Arms: tamoxifen vs anastrozole vs
combination
•
BIG 1:-98: Arms: tamoxifen vs letrozole
•
MA.27: Arms: anastrozole vs exemestane
•
FACE: Arms: anastrozole vs letrozole
b. Premenopausal
•
ABCSG 12: Arms (all with goserelin, ± zoledronic
acid): tamoxifen vs OFS + exemestane
•
SOFT: Arms: tamoxifen vs ovarian function
suppression (OFS) + tamoxifen vs OFS + exemestane
•
TEXT: Arms: OFS + tamoxifen vs OFS + exemestane
2. Sequential use of aromatase inhibitors after < 5
years (usually 2-3 years) of tamoxifen vs tamoxifen
for a total of 5 years of therapy
•
•
•
•
IES: Arms (after 2-3 years of tamoxifen (5 years) vs
tamoxifen (2 years) then anastrozole (3 years)
ITA: Arms (after 2-3 years of tamoxifen): tamoxifen vs
anastrozole
ARNO 95: Arms (after 2 years of tamoxifen):
tamoxifen vs anastroxole
NSAS BC-03: Arms (after 1-4 years tamoxifen):
tamoxifen vs exemestane
Stephen R.D. Johnston; Nature Reviews. Cancer (Nov 2003)
3. Sequencing of aromatase inhibitors and tamoxifen
vs aromatase inhibitor monotherapy for a total of 5
years of therapy
•
BIG 1-98: Arms: tamoxifen to letrozole and letrozole to
tamoxifen, both compared with letrozole monotherapy
•
TEAM: Arms: tamoxifen (2.5 to 3 years) then exemestane
vs exemestane monotherapy
ATAC
BIG 1-98/IBCSG 18-98
Coorte 1: 9856 pacientes TAM 5 anos x IA 5 anos
Recaída
F/U 5.8 years
SG
4. Aromatase inhibitors after about 5 years of tamoxifen
•
MA. 17: Arms: letrozole vs placebo (both for 5 years)
•
NSABP B33: Arms: exemestane vs placebo (both for 5
years)
•
ABCSG 6ª: Arms: anastrozole (3 years) vs observation
•
Later: Arms: letrozole vs placebo (both for 5 years)
5. Duration of aromatase inhibitor therapy (after some
period of aromatase inhibitor)
•
NSABP B42: Arms: exemestane vs placebo (both for 5
years)
•
MA. 17R: Arms: letrozole vs placebo (both for 5 years)
•
ABCSG 16: Arms: anastrozole for 3 years vs anastrozole
for 5 years
6. Intermittent aromatase inhibitor therapy
•
Sole: Arms: continuous letrozole vs intermittent letrozole
Dowsett JCO 2010
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ARNO, IES/BIG 02-97,
ITA, ABCSG VIII
Metanálise de IA x TAM
Visão geral dos estudos de swtich: benefício de
sobrevida global
Coorte 2: 9015 pacientes TAM 5 anos x TAM 2-3 anos switch IA
Recaída
SG
Benefício
em SG
Redução de
29%
IES
(Exemestano) 1-3
Teste
HR 0.79 (SE 0.07)
reduction
2P = .004
n
Desenho
QT
4.724
979
Duplo-cego
Aberto
Sim (32%)
Não
Nodo +
48%
26%
91 meses
30 meses
HR – DFS
0,82 (0,73 – 0,92)
p = 0,0009
0,66 (0,44 – 1,00)
p = 0,049
Benefício de sobrevidal
global
0,86 (0,75 – 0,99)
p = 0,04
0,53 (0,28 – 0,99)
p = 0,045
F/U
Dowsett JCO 2010
ARNO 95
(Anastrozol)4
1. Coombes RC et al. Lancet. 2007;369: 559-570; 2. Coombes RC et al. N Engl J Med. 2004; 350: 1081-1092;
3. Bliss JM et al. J Clin Oncol. 2012; 30: 709-717; 4. Kaufmann M et al. J Clin Oncol. 2007; 25: 2664-2670
A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen
Therapy in Postmenopausal Women with Primary Breast Cancer
A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen
Therapy in Postmenopausal Women with Primary Breast Cancer
Diagnosis of breast cancer and
treatment for primary disease
2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive
tamoxifen.
2–3 yr of tamoxifen therapy
Yr after
randomization
0
2-3
183 First events
8.4% of patients continue
toRandomization
receive treatment
2–3 Yr of tamoxifen therapy
n=2362
2–3 Yr of exemestane therapy
n=2380
266 First events
8.6% of patients continue
to receive treatment
183 First events
8.4% of patients continue
to receive treatment
Yr after
start of
tamoxifen
therapy
Disease-free Survival
Overall Survival
0
absolute benefit in
terms of disease-free
survival of 4.7 percent
2-3
5
Coombes NEJM 2004
Overall survival was not
significantly different
Exemestane therapy after two to there years tamoxifen therapy significantly improved
disease=free survival compared with the standard five years of tamoxifen treatment.
follow-up of 30.6 months
Coombes NEJM 2004
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30/05/2016
A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen
Therapy in Postmenopausal Women with Primary Breast Cancer
Disease-Related Outcomes With Long-Term Follow-Up: An
Updated Analysis of the Intergroup Exemestane Study
Subgroup Analysis of Disease-free Survival
Favo rs
Exem estan e
Su bgro up (no.)
F avo rs
Tam oxifen
Hazard Ratio
Hormone-receptor status
Estrogen-receptor–positive (3853)
0.64 (0.52–0.79)
Progesterone-recept
or–positive (2619)
0.66 (0.51–0.87)
Progesterone-receptor–negative (735)
0.58 (0.38–0.90)
Progesterone-receptor status
unknown (499)
0.67 (0.39–1.16)
Estrogen-receptor status negative
or unknown (889)
0.85 (0.57–1.29)
Nodal status
Negative (2422)
0.68 (0.48–0.95)
1–3 Positive nodes (1421)
0.71 (0.51–0.98)
≥4 Positive nodes (651)
0.58 (0.42–0.81)
Previous hormone-replacement therapy
Yes (1124)
0.63 (0.40–0.99)
No (3470)
0.69 (0.56–0.85)
Previous chemotherapy
Yes (1531)
0.69 (0.51–0.92)
No (3171)
0.67 (0.52–0.86)
All patients (4742)
0.67 (0.56–0.82)
0.4
0.6
0.8
1.0
median follow-up was 91 months
1.2
Hazard Ratio (log scale)
Bliss, JCO 2012
Coombes NEJM 2004
Disease-Related Outcomes With Long-Term Follow-Up: An
Updated Analysis of the Intergroup Exemestane Study
Assessment of letrozole and tamoxifen alone and in sequence for
postmenopausal women with steroid hormone receptor-positive breast cancer:
the BIG 1-98 randomised clinical trial at 8—1 years median follow-up
Events by Treatment Group in the ER-Positive/ER-Unknown Population
Trial profile
ER-Positive/ER-Unknown Population
T wo-arm option (1998–2000)
Exemestane
(n = 2,294)
Tamoxifen
(n = 2,305)
Total
(N = 4,599)
Conclusion
No.
%
No.
%
No.
%
The
protective effect of352switching
to exemestane
Overall survival
15.3
405
17.6
757
16.5
compared
with continuing
on tamoxifen
on
risk of
Breast cancer death
245
290
535
relapse or death was maintained for at least 5
Death from unknown cause
25
34
59
years post-treatment and was associated with a
Death from other know cause
107
115
222
continuing
beneficial impact
on overall
survival.
Other cancer
31
52
83
Vascular
Cardiac
Other
23
22
31
19
20
24
42
42
55
Bliss, JCO 2012
A
T amoxifen
n=911
B
Letrozole
n=917
n=1 82 8
n=4922
Monotherapy
analysis
F our-ar m opti on (1 99 9–2 00 3 )
A
T amoxifen
n=1548
B
Letrozole
n=1546
C
T amoxifen
Letrozole
D
Letrozole
Tamoxifen
0
1
2
3
n=1548
4
n=8010
n=6182
Sequential
treatment
analysis
n=1540
5
Years
Regan, Lancet 2011
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Assessment of letrozole and tamoxifen alone and in sequence for
postmenopausal women with steroid hormone receptor-positive breast cancer:
the BIG 1-98 randomised clinical trial at 8—1 years median follow-up
Assessment of letrozole and tamoxifen alone and in sequence for
postmenopausal women with steroid hormone receptor-positive breast cancer:
the BIG 1-98 randomised clinical trial at 8—1 years median follow-up
Sequential treatment analysis
Interpretation
For postmenopausal women with endocrine-responsive
early breast cancer, a reduction in breast cancer
recurrence and mortality is obtained by letrozole
monotherapy
when
compared
with
tamoxifen
montherapy.
Sequential treatments involving tamoxifen and letrozole do
not improve outcome compared with letrozole
monotherapy, but might be useful strategies when
considering an individual patient’s risk of recurrence and
treatment tolerability.
follow-up of 8.1 years
Regan, Lancet 2011
Regan, Lancet 2011
T o x ic id a d e s
Josefsson. The Breast 2010; 19: 76-83
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Reversal of skeletal effects of endocrine treatments
in the Intergroup Exemestane Study
Quadril
Coluna Lombar
Visita (meses desde a randomização)
0
6
12 18 24 EOT
Visita (meses desde a randomização)
EOT+12 EOT+24
1
0
0
-0,179
-0,622
-0,925
Josefsson. The Breast 2010; 19: 76-83
Transição entre os estados normal, osteopenia e
osteoporose 24m após fim do tratamento
EOT+12 EOT+24
-2,689
-2,774
-2,637
-3,132
-3,081
-3,147
-3,933
-0,179
-1
-2
-4
12 18 24 EOT
-0,180
0
-1
-3
6
1
-0,290
-2
-0,994
-1,531
-1,359
-2,304
-2,976
-3
-2,882
-2,989
-3,110
-3,132
-3,947
-4
-4,166
-5
-5
-6
-6
Exemestano
Tamoxifeno
206 patients
(Exemestane [E] = 101, Tamoxifen [T] = 105) Coleman RE et al. Breast Cancer Res Treat. 2010; 124: 153-161
IES: Eventos ginecológicos
Favorece o exemestano
Favorece o tamoxifeno
E%* v T%**; valor p
População Chave
Evento
Ginecológico grave
(incluindo a
histerectomia
e D&C uterina)
Todas
6,8 v 10,4; < 0,001
Durante
Após
4,9 vs 7,2; 0,001
Sangramento
vaginal
Hiperplasia
endometrial /
pólipos e
miomas
uterinos
1,5 v 3,9; < 0,001
0,2
0,4
0,8
1,0
1,7
Razão de possibilidade (99% de CI)
*N = 2319 **N = 2338 p/ sangramento vaginal;
Coleman, Breast Can Res Treat 2010
*N = 2038 **N = 2059 para outros eventos
Coombes RC et al. ECCO15/ESMO 34 2009. Resumo 5.010.
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Relação entre eventos adversos e a eficácia
do exemestano
Ondas de calor:
HR 0,39, 95% de CI 0,19 – 0,81 p = 0,012
Long-term assessment of quality of life in the Intergroup
Exemestane Study: 5 years post-randomisation
Ferramentas usadas:
• FACT-B trimestralmente por um ano
• ES semestralmente por 5 anos
• 582 pacientes de oito países
• Conformidade de 84,5% com o questionário
Músculo-esqueletico:
HR 0,68, 95% de CI 0,39 – 1,17 p = 0,16
Meta primária:
• O índice de resultado de teste (TOI), que é a soma da
subescala referente a preocupações físicas, funcionais
e do câncer de mama.
QoL – qualidade de vida
Fontein DB et al. Ann Oncol. 2012; 23: 3091-3097
Mean change from baseline
Long-term assessment of quality of life in the Intergroup
Exemestane Study: 5 years post-randomisation
12
10
8
6
4
2
0
-2
-4
-6
-8
-10
-12
Fallowfield LJ et al. Br J cancer. 2012; 106: 1062 - 1067
IAs e Tamoxifeno
Riscos e benefícios potenciais
Exemestane
Tamoxifen
Sem diferença
QOL
↓ Câncer de mama contra-lateral
↓ Risco de osteoporose
↓ Mialgia
↓ Hiperlipidemia
Tamoxifeno
↓ Câncer de mama contra-lateral
↓ Trombose venosa profunda
↓ Câncer endometrial
↓ Ondas de calor
Neurocognição
Função sexual
Doença cardiovascular
AI
End of
treatment
0
3 6 9 12
18
24
30
36
48
60
Months from randomisation
Mean change from baseline TOI scores within treatment groups.
Fallowfield British Journal of Cancer, 2012
↑ Ondas de calor
↑ Tromboembolias
↑ Câncer endometrial
↑ Efeitos adversos no trato geniturinário
↑ Artralgia / mialgia
↑ Risco de osteoporose
↑ Riscos cardiovasculares ?
Burstein HJ et al. J Clin Oncol. 2010; 28: 3784-3796
Amir E et al. J natl Cancer Inst. 2011; 103: 1299-1309
Phillips KA et al. Breast Cancer Res. 2011; 13: 203
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Aromatase inhibitors versus tamoxifen in early breast
cancer: patient-level meta-analysis of the randomised trials
Lancet 2015; 386: 1341–52
Aromatase inhibitors versus tamoxifen in early breast
cancer: patient-level meta-analysis of the randomised trials
Lancet 2015; 386: 1341–52
HT pós menopausa: Algoritmo da ASCO
Considerações finais
daniele.xassad@hsl.org.br
Journal of Clinical Oncology, Vol 31, No 11 (April 10), 2013: pp 1391-1397
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