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