Is mammacarcinoom onder de veertig jaar morfologisch
en genetisch een andere ziekte?
Marc van de Vijver, Netherlands Cancer Institute, Amsterdam, NL
Age & local controlLocal recurrence risk for 1393 breast carcinomas treated with BCT according to different age groups
Elkhuizen et al. Int J Radiat Oncol Biol Phys 40: 859-867, 1998
Age
<35
35-44
45-54
55-64 65-74
75
LOCAL RECURRENCE RISK3
0
20
10
0
years
121086420
% e
ve
nt fr
ee
1,0
,9
,8
,7
,6
,5
,4
,3
,2
,1
0,0
> 40
<= 40
RR 1.37, P < 0.001
Overall survival adjusted for tumor size, nodal status, chemotherapy and trial
9500+ patients with primary operable breast cancer from 4 randomized EORTC trials
Histologische classificatietype en graad
Differences between breast carcinoma in young patients compared to older patients
<40 years• 50% grade 3• 50% ER negative
> 60 years• 20% grade 3• 20% ER negative
There are also small differences in sizeand % of lymph node positive patients
Histopathological factors
Clinical detection
Time (years)
Grade 3(faster growth)
Grade 1(slower growth)
common precursor?
LCIS
well diff DCIS
moder diff DCIS
poorly diff DCIS
?
E-cadherininactivation
LOH 16q
invasive lobular carcinoma
invasive ductal carc.grade 1
invasive ductal carc.grade 2
invasive ductal carc.grade 3
invasive ductal carc.grade 3
p53 mut., HER2 gene amplif.BRCA1/2germline mutation
inactivationof BRCA1/2 wildtypeallele
Differences between breast carcinoma in young patients compared to older patients
<40 years• 10% is BRCA1/2
associated
> 60 years• 2% is BRCA1/2
associated
No major differences in the type of genetic alterations in sporadic tumors
Genetic factors
Histologic grade
Control BRCA1 BRCA2
Grade 1 24% 9% 11%
Grade 2 40% 25% 48%
Grade 3 36% 66% 41%
Lakhani et al., J Clin Oncol 2003
Estrogen receptor in BRCA1 and 2 associated breast carcinomas
ER % cells positive
contr
BRCA1
BRCA2
<1 36%
90% 34%
1-50 11% 5% 8%
>50 52% 6% 54%
Lakhani et al., J Clin Oncol 2003
HER2 in BRCA1 and 2 associated breast carcinomas
HER2/neu control BRCA1 BRCA2
+ 15% 3% 3%
- 85% 97% 97%
Lakhani et al.JCO2003
P53 in BRCA1 and 2 associated breast carcinomas
P53(cut-off 50%)
control BRCA1 BRCA2
+ 22% 44% 39%
- 78% 56% 61%
Lakhani et al. JCO2003
Basal keratins in BRCA1 and 2 associated breast carcinomas
CK5/6 CK14
control BRCA1 BRCA2
+
14% 70% 23%
- 86% 30% 77%
Lakhani et al. (Breast Cancer Linkage Consortium) submitted
Scanned image of a flexjet25,000 gene human
microarray
Hybridized with mixture of ‘red’-labeled cRNA of a tumor sample and ‘green’-labeled reference cRNA
Analysis of gene expression in breast cancer
Perou et al., Nature 406 (2000)
Subgroup analysisof the N4+ study
Juliane Hannemann, Marc van de Vijver
Harm van Tinteren, Sjoerd Rodenhuis
Definition of subgroups
Sample Frequency
Recurrence-free survival associated
with molecular subtypes
Overall survival associatedwith molecular subtypes
Conclusions:
• Breast carcinomas in young patients are more frequently of high histologic grade and ER negative;
• However, this only partly explains poor outcome in these patients, especially the high local recurrence rate after BCT
• BRCA1/2 associated tumors have distinct histological and genetic features, but only represent a small proportion of all tumors, even in young patients
• No specific genetic alterations have been found to be associated with tumors in young patients
