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

Sites of event in BC

Pestalozzi BC et al. Annals of Oncology 2006

Gori s. et al.The Oncologist 2007

OS from the time of diagnosis of MBC

Breast cancer: not a single disease

Sorlie T. et al. EJC 2004

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

HER2 testing algorithm

HER-2 amplification and CNS metastases

Duchonowska R. et a. Cancer treatment raviews, 2005

•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

Trastuzumab efficacy

CNS penetration of Trastuzumab

Contessa j. N. et al Molecular Pharmacology 2008

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