DEPARTMENT OF ONCOLOGY AND HEMATOLOGY

1
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
2
End points of cancer registry

• Incidence
• Mortality
• Temporal trends in incidence and mortality
• To allow for a rational planning of cancer
  control

3
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

4
Adjuvant Chemotherapy for Breast CancerBeyond
anatomic staging is it time to take the leap
into molecular era?Working group
5
Breast Cancer Registry and Molecular Subtypes

• Prevention
• Treatment
• Follow up

6
BRCA 1 2
location tumor BRCA 1 17q21 breast,
ovary,prostate BRCA2 13q13 breast, male breast,
colon pancreas

7
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

8
BRCA 1 2 Prophylaxis Healthy carriers

• Chemoprevention
• tamoxifen
• droloxifen
• raloxifen
• AIs
• Prophylactic mastectomy

• Chemical castration
• Prophylactic bilateral oophorectomy

9
Breast Cancer Registry and Molecular Subtypes

• Prevention
• Treatment
• Follow up

10
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 IIa
• Tau protein
• C-myc amplification
• ß-tubulin mutations
• Genetic polymorphism
• Gene espression profile
• Serum Biomarkers (CA 15.3, ECD,
• N-telopeptide)
• p53

11
EARLY BC RISK CATEGORIES (ST. GALLEN 2005)
LOW RISK N - and ALL of the following features
pT 2cm
G1
Absence of peritumoral vascular invasion
HER2/neu gene neither overexpressed or amplified
Age gt 35 yrs
INTERMEDIATE N - and at least ONE of the following features
pT gt 2cm
G2-3
Peritumoral vascular invasion
HER2/neu gene overexpressed or amplified
Age lt 35 yrs
N (1-3 involved nodes) and
HER2/neu gene neither overexpressed or amplified
HIGH N (1-3 involved nodes) and
HER2/neu gene overexpressed or amplified
N (4 or more involved nodes)
12
GENERAL TREATMENT RECOMMENDATIONS (ST.GALLEN
2005)
Risk Category Endocrine Responsive Doubtful Endocrine Resp Endocrine Non-Responsive
LOW ET ET -
INTERMEDIATE ET, or CT ? ET CT ? ET CT
HIGH CT ? ET CT ? ET CT
13
Node BC Evolvement of Adjuvant Chemotherapy
Simulation
Relapse-free
100 80 60 40 20 0
Relapse risk/year TAC4 6,5 (-
32) AC T3 FEC2 AC1 10,0 (- 11)
CMF1 11,4 (- 24) Nil1 15,0
? 8 (-17)
TAC
0
2
4
6
8
10
Years
1 EBCTCG 2000 2 Levine, JCO 1998 FASG, JCO 2001
3 Henderson, JCO 2003 4 Martin, NEJM 2005
14
DEFINING THE TARGET IHC AND FISH
Abnormal 2
Abnormal 3
Normal 0
Normal 1
Normal
Normal
IHC Images by Kornstein, MD, Medical College of
Virginia
15
Distant DFS by HER-2 status in pT1N0M0 stage a
nationwide population-based study (852 patients)
Joensuu H et al. Clin Cancer Res, 2003
16
Disease-Free Survival
AC?TH
87
85
AC?T
78

N Events AC?T 1679 261 AC?TH 1672 134
75
67
HR0.48, 2P3x10-12
Years From Randomization
B31/N9831
17
How many breast cancers are HER2 ?

• 15-25
• (Slamon DJ, Science 1987)
• 10- 34
• (Molecular Oncology of Breast Cancer, JS
  RossGN Hortobagyi,2005)
• 20
• (NCI www.cancer.org 2005)
• 14.5
• (Modena Cancer Center, 2005)

18
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

19
Disease-Free Survival
AC?TH
87
85
AC?T
78
71

N Events AC?T 1679 261 AC?TH 1672 134
75
67
HR0.48, 2P3x10-12
Years From Randomization
B31/N9831
20
HER 2 TESTING CONCORDANCE BETWEEN LOCAL AND
CENTRAL LAB (N 9831 TRIAL)
Central HercepTest Score Central HercepTest Score Central HercepTest Score Central HercepTest Score Central HercepTest Score
0 0 1 2 3 Total
Local Her2 testing Local Her2 testing Local Her2 testing Local Her2 testing Local Her2 testing Local Her2 testing Local Her2 testing
IHC 8 9 9 12 81 110
FISH 1 1 1 0 7 9
Total 9 10 10 12 88 119
P Roche et al, JNCI 2002
21
Molecular Portrait of Breast Cancers
Luminal B
Normal
HER-2
Basal-like
Luminal A
Sorlie T et al, PNAS 2001
22
Kaplan-Meier analysis of disease outcome in two
patient cohorts
S0rlie, Therese et al. (2003) Proc. Natl. Acad.
Sci. USA 100, 8418-8423
23
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
24
Breast cancer heterogeneity results of
gene-expression profile studies
Breast cancer type IHC surrogates pts
Basal-like ER- PR- HER2- HER1 20
HER2 HER2 ER- PR- 7
Luminal A ER or PR HER2- 51
Luminal B ER or PR HER2 16
Carey ASCO 2005
25
Breast Cancer Registry and Molecular Subtypes

• Prevention
• Treatment
• Follow up

26
Annual risk of recurrence by N
Saphner T, et al. J Clin Oncol 14 2738, 1996
27
Annual risk of recurrence by ER
Saphner T, et al. J Clin Oncol 14 2738, 1996
28
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