Noa Efrat Ben Baruch : Neo-adjuvant treatment in breast cancer

Neo-‐adjuvant Treatment in Breast Cancer

Past, Present and Future

Noa Efrat Ben-‐Baruch Kaplan Medical Center Rehovot, Israel


•  Inoperable breast cancer – Haagensen grave signs

•  Operable Breast cancer – One size fits all –  Is it beGer than adjuvant therapy? – Treat by biological subtypes – Use for rapid approval of new drugs – Use for screening of molecularly targeted drugs

•  1.Skin ulceraPon •  2.FixaPon of tumor to the chest wall •  3.Axillary nodes > 2.5 cm in diameter •  4.Edema of < 1/3rd of the skin of breast •  5.Presence of fixed axillary nodes

Relation Between Clinical Presentation and Outcomes: LABC, IBC, and Non-LABC/IBC

Hance et al. JNCI 2005; 97: 966



•  Operable Breast cancer – One size fits all? –  Is it be3er than adjuvant therapy? – Treat by biological subtypes – Use for rapid approval of new drugs – Use for screening of molecularly targeted drugs

Operation

Operation

AC X4 + TAM if >50 years

AC X4

+ TAM if >50 years

NSABP Protocol B-18

Operable Breast Cancer

Stratification Age Clinical Tumor Size Clinical Nodal Status

79

36

0%

40%

20%

Tumor Response (685pts.)

100%

80%

60%

PR cCR

13

pCR *25% pCR w DCIS

NSABP B-18:Neoadjuvant Chemotherapy Increases the Likelihood of BCT for Operable Breast Cancer

40

60

32

68

0

80 60 40 20

100

Postop Preop

%

P<.01

For >5 cm tumors, 22% BCT versus 8%

Mastectomy

Lumpectomy

Fisher B, et al. J Clin Oncol. 1997;15(7): 2483-2493.

90 80 70 60 50 40 30

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Survival

N Ev HR P Post 751 311 Pre 742 308 .99 0.90

40 30

50

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

N Ev HR No pCR pCR

599 344 86 29 .47

No pCR

NSABP B-18: DFS and pCR

P<.0001

75

pCR

52

100 90

80

70

% 60

Years Wolmark N. Presented at: National Cancer Institute State of the Science Conference on Preoperative Therapy in Invasive Breast Cancer; March 26-27, 2007; Bethesda, Maryland.

B-27

OPERABLE BREAST CANCER

Age, T, cN

AC

OPERATION

AC→Txt*

OPERATION

*100mg/m² x 4; Tam for all

AC OPERATION

Txt



•  Operable Breast cancer – One size fits all –  Is it better than adjuvant therapy? – Treat by biological subtypes – Use for rapid approval of new drugs – Use for screening of molecularly targeted drugs

HER Family Signaling

Hudis C. N Engl J Med 2007

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 only Lapatinib

NOAH, all patients

Phase 3 MDACC trial

P q3w x 4 → FEC q3w x 4

Eligibility Invasive operable HER 2+ breast cancer

Stage II to IIIA

LVEF ≥ 45%

StraRficaRon

Size (T) node status ER/PR

S U R G E R Y

R

P q3w x 4 + H qw → FEC q3w x 4 + H qw

C = cyclophosphamide, E = epirubicin, F =5-‐fluorouracil,

H = HercepPn, P = paclitaxel

n=23 + 22

n=19

Primary objective: pCR rate (ypT0 and ypN0)

The planed sample size was 164 pts. A`er 34 pts had completed therapy, the trial was stopped b/c superiority of

H + chemo

J clin Oncol. 2005; 23: 3676 Clin Cancer Res. 2007; 13: 228

66%

26%

T-FEC T-FEC + Tras 0

20

50

75 %

of

patie

nts

pCR with CT ±Trastuzumab

Buzdar AU, Clin Cancer Res 2007

P=0.041

Clin Cancer Res. 2007; 13: 228

P + FEC alone (n=19)

P + FEC +H (n=45)

pCR, percentage (95%CI) 26.3 (9-‐51) 60 (44.3-‐74.3)

85.3%

CMF q4w x 3 cycles

NOAH

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

AT q3w x 3 cycles

T q3w x 4 cycles

H + AT q3w x 3 cycles

H + T q3w x 4 cycles

H q3w x 4 cycles + CMF q4w x 3 cycles

H continued q3w to week 52

(n=115) (n=113) AT

q3w x 3 cycles

T q3w x 4 cycles

CMF q4w x 3 cycles

HER2-negative LABC (IHC 0/1+)

Surgery followed by radiotherapya

(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

Three Neoadjuvant Trials Using Targeted Therapies for HER-2 Positive BC

NeoALTO 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 operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF ≥ 50% N=450

34 weeks

52 weeks of anti-HER2 therapy

lapatinib

trastuzumab

lapatinib trastuzumab

FEC X 3

S U R G E R Y

R A N D O M I Z E

lapatinib

trastuzumab

lapatinib trastuzumab

paclitaxel

paclitaxel

paclitaxel

+ 12 wks 6 wks

Efficacy – pCR and tpCR

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 3 trastuzumab q3w cycles 5–17



Study dosing: q3w x 4

TH (n=107) docetaxel + trastuzumab

PaPents with operable or locally advanced /inflammatory* HER2-‐posiPve 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, M0 H, trastuzumab; P, pertuzumab; T, docetaxel

Gianni L et al. SABCS 2010

H, trastuzumab; P, pertuzumab; T, docetaxel

NeoSphere pCR rates: ITT population summary

p = 0.0141 50

40

30

20

10

0 TH THP HP TP

pCR, % ± 95%

CI

p = 0.0198

p = 0.003

29.0

45.8

16.8 24.0

6 Gianni L et al. SABCS 2010

0

10

20

30

40

50

60

70

TH THP HP TP

ER or PR pos ER and PR neg

20.0 26.0

17.4

36.8

29.1 30.0

63.2

5.9

pCR

, % ±

95%

C

I

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

NEOSPHERE: pCR and hormone receptors status

Triple NegaPve Breast Cancer

Bevacizumab?

Von Minckwitz G, SABCS 2010

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


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

Operable Breast Cancer R

Tissue for Biomarkers

SURGERY

Tissue for Biomarkers

+/-

+/-

X10

T docetaxel X capecitabine G gemcitabine B bevacizumab

NSABP B-40: Chemotherapy ± Bevacizumab in Patients with Operable

HER2-Negative Breast Cancer

Endpoints: pCR, cCR, DFS, gene expression patterns

T - AC TX - AC* TG - AC*

pCRbreast (n = 395; 394; 391) 32.7% 29.7% 32.0%

pCRbreast + nodes (n = 393; 390; 388) 26.0% 23.3% 27.3%

* p-value not significant versus T - AC T = docetaxel; X = capecitabine; G = gemcitabine

NSABP B-40: Effect of Capecitabine or Gemcitabine Added

to Docetaxel on pCR Rates


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)



•  Operable Breast cancer – One size fits all –  Is it better than adjuvant therapy? – Treat by biological subtypes – Use for rapid approval of new drugs – Use for screening of molecularly targeted

drugs

Background PI: Laura Esserman M.D. and UCSF The I-SPY TRIALS I-SPY 1àI-SPY 2

National trials to integrate imaging and tissue biomarkers to

Predict response to Rx à Tailor Rx to response

clinicaloptions.com/oncology An Update on Breast Cancer

I-SPY2: Efficacy of Neoadjuvant Veliparib/Carboplatin + Paclitaxel

Signature, % Estimated pCR Rate (95% Probability Interval)

Probability Veliparib/Carboplatin Superior to

Control

Predictive Probability of Success in Phase III Trial HR+ HR-

All HER2- 33 (22-43) 22 (10-35) 92 55

HR+/HER2- 14 (4-27) 19 (6-35) 28 9

HR-/HER2- 52 (35-69) 26 (11-40) 99 90 Rugo HS, et al. SABCS 2013. Abstract S5-02. Reproduced with permission.

Estimated pCR Rate: All HER2- Signature

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 pCR Rate

Control V/C

Probability V/C is superior to control = 0.92

Estimated pCR Rate: Triple-Negative Signature

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 pCR Rate

Control V/C


Estimated pCR Rate: HER2-/HR+ Signature

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 pCR Rate

Control

V/C


clinicaloptions.com/oncology An Update on Breast Cancer

I-SPY2: Conclusions

§  Adaptive trial design found veliparib/carboplatin treatment efficacious in patients with triple-negative breast cancer

–  Trial not designed to evaluate individual contributions of veliparib and carboplatin

§  Adverse events increased with veliparib/carboplatin regimen

–  Toxicity may be managed with dose reductions and delay

§  I-SPY2 trial design efficiently evaluated treatment regimen in patient subsets based on biomarker analysis

–  Additional response predictors currently under investigation

Rugo HS, et al. SABCS 2013. Abstract S5-02.

pCR as Regulatory Endpoint



•  Operable Breast cancer – One size fits all –  Is it better than adjuvant therapy? – Treat by biological subtypes – Use for rapid approval of new drugs – Use for screening of molecularly targeted drugs

Noa Efrat Ben Baruch : Neo-adjuvant treatment in breast cancer

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