1. Is mammacarcinoom onder de veertig jaar morfologisch en genetisch een andere ziekte? Marc van de Vijver, Netherlands Cancer Institute, Amsterdam, NL

2. Age & local control Local 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 RISK 30201003020100

3. 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

4. Histologische classificatie type en graad

5. 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 size and % of lymph node positive patients Histopathological factors

6. Clinical detection Time (years) Grade 3 (faster growth) Grade 1 (slower growth)

7. common precursor? LCIS well diff DCIS moder diff DCIS poorly diff DCIS ? E-cadherin inactivation 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. BRCA1/2 germline mutation inactivation of BRCA1/2 wildtype allele

8. 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

9. Histologic grade Lakhani et al., J Clin Oncol 2003

10. Estrogen receptor in BRCA1 and 2 associated breast carcinomas Lakhani et al., J Clin Oncol 2003

11. HER2 in BRCA1 and 2 associated breast carcinomas Lakhani et al.JCO2003

12. P53 in BRCA1 and 2 associated breast carcinomas Lakhani et al. JCO2003

13. Basal keratins in BRCA1 and 2 associated breast carcinomas Lakhani et al. (Breast Cancer Linkage Consortium) submitted

14. Scanned image of a flexjet 25,000 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

15. Perou et al., Nature 406 (2000)

17. Subgroup analysis of the N4+ study Juliane Hannemann, Marc van de Vijver Harm van Tinteren, Sjoerd Rodenhuis

18. Definition of subgroups

19. Sample Frequency

20. Recurrence-free survival associated with molecular subtypes

21. Overall survival associated with molecular subtypes

22. 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