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

Obrigadajumpimenta@yahoo.com.br