SABCS 2008 Primär systemische Therapie · 2014. 12. 8. · Activation of PI3 kinase pathway is...

SABCS 2008Primär systemische Therapie

München08.01.2009

Dr. Claus A. HanuschOberarzt onkologische Tagesklinik

Leiter der Studienzentrale

ROTKREUZKLINIKUM München, FrauenklinikÄrztlicher Direktor: Prof. W. Eiermann

Akadem. Lehrkrankenhaus der TU MünchenEUSOMA –Brustzentrum

Breast Cancer Internat. Research Group (BCIRG)Translational Research In Oncology (TRIO)

Michelangelo Foundation GABG - GBG

N O A H (Gianni L)

INTEGRATED META-ANALYSIS (v. Minckwitz G)

PI3 KINASE ACTIVATION (Migliaccio I)

Neoadjuvant trastuzumab inpatients with HER2-positive locallyadvanced breast cancer: primaryefficacy analysis of the NOAH trial

L Gianni, W Eiermann, V Semiglazov, GM Manikhas,A Lluch, S Tjulandin, A Feyereislova, P Valagussa, J

BaselgaThe study is co-sponsored by the Michelangelo Foundation and F Hoffmann-La Roche

ATq3w x 3 cycles

Tq3w x 4 cycles

CMFq4w x 3 cycles

CMFq4w x 3 cycles

NOAH study design

IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation;H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); AT, doxorubicin (60 mg/m2), paclitaxel (150 mg/m2);

q3w, every 3 weeks; T, paclitaxel (175 mg/m2); q4w, every 4 weeksaHormone receptor-positive patients will receive adjuvant tamoxifen

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

HER2-negative LABC(IHC 0/1+)

ATq3w x 3 cycles

Tq3w x 4 cycles

Surgery followed byradiotherapya

H + ATq3w x 3 cycles

H + Tq3w x 4 cycles

H q3w x 4 cycles+ CMF q4w x 3 cycles

H continued q3wto week 52

(n=115) (n=113) (n=99)

Surgery followed byradiotherapya

Surgery followed byradiotherapya

19 crossed over to H

End points

• Primary (final analysis)– EFS defined by either progression on

therapy or relapse after surgery or death dueto any cause

• Secondary– pCR rate– overall response rate– safety and tolerability

EFS, event-free survival; pCR, pathological complete response

NOAH Trial

ASCO 2008: Biomarker as potential predictors for pCR(Gianni L, Abstract 504)

EBCC 2008: Hormone-receptor status and likelihood of predicting pCR (Eiermann W, Abstract 228)

ASCO 2007: Neoadjuvant trastuzumab in LABC- Antitumour and safety analysis(Gianni L, Abstract 532)

Baseline characteristics (1)

Stage group, %T4, non-inflammatoryInflammatory diseaseN2 or ipsilateral nodes

Hormone receptor status, %ER and / or PgR positiveBoth negative

Age group, %<50 years≥50 years

441441

6436

5149

432730

3565

4159

422731

3565

4654

Without H (n=112a)With H (n=115)

HER2 positive HER2 negative

(n=99)

ER, oestrogen receptor; PgR, progesterone receptor

a1/113 did not receive ethics approval for the last protocol amendment at the moment of the analysis

Baseline characteristics (2)

Axillary nodes, %N0N1N2

Ipsilateral supraclavicular nodes, %NoYes

Median baseline LVEF

173844

964

63

164638

964

63

134443

946

63

Without H (n=112a)With H (n=115)

HER2 positive HER2 negative

(n=99)

LVEF, left ventricular ejection fraction

a1/113 did not receive ethics approval for the last protocol amendment at the moment of the analysis

EFS: HER2-positive population1.00

0.75

0.50

0.25

0.000 6 12 18 24 30 36 42

Probability,EFS

Months

H + CTCT

Events3652

HRa

0.56pa

0.006Patients

115112

Median follow-up is 3 yearsaUnadjusted for stratification variables: adjusted HR=0.55, p=0.0062HR, hazard ratio; CI, confidence interval; CT, chemotherapy

95% CI0.36-0.85

Overall survival: HER2-positivepopulation

0 6 12 18 24 30 36 42

Probability,overall survival

Months

Events1722

Patients115112

HR0.65

p0.18

Median follow-up is 3 years

95% CI0.34-1.23H + CT

CT

1.00

0.75

0.50

0.25

0.00

LVEF during and after therapyHER2-positive control

End

of C

MF

18 m

onth

s24

mon

ths

Base

line

20

40

60

80

HER2-positive trastuzumabEn

d of

CM

F

18 m

onth

s24

mon

ths

Base

line

20

40

60

80

LVEF

End

of tr

astu

zum

ab12

mon

ths

End

of tr

astu

zum

ab12

mon

ths

Conclusions• Neoadjuvant trastuzumab with an anthracycline- and

taxane-containing chemotherapy significantly extendsEFS in patients with HER2-positive disease

• The neoadjuvant regimen is well tolerated withacceptable cardiac safety

• The neoadjuvant chemotherapy without trastuzumab issimilarly active in patients with HER2-positive andHER2-negative disease

• These data establish neoadjuvant trastuzumab withchemotherapy as a standard treatment option in womenwith HER2-positive LABC

Integrated meta-analysis on

6634 patients with early breast cancer

receiving neoadjuvant

anthracycline-taxane +/- trastuzumab

containing chemotherapy

von Minckwitz G, Kaufmann M, Kümmel S, Fasching P, Eiermann W, Blohmer JU, Costa SD,

Loibl S, Mehta K, Untch M

for the

and

A G OA G O

Three AGO TrialsAGO 1 (N=668)

EPx4R

ddE160x3→ddP260x3Untch M et al, SABCS 2007

Prepare (N=733)ECx4→Px4

RddE150x3→ddP225x3→CMFx3

Untch M et al, ASCO 2008

TECHNO (N=226)HER2 pos:

ECx4 → PHx4Untch M et al, SABCS 2005

C=Cyclophosphamide; dd=dose-dense/bi-weekly; E=Epirubicin; H=Trastuzumab; M=Methotrexate; P=Paclitaxel; R=randomization

Goals• Overall pCR rate

• Effects by treatment groups– Trastuzumab

– Dose-density

– Treatment duration

– Concomitant / sequential

• Predictive factors for pCR

14.7%

9.4%

17.2%

4.6%

3.3%

5.3%

0%

5%

10%

15%

20%

25%

Total 1998-2002 2003-2006

pCR

Overall pCR rate

N=6634 N=4526N=2108

ypTis NoypT0 No

P<0.001

17.1%

27.7%

5.6%

13.4%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

without Trastuzumab with Trastuzumab

pC

R

Treatment Group Effects*Use of Trastuzumab

in Patients with HER2-Positive Tumors

N=736 N=671

* excluding patients with HER2 negative or HER2 unknown tumors

P<0.001ypTis NoypT0 No

4.2%9.6%

21.5%

2.5%

3.3%

6.3%

0%

5%

10%

15%

20%

25%

30%

35%

grade 1 grade 2 grade 3

pC

RPredictive FactorsHistological Grade

N=3448 N=2497N=237

P<0.001ypTis NoypT0 No

Conclusions• Largest, integrated meta-analysis of breast cancer patients treated with

neoadjuvant anthracyclines and taxanes (+ trastuzumab)

• Increase of pCR rates over time achieved by longer treatment duration

and use of trastuzumab

• Patients at young age with smaller, node-negative tumors,

undifferentiated, negative hormone receptor, and/or positive HER2-status

have a high chance for pathological complete response

Results 1:

Significant decrease in clinical tumour size after three weeks of trastuzumab (n=35, median=-20%) and significant decrease in clinical tumour size after six weeks of lapatinib (n=49, median=-74%) (p<0.001). At surgery, pathologic complete response 38% in patients on upfront T and 70% patient on L.

Results 2:

Significant increase in apoptosis (median=3.5% to 4.7%, p=0.006)within one week after T, with no significant change in Ki67 at any of the time point.

No significant increase in apoptosis but a significant decrease in Ki67at week 2, 4, and 6 of therapy (p<0.001) after L.

Low PTEN or PIK3CA mutations: significantly less pCR to T (p<0.005).

Low PTEN or PIK3CA mutations: not significantly associated with pathologic resistance to L.

Conclusion

Activation of PI3 kinase pathway is associated with trastuzumabbut not lapatinib resistance

Lapatinib may affect signalling through the Ras/Raf/MAPK/ERK pathway,inhibiting cell division

Low PTEN expression was not associated with lapatinib resistance,and may explain the clinical efficacy of lapatinib in trastuzumab-resistant pts.

Data supporting clinical trials for the combination of both agents

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