open issues in multidisciplinary breast cancer management mediterranean school of oncology rome,...

OPEN ISSUES IN MULTIDISCIPLINARY BREAST CANCER MANAGEMENTMediterranean School of Oncology

Rome, March 30, 2012

NEOADJUVANT THERAPY

Lucia MentucciaOncologia Medica, Sora

• To improve surgical outcomes and options- For operable breast cancer, the aim is to increase the

chance of breast conserving surgery in patients who would otherwise require mastectomy

- For inoperable locally advanced breast cancers, the aim is to achieve operability

• To gain information on tumor response

• To define short-term surrogate markers of response

Goals of Neoadjuvant Theapy in Breast Cancer

1523 pts with clinical T1-3, N0-N1 breast cancer

Stratification

• Age

• Clinical Tumor Size

• Clinical Nodal Status

Operation

Operation

NSABP B-18

Wolmark N t al; J Natl Cancer Inst Monogr. 2001

AC x 4

AC x 4

36%

20%

43%

cCR(249 pts)

cPR(296 pts)

cSD + cPD(140 pts)

23%

4%

9%

pInv(160 pts)

pNon-Inv(26 pts)

pCR(63 pts)

NSABP B-18: Clinical and Pathologic Breast Tumor Response


NSABP B-18: Surgery Performed

100

80

60

40

20

0

%

P < 0.01

Mast

Lump

60

40

68

32

Preop- ChemoPostop-Chemo


NSABP B-27 Pts with T1c-3 N0 or T1-3N1 breast cancer

Randomization

AC x 4 Tam X 5 Yrs

AC x 4 Tam X 5 Yrs

AC x 4 Tam X 5 Yrs

Surgery Taxotere x 4 Surgery

Surgery Taxotere x 4

2411 pts

Bear HD, et al. J ClinOncol. 2006;24(13):2019-2027.

NSABP B-27PathologicComplete

Response in Breast


Disease free-survival Overall Survival

pCR to Neoadjuvant Chemotherapy is correlated with improved DFS &

OS (NSABP B-27)


NSABP B-27: Overall Survival Nodal Status

Pts without pCR Pts with pCR

NSABP B-27: OS, DFS, RFS

Preoperative vs postoperative, Overall Survival

The Cochrane Library, Issue 3, 2008

pCR vs residual disease, Overall Survival

The Cochrane Library, Issue 3, 2008

Intrinsic sub-types have different prognosis and

different response to primary CT

0 10 20 30 40 50 60 70 80 90 100

Christofanilli et al 2006, n=30

Bines et al 2003, n=32

Burstein et al 2003, n=40

Kelly et al 2006, n=37

Harris et al 2003, n=40

Hurley et al 2002, n=48

Griggs et al 2005, n=18

Limentani et al 2007, n=31

Gianni et al 2007, n=115

Lybaert et al 2006, n=89

Coudert et al 2005, n=33

Buzdar et al 2007, n=64

Pernas et al 2006, n=16

Response Rates with Neoadjuvant Trastuzumab

pCR (%)

T + L (IBC only)

D + H

T + H (including IBC)

AC → T + H (including IBC)

V + H (including IBC)

D + cisplatin + H (including IBC)

D + H

D + V + T (including IBC)

X + D + H

AT → T → CMF + H

D + H

T → FEC + H

T → FEC + H

Study

L, lapatinib; V, vinorelbine; X, capecitabine; FEC, 5-fluorouracil, epirubicin, cyclophosphamide

AT → T → CMF + H (IBC only)Baselga et al 2007, n=31

Trastuzumab

NOAH, IBC onlyLapatinib

NOAH, all patients

Paclitaxel q3wk x 4 + H x 12N=23

FEC x 4 + H x 12

R

Paclitaxel q3wk x 4N=19

FEC x 4BC ptsM0, T1-3, No-1,

HER2+ (FISH or ICH 3+)

N=42

FEC, 5-fluorouracil, epirubicin, cyclophosphamideH, trastuzumab

The MD Anderson Study

Buzdar AU, Clin Cancer Res 2007

Additional 22 pts

66%

26%

T-FEC T-FEC + Tras0

20

50

75%

of

pat

ien

ts

pCR with CT Trastuzumab


MD Anderson Neoadjuvant Trial DFS at 72 months FU

Buzdar A et al ASCO Breast 2009


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)



19 crossed over to H

Gianni L et al. Lancet 2010; 375: 377–84

Patients (%)

39%

20%

0

10

20

30

40

50

With H Without H

HER2 positive

p=0.002

pCR rates in the NOAH trial:intent-to-treat population

Gianni L et al. Lancet 2010; 375: 377–84

EFS: HER2-positive population

L. Gianni et al., The Lancet, 2010

… Future Clinical Practice….

Anti-HER2 Treatment: mechanisms of action

Three Neoadjuvant Trials Using Targeted Therapies for HER-2 Positive

BC

LAPATINIB VS TRASTUZUMAB IN COMBINATION WITH NEOADJUVANT

ANTHRACYCLINE-TAXANE-BASED CHEMOTHERAPY:

PRIMARY EFFICACY ENDPOINT ANALYSIS OF THE

GEPARQUINTO STUDY (GBG 44)

Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching P,

Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kühn T, Nekljudova V, von

Minckwitz G for the

GBG /AGO study group

This presentation is the intellectual property of the author/presenter Contact them for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8-12, 2010

Conclusions from Run-in Phase(N=60)

• Neutropenia Grade III/ IV in 82% G-CSF made mandatory together with L

• Treatment discontinuations in 34.5%L dose reduced from 1250 to 1000 mg/ d

• Diarrhea Grade III/ IV in 6.9%Loperamide given as stand-by medication

for L* von Minckwitz, M. Untch et al, Ann Oncol 2010

Breast Conservation Rate

65.6% 56.0%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

EC-Doc + T EC-Doc + L

Conclusions

Anthracycline-taxane based CT + T achieved a pCR (ypT0/is ypN-/+) rate of 50% in HER2-positive patients, confirming our previous findings (TECHNO, GeparQuattro)

CT + L (1250/ 1000 mg) resulted in a significantly lower pCR rate of 35% (Caveat: 10% more discontinuations with L).

Compliance of L with EC and Docetaxel was lower than with T.

Results should be seen in the context of other studies like Neo-ALTTO, which uses a higher dose of L (1500 mg/d) but a shorter pre-operative treatment duration.

First results of the Neo-ALTTO trial (BIG 01-06 / EGF 106903): A phase III, randomized, open label,

neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with

HER2-positive primary breast cancer

José Baselga, Ian Bradbury, Holger Eidtmann, Serena Di Cosimo, Claudia Aura, Evandro de Azambuja, Henry Gomez, Phuong Dinh,

Karine Fauria, Veerle Van Dooren, Paolo Paoletti, Aron Goldhirsch, Tsai-Wang Chang, Istvan Lang, Michael Untch,

Richard D. Gelber and Martine Piccart-Gebhart on behalf of the Neo-ALTTO Study Team

December 10, 2010

Study Design

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

lapatinib

trastuzumab

FEC

X

3

SURGERY

RANDOMIZE

lapatinib

trastuzumab

lapatinib

trastuzumab

paclitaxel

paclitaxel

paclitaxel

+ 12 wks6 wks

Efficacy – pCR and tpCR

Efficacy – Overall (Clinical) Responseat 6 weeks (w/o chemo) and at surgery

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

Safety

• No major cardiac dysfunction• One death in L+T immediately after end of

treatment

L(N= 154)

T(N= 149)

L+T(N= 152)

Diarrhea 36 (23%) 3 (2%) 32 (21%)

Hepatic * 20 (13%) 2 (1%) 13 ( 9%)

Neutropenia 24 (16%) 4 (3%) 13 ( 9%)

Skin disorders 10 (7%) 4 (3%) 10 (7%)

Number (%) of patients with AEs at Grade ≥ 3

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

* Includes 2 patients with Hy’s Law criteria in T, and one patient in L

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

121 paz

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

NeoSphere: study design

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



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

Gianni L et al. SABCS 2010

H, trastuzumab; P, pertuzumab; T, docetaxel

NeoSphere pCR rates: ITT population summary

p = 0.014150

40

30

20

10

0TH THP HP TP

pCR,

%

95%

CI

p = 0.0198p = 0.0198

p = 0.003

29.0

45.8

16.824.0

6Gianni L et al. SABCS 2010

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

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-

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

Neoadjuvant therapy 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• The preoperative setting is ideal to test new

combinations through the “window of opportunity model”

• Should neoadjuvant regimens for HER2-positive disease always contain anti-HER2 drug?

Yes No A

• Is dual HER2-targeting a reasonable option for the preoperative setting for HER2 disease?

Yes No A

8.5%87.2% 4.3%

67.4%21.7% 10.9%

Neo Adjuvant Systemic Therapy

St Gallen 2011

Von Minckwitz G, SABCS 2010

OBJECTIVES


CHARACTERISTICS OF PATIENTS

Neoadjuvant Bevacizumab and Anthracycline-Taxane Based Chemotherapy in 684 Triple Negative Primary Breast Cancers: Secondary Endpoint Analysis of the GEPARQUINTO Study (GBG 44)

Gerber B et al. Proc ASCO 2011;Abstract 1006.

Gerber B et al. Proc ASCO 2011;Abstract 1006. Gerber B et al. Proc ASCO 2011;Abstract 1006.

GEPARQUINTO: Benefit of Bevacizumab

Added to Neoadjuvant Chemotherapy in TNBC Subgroup


• Benefit of bev limited to TNBC subgroup

• pCRbreast (with bev vs without bev)*• TNBC patients: 36.4 vs 27.8% (p =

0.021)• All patients: 15.0 vs 17.5% (p = NS)

* pCRbreast = no inv/non-inv in breast and nodes


The Effect of pCR of Bevacizumab and/or Antimetabolites Added to Standard Neoadjuvant Chemotherapy: NSABP Protocol B-40

Bear HD et al. Proc ASCO 2011;Abstract LBA1005.


NSABP B-40: Chemotherapy ± Bevacizumab in Patients with Operable HER2-Negative Breast Cancer

OperableBreastCancer

R

Tissue forBiomarkers

SURG

ERY

Tissue forBiomarkers

+/-

+/-

X10

T docetaxelX capecitabine G gemcitabine B bevacizumab

NSABP B-40: Benefit of Adding Bevacizumab to Standard

Chemotherapy


• Benefit of bev predominant in HR+ and not TNBC patient subgroup

• pCRbreast (with bev vs without bev):• HR+ patients: 23.3 vs 15.2% (p = 0.008)

• TNBC patients: 51.3 vs 47.3% (p = 0.44)

Yes No A

• If YES, for which duration (choose one)?

2.2%97.8% 0%

Neo Adjuvant Systemic Therapy

• Is neodjuvant endocrine therapy alone a reasonable option for postmenopausal pts with highly endocrine-responsive disease?

- 3-4 months

- 4-8 months

- Maximal response

15.2%

39.1%

45.7%

St Gallen 2011

Grazie!

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