Transcript Document
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
BRCA 1 location 17q21 tumor breast, ovary,prostate BRCA2 13q13 breast, male breast, colon pancreas
BRCA 1 & 2 Surveillance Healthy carriers
Breast • Breast self-exams • Clinical breast exams • Mammography • New technologies ..
(MRI) Ovary • Clinical examinations • Pelvic ultrasound • Transvaginal ...ultrasound
• 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 II α • 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 LOW INTERMEDIATE HIGH Endocrine Responsive ET Doubtful Endocrine Resp ET Endocrine Non-Responsive CT
ET CT ET, or CT
ET CT
ET CT
ET CT
Node + BC: Evolvement of Adjuvant Chemotherapy
Simulation* % Relapse-free
100 80 60 40 20 0 0
TAC AC - T/FEC AC CMF Nil
2 4
Years
6 8 10
Relapse risk/year TAC
4
AC
–
T
3
= 6,5 % (- 32%) ~ 8 % (-17%) FEC
2
AC
1
CMF
1
Nil
1
= = = 10,0 % (- 11%) 11,4 % (- 24%) 15,0 %
* 1 EBCTCG 2000 2 Levine, 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 % AC T AC TH 87% 78 % 85% N AC T 1679 AC TH 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 % AC TH 87% 85% AC T 78 % 71% N AC T 1679 AC TH 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 Local Her2 testing IHC FISH Total 8 1 9 9 1 10 12 0 12 81 7 88 110 9 119 P Roche et al, JNCI 2002
Basal-like Molecular Portrait of Breast Cancers HER-2 “Normal” Luminal B Luminal A
Sorlie T et al, PNAS 2001
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 Her2+ Luminal Normal-like 45% 45% 6% 0 Rouzier et al, Clin Cancer Res 2005
Breast cancer heterogeneity: results of gene-expression profile studies % pts Breast cancer type Basal-like HER2+ Luminal A Luminal B IHC surrogates
ER- PR HER2- HER1+ HER2+ ER- PR ER+ or PR+ HER2 ER+ or PR+ HER2+ 20 7 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