fattori di rischio per metastasi cerebrali nel carcinoma ... · †targets her2 protein †high...
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Fattori di rischio per metastasi cerebrali nelcarcinoma mammario: primi risultati da uno studio
di popolazione da registro tumori
Dr. Michele Panebianco
Siracusa, 7 Maggio 2009
U.O.C. Oncologia Medica
Azienda Ospedaliero-Universitaria di Parma
Convegno AIRTUM
erb-b1
EGFR
HER1
neu
Erb-b2
HER2
Erb-b3
HER3Erb-b4
HER4
TG
F
EG
F
HR
G(N
RG
1)
Ep
i
-cel
HB
-EG
F
Am
p
Ep
i
HB
-GF
NR
G1
NR
G2
NRG
3
NRG
4
Tyrosine
kinase
domain
Ligand
binding
domain
Transmembrane
Mendelsohn and Baselga. Oncogene. 2000;19:6550.
Olayioye et al. EMBO J. 2000;19:3159.
Prigent and Lemoine. Prog Growth Factor Res. 1992;4:1.
Harari and Yarden. Oncogene. 2000;19:6102.
Earp et al. Breast Cancer Res Treat. 1995;35:115.
The EGFR/HER Family
X
•Targets HER2 protein
•High affinity (Kd = 0.1 nM)
and specificity
•95% human, 5% murine
– Decreases potential
for immunogenicity
– Increases potential
for recruiting
immune effector
mechanisms
HER2 epitopes recognized by
hypervariable murine
antibody fragment
Human
IgG-1
Trastuzumab:Humanized Anti-HER2 Antibody
Study Objective
To evaluate the role of HER2 as a risk factorfor CNS metastases
To define trastuzumab role in increasing risk
End-points
Overall survival by HER 2 status
CNS relapse-free survival by HER-2
CNS relapse-free survival by HER 2 and Trastuzumab
Overall Survival and disease free survival by HER2 and
Trastuzumab in early breast cancer
Population
1537 patients from the province of Parma,
with invasive breast cancer diagnosis
from January 2004 to December 2007
Assessed by Registro Provinciale dei Tumori di
Parma
Data collection
Database of Registro Tumori di Parma
Clinical record review from U.O. MedicalOncology;
Clinical record review from other medicaldepartments of Province of Parma;
Interviews to family doctors;
Review of cyto/istologic slides.
MEDICO DI BASE:…………………………………
ANNO DIAGNOSI:…………………………………
COGNOME:……………………………………………NOME:…………………………………
NATA IL:…………………………………
Familiarità per tumori: � NO; � SI; � NON SO.
Altri tumori della paziente: � NO; � SI, sede……………………………………………
Screening mammografico: � NO; � SI.
Diagnosi in fase � ASINTOMATICA � SINTOMATICA (autoriscontro)
Metastasi presenti alla diagnosi: � NO; � SI.
INTERVENTO: Data:………………………………………
Tipo:………………………………………
Sede intervento (Ospedale; città):………………………………………
Stato oncogene c-erbB2 (HER-2): � iperespresso/amplificato; � non iperespresso/amplificato
Trattamento post-operatorio: • Chemioterapia adiuvante � SI; � NO. • Trastuzumab (Herceptin) � SI; � NO. • Ormonoterapia � SI; � NO. • Radioterapia � SI; � NO.
Recidiva di malattia: � SI; � NO.
• 1° recidiva: Sede:………………………
Data:……………………… • Ulteriori recidive: � Encefalo; se si, Data………………………
� Altre sedi.
Ultimo follow-up: Data………………………
Performance status: � 1; � 2; � 3; � 4.
(0: nessuna restrizione della normale attività
1: limite all’attività fisica max, lavoro leggero/sedentario
2: accudisce se stesso, incapacità lavorativa, resta alzato per più del 50% della veglia
3: accudisce se stesso solo parzialmente, costretto a letto per più del 50% della veglia
4: paziente grave costretto a letto e non in grado di accudire se stesso
5: morto).
Decesso: � SI; � NO. • Data:……………………… • Causa: � Malattia di base;
� Altro.
Statistical analysis
Clinical and pathological characteristics of study
patients were compared using the Chi square test.
Survival data were calculated using the Kaplan-Meier
method. Differences in survival analyses according to
study endpoints were compared using the log rank test
Patients’ characteristics 1
Percentages were calculated after exclusion of cases in which data were unknown.
Age at diagnosis Yr 64
N (%)
Stage of diagnosis I-II III IV
783 (58) 488 (36)
76 (6)
HR positive HR negative
1218 (83)
237 (17)
Ki67 10
Ki 67 10
794 (57)
605 (43)
HER 2+
HER 2-
212 (15)
1184 (85)
Screening 661 (43)
HER 2+ with T
HER 2+ without T
71 (34)
141 (66)
Adjuvant T
T for metastatic disease
43 (60)
28 (40)
Median follow up Yr 2.76
Patients’ characteristics 2
Percentages were calculated after exclusion of cases in which data were unknown.
Overall Survival by HER2
0.0
00.2
50.5
00.7
51.0
0
0 1 2 3 4 5
analysis time
HER2 = Negativo HER2 = Positivo
Kaplan-Meier survival estimates, by HER2
P=0.0001
HER2 status Symptomatic
diagnosis n(%) Asymptomatic diagnosis n(%)
P†
HER 2 + 56 (62) 34 (38)
0.002
HER 2 - 217 (45) 267 (55)
Percentages were calculated after exclusion of cases in which data were unknown.
† Chi square test
HER2 and CNS metastases
HER2 status CNS metastases
n(%) No CNS metastases
n(%) P†
HER 2 + 9 (4.2) 203 (95.8)
HER 2 - 15 (1.3) 1169 (98.7)
0.002
Percentages were calculated after exclusion of cases in which data were unknown.
† Chi square test
CNS relapse-free survival by HER-2
0.0
00.2
50.5
00.7
51.0
0
0 1 2 3 4 5
analysis time
HER2 = Negativo HER2 = Positivo
Kaplan-Meier survival estimates, by HER2
P =
0.0014
0.0
00.2
50.5
00.7
51.0
0
0 1 2 3 4 5analysis time
HER2 = Negativo/T = no HER2 = Positivo/T = no
HER2 = Positivo/T = sì
Kaplan-Meier survival estimates, by HER2 T
P<0.0001
CNS relapse-free survival and Trastuzumab
Survival and Trastuzumab in early breast cancer0.0
00.2
50.5
00.7
51.0
0
0 1 2 3 4 5analysis time
HER2 = Negativo/T2 = 0 HER2 = Positivo/T2 = 0
HER2 = Positivo/T2 = 1
Kaplan-Meier survival estimates, by HER2 T2
0.0
00.2
50.5
00.7
51.0
0
0 1 2 3 4 5analysis time
HER2 = Negativo/T2 = 0 HER2 = Positivo/T2 = 0
HER2 = Positivo/T2 = 1
Kaplan-Meier survival estimates, by HER2 T2
Overall survival Disease-free survival
P=0.0160 P=0.0002
Conclusions
•HER-2 + breast cancer confers an increased risk of CNS
metastases
•HER-2 + patients who receive trastuzumab have a significant
increase in incidence of brain metastases
•The incidence of brain metastases is likely to increase as new
systemic treatment options become available that increase the
longevity (Lead time bias)
•Follow up continuation
•Missing data evaluation
•Considering 2008 data
•Multivariate analysis (Age, HR, Grading, Stage….)
Future perspectives
Thanks to:
Medical Oncology Unit
University Hospital of Parma:
Antonino Musolino, MD, PhD
Elisa Fontana, MD
Daniele Zanoni, MD
Maria Michiara, MD
Andrea Ardizzoni, MD
Dept. of Preventiveand Predictive MedicineINT, MilanLaura Ciccolallo, PhD
Registro Provinciale dei
Tumori di Parma:
Vincenzo De Lisi, MD
Paolo Sgargi, PhD
Francesco Bozzani, PhD
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