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