Terapia NeoadiuvanteRevisione delle evidenze scientifiche

Valentina GuarneriNonantola, 19 Novembre 2011

The Cochrane Library, Issue 3, 2008

DDFS o OS???

Preoperative vs postoperative, Overall Survival

The Cochrane Library, Issue 3, 2008

pCR vs residual disease, Overall Survival

T-FEC 19 pts

T-FEC + H

23 pts

pCR 26.3 % 65.2 %

pCR ER pos 27 % 61 %

pCR ER neg 25 % 70 %

pN0 78.9 % 86.9 %

Buzdar, J Clin Oncol 2005

NEOADJUVANT P-FEC TRASTUZUMAB IN HER2+ OPERABLE BREAST CANCER

Buzdar AU, Clin Cancer Res 2007

CMFq4w x 3 cycles

NOAH

HER2-positive LABC(IHC 3+ or FISH+)

ATq3w x 3 cycles

Tq3w x 4 cycles

H + ATq3w x 3 cycles

H + T q3w x 4 cycles

H q3w x 4 cycles+ CMF q4w x 3 cycles

H continued q3wto week 52

(n=115) (n=113)

ATq3w x 3 cycles

Tq3w x 4 cycles

CMFq4w x 3 cycles

HER2-negative LABC(IHC 0/1+)

Surgery followed byradiotherapya

(n=99)

Surgery followed byradiotherapya

Surgery followed byradiotherapya

19 crossed over to H

Gianni L, Lancet 2010

HR negative, or HR+ with cN+

GEPAR-QUATTRO: EFFICACY OUTCOMES

0

10

20

30

40

50

60

70

80

ypT0 ypTis ypT0/is, N0 ypN0

Untch M, J Clin Oncol 2010

Untch M et al, J Clin Oncol 2011

Stratification:• T ≤ 5 cm vs. T > 5 cm•ER or PgR + vs. ER & PgR –• N 0-1 vs. N ≥ 2•Conservative surgery or not

Invasive operableHER2+ BCT > 2 cm (inflammatory BC excluded)LVEF 50%N=450

34 weeks

52 weeks of anti-HER2 therapy

lapatinib

trastuzumab

lapatinibtrastuzumab

FEC

X

3

SURGERY

RANDOMIZE

lapatinib

trastuzumab

lapatinibtrastuzumab

paclitaxel

paclitaxel

paclitaxel

+ 12 wks6 wks

NEO-ALTTO STUDY DESIGN

Baselga J et al. SABCS 2010

L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumabpCR pathologic complete response

Neo-ALLTO: PATHOLOGIC RESPONSE

Baselga J et al. SABCS 2010

RANDOMIZATION Lapatinib 1000 mg/daily

Lapatinib 1500 mg/daily

CORE

BIOPSY

SURGERY

Chemotherapy

A

B

C

TXL 80 mg/m2

Trastuzumab 2 mg/kg

5 FU 600 mg/m2

Epi 75 mg/m2

CTX 600 mg/m2

CHER LOB Trial: study plan

Guarneri V, ASCO 2011

pCR (breast & axilla) Node negativity Breast conservation

0

10

20

30

40

50

60

70

80

90

Arm A:CT +trastuzumab

Arm B: CT +lapatinib

Arm C: CT +trastuzumab/lapatinib

CHER-LOB: EFFICACY OUTCOMES

Guarneri V, ASCO 2011

THP (n=107)docetaxel + trastuzumab +pertuzumab

HP (n=107)trastuzumab + pertuzumab

TP (n=96)docetaxel + pertuzumab

S

U

R

G

E

R

Y

docetaxel q3w x 4→FEC q3w x 3 trastuzumab q3w cycles 5–17

FEC q3w x 3trastuzumab q3w cycles 5–17

FEC q3w x 3trastuzumab q3w cycles 5–17

FEC q3w x 3trastuzumab q3w cycles 5–21

Study dosing: q3w x 4

TH (n=107)docetaxel + trastuzumab

Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417)

BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide*Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0H, trastuzumab; P, pertuzumab; T, docetaxel

NEOSPHERE: STUDY DESIGN

Gianni L et al. SABCS 2010

H, trastuzumab; P, pertuzumab; T, docetaxel

NEOSPHERE: pCR RATES

p = 0.014150

40

30

20

10

0TH THP HP TP

pC

R, %

9

5%

CI

p = 0.0198p = 0.0198

p = 0.003

29.0

45.8

16.8

24.0

6Gianni L et al. SABCS 2010

Trial/author pts # Regimen HR + %

% pCR

HR- HR+

Kemeny 54 FACVb 66 20.0 7.7

Ring 435 CMF, A/E 71 21.6 8.1

Bear 1211 AC 59 13.6 5.7

Bear 565 AC+T 57 22.8 14.1

GEPARDO 250 ddAD+/-T 56 15.4 1.1

GEPARDUO 913 ddAD/CA-D 74 22.8 6.2

GEPARTRIO 286 TAC/TAC-NX 68 36.6 10.1

Guarneri 1731 FAC+/-P 68 23.8 7.8

Gianni 438 A+/P/CMF 63 42.2 11.6

Guarneri 201 FEC/ET/GET 74 16.6 3.5

Colleoni 399 ECF/EC/ET/ViFuP

68 33.3 7.6

HORMONE RECEPTOR STATUS AND pCR

L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumabpCR pathologic complete response HR: hormone receptors

pCR BY HORMONE RECEPTOR STATUS

Baselga J et al. SABCS 2010

T: trastuzumab; L: lapatinib; T+L: trastuzumab plus lapatinib

CHER-LOB: pCR rate by HR

25%22.7%

0

10

20

30

40

50

60

Arm A (CT + T) Arm B (CT +L) Arm C (CT + T + L)

26.6%

35.7%

56.2%

35.7%

HR+ HR+HR+HR- HR-HR-

0

10

20

30

40

50

60

70

TH THP HP TP

ER or PR posER and PR neg

20.026.0

17.4

36.8

29.1 30.0

63.2

5.9

pC

R, %

9

5%

C

I

H, trastuzumab; P, pertuzumab; T, docetaxelGianni L et al. SABCS 2010

NEOSPHERE: pCR AND HORMONE RECEPTORS STATUS

Chang, ASCO 2011

Chang, ASCO 2011

PST IN HER2+ OPERABLE BREAST CANCER: KEY FINDINGS

• Patient selection is mandatory for the integration of novel agents in cancer treatment

• Chemotherapy + trastuzumab is the gold standard• Double-HER2 blockade increases the pCR rate• Endocrine pathway is still important even in presence of

HER2 co-expression• A dual anti-HER2 blockade + endocrine therapy is

promising • The preoperative setting is ideal to test new combinations

through the “window of opportunity model”