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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
ACTH
87%
ACT
85%
78 %
%
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%
ACT
85%
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
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