Terapia neoadjuvante para
tumores triplo negativos
Dra. Juliana Martins Pimenta Hospital BP e BP Mirante
Beneficência Portuguesa de São Paulo
Declaração de Conflito de Interesses
• De acordo com a Norma 1595/2000 do Conselho Federal de Medicina e com a
RDC 96/2008 da ANVISA, declaro que:
− Pesquisa Clínica: como médico investigador, participo de estudos
patrocinados por: MSD, Roche, Novartis
− Apresentações: como palestrante convidado, participo dos eventos de:
Roche, Astrazeneca, Amgen, Eisai, Pfizer, Novartis
− Consultoria: como membro de advisory boards, participo de reuniões com:
Roche, Lilly, Novartis
• Não possuo ações de quaisquer destas companhias farmacêuticas.
Core Bx. AP: Carcinoma mamáreo invasivo GH III
IHQ: RE negativo; RP negativo; HER 2 Escore 1+; Ki 67 positivo 75%.
Feminino, 35 anos
Introdução
▪ Subtipo mais agressivo, comumente diagnosticado em
mulheres jovens.
▪ Não há diferença de sobrevida entre tratamento sistêmico
adjuvante ou neoadjuvante.
▪ Citorredução tumoral pode aumentar a chance de realizar
cirurgia conservadora e permite avaliação de resposta a
quimioterapia.
Introdução
▪ Considerar principalmente em tumores com alta resposta a
quimioterapia (HER 2 positivo ou triplo negativo).
▪ Estudos recentes sugerem aumento de taxa patológica
completa com uso de platinantes na neoadjuvância e
reforçam a importância do uso de antracíclicos.
Introdução
Introdução
Molecular Subtype % pCR (n = 116)
Luminal A 3
Luminal B 16
HER enriched 50
Basal 33
Metanálise EBCTCG 2017
QT Neoadjuvante vs Adjuvante
Years 0-4
2·58 (245/9493)
1·95 (185/9477)
1·35 (1·11-1·64)
30·4/102·0
Years 5-9
1·43 (79/5528)
0·96 (54/5618)
1·53 (1·08-2·17)
13·6/31·8
Years 10-14
0·93 (26/2784)
0·69 (19/2769)
1·29 (0·70-2·38)
2·7/10·3
Years ≥15
2·16 (16/740)
1·42 (11/772)
1·11 (0·48-2·57)
0·6/5·4
Neoadjuvant
Adjuvant
Rate ratio
(95% CI) from
(O-E)/V
0 5 10 15
10
20
30
40
50
60
Local recurrence crude rates (events per woman-years)
and log-rank analyses
Lo
cal re
curr
en
ce (%
)
Neoadjuvant
21·4%
9·0%
12·1%
13·2%
17·9%
Adjuvant
15·9%
4756 women, 635 events
15 year loss 5·5% (95% CI 2·4?8·6)
RR 1·37 (95% CI 1·17?1·61)
Log-rank p=0·0001
Years 0-4
5·69 (568/9983)
5·44 (535/9840)
1·07 (0·94-1·21)
16·5/251·5
Years 5-9
2·58 (162/6291)
2·54 (157/6187)
0·99 (0·79-1·24)
-0·6/75·5
Years 10-14
1·49 (50/3351)
1·84 (60/3270)
0·80 (0·55-1·18)
-5·7/25·8
Years ≥ 15
1·44 (14/974)
1·74 (16/919)
0·75 (0·35-1·61)
-1·9/6·7
0 5 10 15
10
20
30
40
50
60
Distant recurrence at any time crude rates (events per woman-years)
and log-rank analyses
Dis
tan
t re
curr
en
ce a
t an
y t
ime (
%)
Neoadjuvant
38·2%
23·5%
24·9% 32·4%
33·8%
Adjuvant
38·0%
4756 women, 1562 events
15 year loss 0·2% (95% CI ?3·1 to 3·5)
RR 1·02 (95% CI 0·92?1·14)
Log-rank p=0·66
00
NACT
Adjuvant
Papel dos antracíclicos
ABC Trials
ABC Trials
ABC Trials
ABC Trials
ABC Trials
ABC Trials
Plan B Trial
Plan B Trial
Plan B Trial
Plan B Trial
Plan B Trial
Plan B Trial e ABC trials
Papel do esquema Dose Densa
Quimioterapia Dose Densa
Quimioterapia Dose Densa
Quimioterapia Dose Densa
Quimioterapia Dose Densa
Quimioterapia Dose Densa
Papel dos platinantes
315 TNBC patients GeparSixto: Study Design
▪ Randomized phase IIb study in 51 German centers
*TNBC pts also resolved bevacizumab 15 mg/kg IV Q3W, tHER2+ BC pts also received trastuzumab 8 mg/kg IV (initial dose), then 6 mg/kg IV Q3D (subsequente doses) and lapatinib 750 mg QD.‡Dose reduced to AUC 1.5 after 330 pts enrolled.
▪ Primary endpoint: pCR
▪ Secondary endpoints: RFS, DFS, OS
Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early
breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial
Cancer Res 75: abstr S2-07, 2015
Pts with centrally
confirmed TNBC*
or HER2+ BCt
with cT2 – T4a-d
or cT1 with N+
Disease
(N = 588)
PMCbCarboplatin AUC 2‡ Q1W +
Paclitaxel 80 mg/m2 Q1W +
Nonpegylated liposomal doxorubicin 20 mg/m2 Q1W +
(n = 295)
PMCbPaclitaxel 80 mg/m2 Q1W +
Nonpegylated liposomal doxorubicin 20 mg/m2 Q1W +
(n = 293)
.O
Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early
breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial
Cancer Res 75: abstr S2-07, 2015
GeparSixto: pCR Outcomes
pCR, % PMCb PM Odds
Ratio
P Value
All pts 43.7 36.9 .107*
HER2+ (BC (n = 273) 32.8 36.8 0.84 .6t
TNBC (n = 315)
gBRCA wild type (n = 241)
gBRCA mutante (n = 50)
53.2
50.8
61.5
36.9
33.1
50.0
1.94
2.09
1.60
.005t
.005
.413
*Level for significance = 0.2tTest for interaction, P = .015
100
80
60
40
20
00 12 24 36 48
Pts
with
DFS (
%)
Mos
PMPMCb
157158
139144
118126
5050
00
PMCb PM
3-yr DFS, % 85.8 76.1
HR (95% CI) 0.56 (0.33 – 0.96)
Pvalue .0350
TNBC
PM
PMCb
Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week PaclitaxelFollowed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Ratesin Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance)
▪ 443 patients
Paclitaxel 80 mg/m2 wkly x 12 ddAC x 4
Paclitaxel 80 mg/m2 wkly x 12 ddAC x 4
Bevacizumab 10 mg/kg q2wks x 9
Paclitaxel 80 mg/m2 wkly x 12 ddAC x 4
Carboplatin AUC 6 q3wks x 4
Paclitaxel 80 mg/m2 wkly x 12 ddAC x 4
Carboplatin AUC 6 q3wks x 4
Bevacizumab 10 mg/kg q2wks x 9
2 x 2Randomization
SurgeryXRTNo
furthersystematic
therapy
Primary endpoint: pCR breast (ypTO/is (N0/+)
Sikov, SABCS 2013, JCO 2014
Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week PaclitaxelFollowed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete ResponseRates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance)
Sikov, SABCS 2013, JCO 2014
41%
54%
0
10
20
30
40
50
60
No Carbo
(N = 212)
Carbo
(N = 221)
1-sided P = 0.0029
GeparSixto Trial CALBG 40603
Carboplatin Control Carboplatin Control
3 yr DFS 85.8% 76.1% 76% 71%
HR 0.56 p = 0.03 HR 0.84 p = 0.36
3 yr OS NR NR 81% 85%
HR 1.15 p = 0.53
Lancet Oncol 19:497, 2018
BrighTNess
Lancet Oncol 19:497, 2018
BrighTNess
Lancet Oncol 19:497, 2018
Papel da capecitabina adjuvante
CREATE-X: Study Design
.O
Toi et al. SABCS 2015
▪ Preplanned interim analysis of a randomized, open-label phase III study[1]
▪ Primary endpoint: DFS▪ Secondary endpoints: OS, time from first day of
preoperative chemotherapy to recurrence or death, safety, cost-effectiveness
*Anthracycline/taxane, anthracycline containing, or docetaxel/cyclophosphamide.†25 pts were removed from treatment (n = 10) and control (n = 15) arms due to failure to meet ellgibility criteria.‡IDMC recommended extension to 8 cycles following interin safety analysis of first 50 pts receiving 6 cycles.[2]
Pts 20-74 yrs of age
with stage I-IIIB HER2-BC and
residual disease
(non-pCR, N+) after neoadjuvant
chemotherapy* and surgery;
ECOG OS 0 or 1;
no previius oral fluoropyrimidines
(N = 910)t
Capecitabine2500 mg/m2/day PO Days 1-14
Q3W for 8 cycles‡
Hormonal therapy if ER/PgR+(n = 455)t
Stratified by ER status, age, neoadjuvant
Chemotherapy, use of 5-FU, institution, node statusWk 24
Homonal therapy if ER/PgR+No further therapy if ER/PgR-
(n = 455)t
▪ 33% TNBC
Disease Free Survival Overall Survival
CREATE-X
Toi et al. SABCS 2015
Masuda N, et al. N Engl J Med 376:2147, 2017
CREATE-X
Subgroup analysis for DFS
Category (n) HR (95%CI)
Total (885) 0,70 (0,53 – 0,93)
Age <50 (531)
>50 (354)
0,72 (0,50 – 1,03)
0,68 (0,45 – 1,04)
HR + (561)
HR – (296)
0,84 (0,57 – 1,23)
0,58 (0,39 – 0,87)
ypN0 (345)
ypN1 (339)
ypN2 ou 3
0,88 (0,48 – 1,62)
0,54 (0,36 – 0,83)
0,82 (0,52 – 1,29)
Conclusão
Take Home Message
▪ Considerar neoadjuvância se tumor inoperável,
necessidade para melhora do resultado estético,
subtipos de maior taxa de resposta (TNBC ou HER 2 +).
▪ Considerar quimioterapia adjuvante para tumores TN
acima de 0,5 cm ou envolvimento linfonodal.
▪ Para tumores TN, papel dos platinantes permanece
controverso, mas é defendido por alguns experts.
▪ Em pacientes com tumores TN que não atingem RCp
com QT neo, considerar Capecitabina adjuvante.
Take Home Message
▪ Considerar quimioterapia baseada em antracíclico e
taxano para câncer de mama TN T> 1cm ou linfonodo
positivo, preferência para esquema dose densa.
▪ Pode ser avaliado TC x 4 ciclos em T entre 0,5 e 1 cm.
Take Home Message