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DEPARTMENT OF ONCOLOGY AND HEMATOLOGY UNIVERSITY OF MODENA AND REGGIO EMILIA MODENA, ITALY I fattori prognostici del tumore della mammella: è possibile un approccio di popolazione ? Prof. Pier Franco Conte Reggio Emilia, 6 Aprile 2006 End points of cancer registry • Incidence • Mortality • Temporal trends in incidence and mortality To allow for a rational planning of cancer control Breast Cancer in the last decade • Increased Incidence: – lack of efficacy of primary prevention • Decreased mortality: – Efficacy of secondary prevention (screening) – More efficacious treatments • In the adjuvant setting • In the metastatic setting Adjuvant Chemotherapy for Breast Cancer Beyond anatomic staging: is it time to take the leap into molecular era? Working group Breast Cancer Registry and Molecular Subtypes • Prevention • Treatment • Follow up BRCA 1 & 2 location tumor BRCA 1 17q21 breast, ovary,prostate BRCA2 13q13 breast, male breast, colon pancreas BRCA 1 & 2 Surveillance Healthy carriers Breast Ovary • Breast self-exams • Clinical examinations • Clinical breast exams • Pelvic ultrasound • Mammography • Transvaginal ...ultrasound • New technologies ..(MRI) • CA 125 BRCA 1 & 2 Prophylaxis Healthy carriers • Chemoprevention: tamoxifen droloxifen raloxifen AIs • Prophylactic mastectomy • Chemical castration • Prophylactic bilateral oophorectomy Breast Cancer Registry and Molecular Subtypes • Prevention • Treatment • Follow up BREAST CANCER: PROGNOSTIC and PREDICTIVE MARKERS Prognostic Markers • • • • • • • • • • • • • • • Age/PS TNM Nuclear grade Hormone receptor status Proliferative status Her2 status Lymphovascular invasion Upa/PAI1 Oncotype DX Gene expression profile Cyclins E and D1 Cathepsin D p53 Bcl-2 VEGFr Predictive Markers •Hormone receptor status •Her2 status •Topoisomerase IIα •Tau protein •C-myc amplification •β-tubulin mutations •Genetic polymorphism •Gene espression profile •Serum Biomarkers (CA 15.3, ECD, N-telopeptide) •p53 EARLY BC: RISK CATEGORIES (ST. GALLEN 2005) LOW RISK INTERMEDIATE HIGH N - and ALL of the following features: pT ≤ 2cm G1 Absence of peritumoral vascular invasion HER2/neu gene neither overexpressed or amplified Age > 35 yrs N - and at least ONE of the following features pT > 2cm G2-3 Peritumoral vascular invasion HER2/neu gene overexpressed or amplified Age < 35 yrs N + (1-3 involved nodes) and HER2/neu gene neither overexpressed or amplified N + (1-3 involved nodes) and HER2/neu gene overexpressed or amplified N + (4 or more involved nodes) GENERAL TREATMENT RECOMMENDATIONS (ST.GALLEN 2005) Risk Category Endocrine Responsive Doubtful Endocrine Resp Endocrine Non-Responsive ET ET - INTERMEDIATE ET, or CT ET CT ET CT HIGH CT ET CT ET CT LOW Node + BC: Evolvement of Adjuvant Chemotherapy Simulation* % Relapse-free 100 Relapse risk/year 80 TAC4 AC –T3 FEC2 AC1 CMF1 Nil1 60 TAC AC - T/FEC AC CMF Nil 40 20 = 6,5 % (- 32%) ~ 8 % (-17%) = 10,0 % (- 11%) = 11,4 % (- 24%) = 15,0 % 0 0 2 4 6 8 10 Years *1 2 Levine, EBCTCG 2000 JCO 1998; FASG, JCO 2001 *3 Henderson, JCO 2003 4 Martin, NEJM 2005 DEFINING THE TARGET IHC AND FISH Normal 0 Normal 1+ Abnormal 2+ Abnormal 3+ Normal Normal Abnormal low amplification Abnormal high amplification IHC Images by Kornstein, MD, Medical College of Virginia Distant DFS by HER-2 status in pT1N0M0 stage: a nationwide population-based study (852 patients) Joensuu H et al.: Clin Cancer Res, 2003 Disease-Free Survival ACTH 87% ACT 85% 78 % % N ACT 1679 ACTH 1672 Events 261 134 75 % 67 % HR=0.48, 2P=3x10-12 Years From Randomization B31/N9831 How many breast cancers are HER2+ ? 15-25% (Slamon DJ, Science 1987) 10- 34% (Molecular Oncology of Breast Cancer, JS Ross&GN Hortobagyi,2005) ~ 20 % (NCI; www.cancer.org 2005) 14.5 % (Modena Cancer Center, 2005) HER2+ and Age • Median age in trials 49 y • Median age (Omero project) 53 y • Median age (Modena Cancer Center) 56 y Median age of Breast Cancer patients in Modena Cancer Registry: 62.3 yrs Disease-Free Survival ACTH 87% ACT 85% 78 % 71% % N ACT 1679 ACTH 1672 Events 261 134 75 % 67 % HR=0.48, 2P=3x10-12 Years From Randomization B31/N9831 HER 2 TESTING: CONCORDANCE BETWEEN LOCAL AND CENTRAL LAB (N 9831 TRIAL) Central HercepTest Score 0 1+ 2+ 3+ Total IHC 8 9 12 81 110 FISH 1 1 0 7 9 Total 9 10 12 88 119 Local Her2 testing P Roche et al, JNCI 2002 Molecular Portrait of Breast Cancers Basal-like HER-2 “Normal” Sorlie T et al, PNAS 2001 Luminal B Luminal A Kaplan-Meier analysis of disease outcome in two patient cohorts S0rlie, Therese et al. (2003) Proc. Natl. Acad. Sci. USA 100, 8418-8423 Molecular subtypes respond differently to PCT pCR rate after preoperative anthra-taxanes combination Basal like 45% Her2+ 45% Luminal 6% Normal-like 0 Rouzier et al, Clin Cancer Res 2005 Breast cancer heterogeneity: results of gene-expression profile studies Breast cancer type Basal-like HER2+ Luminal A Luminal B IHC surrogates % pts ER- PRHER2- HER1+ 20 HER2+ ER- PRER+ or PR+ HER2- 7 ER+ or PR+ HER2+ 51 16 Carey ASCO 2005 Breast Cancer Registry and Molecular Subtypes • Prevention • Treatment • Follow up Annual risk of recurrence by N Saphner T, et al. J Clin Oncol 14: 2738, 1996 Annual risk of recurrence by ER Saphner T, et al. J Clin Oncol 14: 2738, 1996 Breast Cancer Registry and Molecular Subtypes • Molecular subtypes of breast cancer: - require different diagnostic procedures - may have different risk/benefit ratio for preventive interventions - respond differently to treatments - have different annual risk of relapse A population-based registry of the molecular subtypes of breast cancer would allow a more rational planning of resource allocation