Fattori di rischio per metastasi cerebrali nel carcinoma mammario: primi risultati da uno studio di popolazione da registro tumori

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1 Fattori di rischio per metastasi cerebrali nel carcinoma mammario: primi risultati da uno studio di popolazione da registro tumori Dr. Michele Panebianco U.O.C. Oncologia Medica Azienda Ospedaliero-Universitaria di Parma Siracusa, 7 Maggio 2009 Convegno AIRTUM

2 Sites of event in BC Pestalozzi BC et al. Annals of Oncology 2006

3 OS from the time of diagnosis of MBC Gori s. et al.the Oncologist 2007

4 Breast cancer: not a single disease Sorlie T. et al. EJC 2004

5 The EGFR/HER Family TGF EGF Ligand binding domain Epi -cel HB-EGF Amp X HRG (NRG1) Epi HB-GF NRG1 NRG2 NRG3 NRG4 Transmembrane Tyrosine kinase domain erb-b1 EGFR HER1 neu Erb-b2 HER2 Erb-b3 HER3 Erb-b4 HER4 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.

6 HER2 testing algorithm

7 HER-2 amplification and CNS metastases Duchonowska R. et a. Cancer treatment raviews, 2005

8 Trastuzumab: Humanized Anti-HER2 Antibody HER2 epitopes recognized by hypervariable murine antibody fragment Human IgG-1 Targets HER2 protein High affinity (K d = 0.1 nm) and specificity 95% human, 5% murine Decreases potential for immunogenicity Increases potential for recruiting immune effector mechanisms

9 Trastuzumab efficacy

10 CNS penetration of Trastuzumab Contessa j. N. et al Molecular Pharmacology 2008

11 Study Objective To evaluate the role of HER2 as a risk factor for CNS metastases To define trastuzumab role in increasing risk

12 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

13 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

14 Data collection Database of Registro Tumori di Parma Clinical record review from U.O. Medical Oncology; Clinical record review from other medical departments of Province of Parma; Interviews to family doctors; Review of cyto/istologic slides.

15 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.

16 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

17 Patients characteristics 1 Age at diagnosis Yr 64 Stage of diagnosis I-II III IV HR positive HR negative Ki67 10 Ki N (%) 783 (58) 488 (36) 76 (6) 1218 (83) 237 (17) 794 (57) 605 (43) Percentages were calculated after exclusion of cases in which data were unknown.

18 Patients characteristics 2 HER 2+ HER (15) 1184 (85) Screening 661 (43) HER 2+ with T HER 2+ without T Adjuvant T T for metastatic disease 71 (34) 141 (66) 43 (60) 28 (40) Median follow up Yr 2.76 Percentages were calculated after exclusion of cases in which data were unknown.

19 Overall Survival by HER Kaplan-Meier survival estimates, by HER2 P= analysis time HER2 = Negativo HER2 = Positivo

20 HER2 status Symptomatic diagnosis n(%) Asymptomatic diagnosis n(%) P HER (62) 34 (38) HER (45) 267 (55) Percentages were calculated after exclusion of cases in which data were unknown. Chi square test

21 HER2 and CNS metastases HER2 status CNS metastases n(%) No CNS metastases n(%) P HER (4.2) 203 (95.8) HER 2-15 (1.3) 1169 (98.7) Percentages were calculated after exclusion of cases in which data were unknown. Chi square test

22 CNS relapse-free survival by HER Kaplan-Meier survival estimates, by HER2 P = analysis time HER2 = Negativo HER2 = Positivo

23 CNS relapse-free survival and Trastuzumab Kaplan-Meier survival estimates, by HER2 T P< analysis time HER2 = Negativo/T = no HER2 = Positivo/T = sì HER2 = Positivo/T = no

24 Survival and Trastuzumab in early breast cancer Overall survival Disease-free survival Kaplan-Meier survival estimates, by HER2 T2 P= Kaplan-Meier survival estimates, by HER2 T2 P= analysis time analysis time HER2 = Negativo/T2 = 0 HER2 = Positivo/T2 = 0 HER2 = Positivo/T2 = 1 HER2 = Negativo/T2 = 0 HER2 = Positivo/T2 = 0 HER2 = Positivo/T2 = 1

25 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)

26 Future perspectives Follow up continuation Missing data evaluation Considering 2008 data Multivariate analysis (Age, HR, Grading, Stage.)

27 Thanks to: Medical Oncology Unit University Hospital of Parma: Registro Provinciale dei Tumori di Parma: Antonino Musolino, MD, PhD Elisa Fontana, MD Daniele Zanoni, MD Maria Michiara, MD Andrea Ardizzoni, MD Vincenzo De Lisi, MD Paolo Sgargi, PhD Francesco Bozzani, PhD Dept. of Preventive and Predictive Medicine INT, Milan Laura Ciccolallo, PhD