Hormon Duyarlı Metastatik Meme
Kanserinde Sıralama
Nasıl Olmalı?
Erhan Gökmen
Ege Üniv. Tıp Fakültesi
Hormonal Tedavide Sıralama: Göz Önüne
Alınması Gereken Faktörler
 Menopozal durum:
– Premenopozal
– Postmenopozal
 Önceki tedaviler; nükse kadar geçen süre:
– Adjuvan tedavi sırasında veya sonrasında 12 ay içinde nüks: 2. hat tedavi
– Adjuvan tedaviden >12 ay sonra nüks: 1. hat tedavi
 Tümor biyolojisi:
– HER2 negatif veya pozitif
 Komorbid hastalıklar (kardiak hast., osteoporoz vb)
Premenopozal Hastalarda Hormonal
Tedavi Seçenekleri: Birinci hat
 Over ablasyonu veya supresyonu
 SERM (tamoksifen)
 Over ablasyonu/supresyonu + SERM
 AI kullanılmamalı
Premenopozal Hastalarda Hormonal
Tedavi Seçenekleri: Birinci hat
 Tamoksifen vs Over Ablasyonu:
– 1997 meta-analizi: 4 çalışma, 220 hasta (Breast Cancer Res Treat.
1997;44(3):201)
– PFS ve OS benzer (OR 0.86 ve 0.94), trend tmx lehine
 Tamoksifen + over supresyonu vs over supresyonu
– 2001 meta-analizi: 4 çalışma, 550 hasta (EORTC, J Clin Oncol.
2001;19(2):343)
– PFS ve OS kombinasyonla daha iyi (HR 0.70 ve 0.78)
 Tamoksifen + over supresyonu vs tamoksifen çalışması yok
Premenopozal Hastalarda Hormonal
Tedavide Sıralama
 Birinci hat
– Over supresyonu + tamoksifen
veya
– Tamoksifen
veya
– Over supresyonu/ablasyonu
 İkinci ve ileri hatlar
– İlk hatta kullanılmamış ise over supresyonu
veya
– Over supresyonunun teyidi + postmenopozal algoritma
Postmenopozal Hastalarda Hormonal
Tedavi Seçenekleri: Birinci hat
 Aromataz İnhibitörleri
 SERM (tamoksifen)
 Fulvestrant
 AI+fulvestrant
İlk Hat Letrozol vs Tamoksifen
First-line Letrozole vs Tamoxifen,
Then Crossover
1.0
Median OS
Letrozole: 34 mos
Tamoxifen: 30 mos
Proportion of Patients Alive
0.9
0.8
Time to Crossover
Letrozole: 17 mos
Tamoxifen: 14 mos
0.7
0.6
0.5
0.4
0.3
P = .53 (log-rank test)
0.2
0.1
0
0
6
12
18
24
30
Mos
Letrozole 1st
Mouridsen H, et al. J Clin Oncol. 2003;21:2101-2109.
36
42
48
Tamoxifen 1st
54
60
Postmenopozal Hastalarda Birinci Hat
Tedavi: AI vs Diğer Endokrin Tedaviler
 2006 Meta-analizi
– 23 klinik çalışma; 8504 hasta
– OS
– AI vs tamoksifen (HR 0.89, 95% CI 0.80-0.99), ilk hat
– AI vs diğer endokrin tedaviler (HR 0.87, 95% CI 0.82-0.93), ileri hatlar
Mauri D, J Natl Cancer Inst. 2006;98(18):1285
FIRST Study: Fulvestrant vs Anastrozol
TTP atTTP
Follow-up
Analysis
FIRST Study:
at Follow-up
Analysis
Treatment and Management Approaches in Metastatic Breast Cancer
Proportion of Patients Alive
and Progression Free
clinicaloptions.com/oncology
1.0
Fulvestrant 500 mg
Anastrozole 1 mg
0.8
0.6
0.4
0.2
HR: 0.66 (95% CI: 0.47-0.92;
P = .01)
0
0
6
12
18
24
30
36
42
48
34
21
20
8
6
2
0
0
Mos
Patients at Risk, n
Fulvestrant 500 mg 102
Anastrozole 1 mg 103
74
69
65
55
52
39
45
30
Robertson JF, et al. Breast Cancer Res Treat. 2012;136:503-511.
Treatment and Management Approaches in Metastatic Breast Cancer
FACT:
Phase III Study of First-line Anastrozole
± Fulvestrant in HR+ MBC
clinicaloptions.com/oncology
Post- or premenopausal
women receiving GnRH
agonist, ER- or PgR-positive,
in first relapse after
treatment for localized disease
(N = 514)
Fulvestrant 500 mg on Day 1, then
250 mg on Days 15, 29, then every 4th wk
Anastrozole 1 mg/day PO
(n = 258)
Treat until progression
or undue toxicity
Anastrozole 1 mg/day PO
(n = 256)
Primary endpoint: TTP
Secondary endpoints: ORR, TTF, DoR, clinical benefit rate, OS
Bergh J, et al. J Clin Oncol. 2012;30:1919-1925.
Treatment and Management Approaches in Metastatic Breast Cancer
FACT:
Phase III Study of First-line Anastrozole
± Fulvestrant in HR+ MBC: TTP
clinicaloptions.com/oncology
1.0
Median TTP
Anastrozole (n = 256): 10.2 mos
Anastrozole + fulvestrant (n = 258):
10.8 mos
HR: 0.99 (95% CI: 0.81-1.20;
P = .91)
Probability of Survival
Without Progression
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
6
12
18
Bergh J, et al. J Clin Oncol. 2012;30:1919-1925.
24
30
Mos
36
42
48
54
SWOG S0226: Phase III Study of First-line
Anastrozole ± Fulvestrant in HR+ MBC
Treatment and Management Approaches in Metastatic Breast Cancer
clinicaloptions.com/oncology
Stratified by previous
adjuvant tamoxifen
Postmenopausal
women with HR+
MBC
(N = 707)
Treatment until disease
progression
Anastrozole 1 mg/day PO +
Fulvestrant 500 mg on Day 1,
250 mg on Days 14 and 28,
250 mg q28 days thereafter
(n = 355)
Anastrozole 1 mg/day PO
(n = 352)
 Primary endpoint: PFS
 Secondary endpoints: OS, clinical benefit rate, ORR
Mehta RS, et al. N Engl J Med. 2012;367:435-444.
Women with
progression
encouraged to
cross over to
receive
fulvestrant
S0226 Study of First-line Anastrozole ±
Fulvestrant in HR+ MBC: PFS and OS
Treatment and Management Approaches in Metastatic Breast Cancer
clinicaloptions.com/oncology
Median OS
Combination: 47.7 mos (95% Cl: 43.4-55.7)
Anastrozole: 41.3 mos (95% Cl: 37.2-45.0)
1.00
1.00
0.75
0.75
OS
PFS
Median PFS
Combination: 15.0 mos (95% Cl: 13.2-18.4)
Anastrozole: 13.5 mos (95% Cl: 12.1-15.1)
0.50
Anastrozole
(297 events)
0.25
0
Anastrozole
(176 deaths)
0.50
Anastrozole + Fulvestrant
(268 events)
0.25
HR: 0.81 (95% Cl: 0.65-1.00;
P = .049 by stratified log-rank test)
HR: 0.80 (95% Cl: 0.68-0.94;
P = .007 by stratified log-rank test)
0
12
24
36
48
Mos Since Randomization
Mehta RS, et al. N Engl J Med. 2012;367:435-444.
Anastrozole + Fulvestrant
(154 deaths)
0
60
0
12
24
36
48
60
Mos Since Randomization
72
Treatment and Management Approaches in Metastatic Breast Cancer
S0226:
PFS and OS Overall and by Previous
Adjuvant Tamoxifen
clinicaloptions.com/oncology
Endpoint
Anastrozole +
Fulvestrant
Anastrozole
HR (95% CI)
P
Value
15.0
13.5
0.80
(0.68-0.94)
.007
 No previous adjuvant
tamoxifen (n = 414)
17.0
12.6
0.74
(0.59-0.92)
.0055
 Previous adjuvant
tamoxifen (n = 280)
13.5
14.1
0.89
(0.69-1.15)
.37
Median OS (n = 694), mos
47.7
41.3
0.81
(0.65-1.00)
.049
 No previous adjuvant
tamoxifen (n = 414)
47.7
39.7
0.74
(0.56-0.98)
.0362
 Previous adjuvant
tamoxifen (n = 280)
49.6
44.5
0.91
(0.65-1.28)
.59
Median PFS (n = 694), mos
Mehta RS, et al. N Engl J Med. 2012;367:435-444.
First-line Anastrozole ± Fulvestrant in
HR+ MBC: FACT vs SWOG S0226
Treatment and Management Approaches in Metastatic Breast Cancer
clinicaloptions.com/oncology
FACT[1]
SWOG S0226[2]
Patients, n
514
707
De novo metastatic disease, %
13
39
Prior adjuvant chemotherapy, %
45
33
Previous adjuvant endocrine
therapy (tamoxifen), %
68
40
10-11
13-15
No
Yes
Mean PFS range, mos
PFS benefit
1. Bergh J, et al. J Clin Oncol. 2012;30:1919-1925. 2. Mehta RS, et al. N Engl J Med. 2012;367:435-444.
Postmenopozal Hastalarda Hormonal
Tedavide Sıralama
 Birinci hat
– Aromataz inhibitörü
– Aİ’nün uygun olmadığı veya tolere edilemediği durumlarda
– Tamoksifen
– Fulvestrant (faz II randomize çalışma)
 Aİ+fulvestrant kullanımı standart değil
Postmenopozal Hastalarda Hormonal
Tedavide Sıralama: İkinci Hat Tedavi
 Çapraz direnç göstermeyen Aİ
 Fulvestrant
 Tamoksifen
 Exemestan+everolimus
AI sonrası İkinci Hatta Tamoksifen
Efficacy of tamoxifen following anastrozole (‘Arimidex’) compared with anastrozole following tamoxifen as first-line
treatment for advanced breast cancer in postmenopausal women
European Journal of Cancer, Volume 39, Issue 16, 2003, 2310 - 2317
AI sonrası İkinci Hatta Tamoksifen
Objective response and clinical benefit following cross-over treatment with anastrozole and tamoxifen
for patients with oestrogen and/or progesterone receptor-positive status
European Journal of Cancer, Volume 39, Issue 16, 2003, 2310 - 2317
İkinci Hat Tedavi: EFFECT
EFECT
• Fulvestrant similar to exemestane in postmenopausal
women progressing following prior NSAI with HR+ ABC
in phase lll placebo-controlled trial
N = 693
FUL 500 mg day 1,
250 mg day 14, 28, monthly
Primary:
TTP
EXE 25 mg QD
Secondary:
ORR, CBR, DOR,
TTR, OS,
tolerability
PMW with HR+
ABC after failure
of NSAI therapy
FUL
n = 351
EXE
n = 342
P Value
TTP, mo
3.7
3.7
.653
ORR, %
7.4
6.7
.736
CBR, %
32.2
31.5
.853
CBR, clinical benefit rate; DOR, duration of response; EXE, exemestane; FUL, fulvestrant; OS, overall survival; PMW;
postmenopausal women; TTR, time to response
et al. J Clin Oncol. 2008;26(10):1664-1670.
ChiaChia
S, JS,Clin
Oncol. 2008;26(10):1664
İkinci Hat Tedavi: SoFEA
SoFEA
•
Fulvestrant + anastrozole similar to fulvestrant alone or
exemestane alone in postmenopausal women with HR+ ABC
progressing following prior NSAI therapy
N = 723
PMW with HR+
ABC following
progression on
NSAI
FUL 500 mg loading day 0, then 250 mg
monthly
+ ANA 1 mg/daily
(F + A vs F;
F vs E)
FUL 500 mg loading day 0, then
250 mg monthly
Secondary:
ORR, CBR,
OS,
tolerability
EXE 25 mg/daily
EXE
n = 249
FUL
n = 231
ANA + FUL
n = 243
3.4
4.8
4.4
PFS, mo
EXE vs FUL
HR 0·95, 0·79-1·14; log-rank p=0·56
No differences were observed in PFS, ORR, CBR, or OS.
Johnston S, et al. Eur J Cancer. 2012;48(Suppl 3):2LBA.
Johnston SR, Lancet Oncol. 2013;14(10):989
Primary:
PFS
HR (95% CI): 1.00 (0.83 – 1.21) P = .98
BOLERO-2: Exemestane ± Everolimus in
Nonsteroidal AI–Refractory Advanced BC
Treatment and Management Approaches in Metastatic Breast Cancer
clinicaloptions.com/oncology
Postmenopausal women
with HR-positive,
HER2-negative advanced
breast cancer refractory to
letrozole or anastrozole
(N = 724)
 Refractory to therapy:
– Recurrence during or within
12 mos of end of adjuvant
treatment
– Progression during or within
1 mo after end of treatment for
advanced disease
Baselga J, et al. N Engl J Med. 2012;366:520-529.
Everolimus 10 mg/day +
Exemestane 25 mg/day
(n = 485)
Placebo +
Exemestane 25 mg/day
(n = 239)
 Stratification:
– Sensitivity to previous hormonal
therapy
– Presence of visceral disease
 No crossover allowed
 Primary endpoint: PFS
– Secondary endpoints: OS, ORR,
CBR, safety, QoL, bone markers
Treatment and Management Approaches in Metastatic Breast Cancer
clinicaloptions.com/oncology
BOLERO-2: PFS at 18-Mo Follow-up
Higher ORR (9.5 versus 0.4 percent)
100
Censoring Times
EVE + EXE (n/N = 310/485)
PBO + EXE (n/N = 200/239)
80
Patients (%)
Median PFS, Mos
EVE + EXE: 7.82
PBO + EXE: 3.19
HR: 0.45 (95% CI: 0.380.54; Log-rank P < .0001)
60
40
20
0
0
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
Week
Patients at Risk, n
EVE + EXE
485 436 366 304 257 221 185 158 124 91
PBO + EXE
239 190 132 96 67 50 39 30 21 15
Piccart-Gebhart M, et al. ASCO 2012. Abstract 559.
66
10
50
8
35
5
24
3
22
1
13
1
10
1
8
0
2
0
1
0
0
0
Treatment and Management Approaches in Metastatic Breast Cancer
clinicaloptions.com/oncology
BOLERO-2: Advers Events at 18-Mo Follow-up
Everolimus + Exemestane
(n = 482)
Placebo + Exemestane
(n = 238)
Grade
Grade
Adverse Event, %
All
3
4
All
3
4
Total
100
44
9
91
23
5
Stomatitis
59
8
0
12
<1
0
Rash
39
1
0
7
0
0
Fatigue
37
4
<1
27
1
0
Diarrhea
34
2
<1
19
<1
0
Nausea
31
<1
<1
29
1
0
Appetite decreased
31
1
0
13
1
0
Noninfectious
pneumonitis
16
3
0
0
0
0
Hyperglycemia
14
5
<1
2
<1
0
Piccart-Gebhart M, et al. ASCO 2012. Abstract 559.
Treatment and Management Approaches in Metastatic Breast Cancer
clinicaloptions.com/oncology
Postmenopozal Hastalarda Hormonal
Tedavide Sıralama: İkinci Hat Tedavi
 Standart tedavi yok:
– Exemestan+everolimus
– Exemestan
– Fulvestrant
– Tamoksifen
Treatment and Management Approaches in Metastatic Breast Cancer
clinicaloptions.com/oncology
Endokrin Duyarlı Meme Kanserinde
Sıralama: Sonuçlar
 Premenopozal
– Birinci hat
– Over supresyonu+tamoksifen
– Tamoksifen
– İkinci hat
– Gonadal supresyon sonrası postmenopozal algoritma
 Postmenopozal
– Birinci hat
– Aromataz İnhibitörü
– İkinci hat
– Exemestan+everolimus, Exemestan, Fulvestrant, Tamoksifen

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