1. ENITEC L1CAM 1 validation study in Endometrial Cancer
ESGO, October 24th 2015, NICE
Johanna Pijnenborg

3. ENITEC meeting at ESGO 2013……

4. Univariate survival analyses according to L1CAM expression in 1021 patients with FIGO stage I, type I endometrial cancers
Univariate survival analyses according to L1CAM expression in 1021 patients with Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stage I, type I endometrial cancers. A) Disease-free survival. B) Overall survival. Differences in survival between L1CAM positive (pos; ie, immunostaining in ≥10% of the tumor cells) and L1CAM negative (neg; ie, immunostaining in <10% of the tumor cells) groups were assessed by the two-sided log-rank test. The numbers of patients at risk are given below the graphs.
Alain G. Zeimet et al. JNCI J Natl Cancer Inst 2013;105:
© The Author Published by Oxford University Press. All rights reserved. For Permissions, please

5. Background L1 Cell Adhesion Molecule (L1CAM)
a transmembrane protein and neuronal cell adhesion molecule
involved in axon guidance and cell migration
associated with a worse prognosis in cancer

6. Aim of the ENITEC collaborative study
Primary objective
To validate the prognostic significance of L1CAM expression in FIGO stage I, endometrioid endometrial cancer, as found by Zeimet et al.
Secondary objective
To determine the prognostic significance of L1CAM expression in:
advanced stage endometrioid endometrial carcinomas
non-endometrioid type endometrial carcinomas

7. Material & Methods Inclusion criteria Staining Scoring Outcome
I: Figo stage I, endometrioid histology
II: Figo stage II+ endometrioid and all non-endometrioid
At least 36 months of follow-up
Staining
L1CAM and H&E
Scoring
Twice, indipendently by pathologists
Four categories: 0%, 1-10%, 11-50% or %
Outcome
Recurrent disease and death of disease
Multivariate regression analysis:
Age, myometrial invasion, grade, LVSI, stage and histology

9. Results: Population Total cases 1215 Stage I EEC 933 (77%)
Stage II-IV EEC
168 (14%)
NEEC
114 (9%)
Mean follow-up
67 months (sd 33)
L1CAM positive
199 (16%)

10. Results: L1CAM expression pattern
EEC 11% L1CAM + / NEEC 68% L1CAM +
Stage I EC 9,6% L1CAM +
Stage II+ EC 18% L1CAM +
Inter-observer variability = 0.8

11. Results: L1CAM cut-off value

12. Results: L1CAM positive- + OR
Stage I EEC
842
91 (10%)
Stage II-IV EEC
138
30 (18%)
NEEC 36
78 (65%)
12 (7-19)

13. Results: recurrence L1CAM - + p Stage I EEC 67 (8%) 19 (21%) <0.01
Stage II-IV EEC
29 (21%)
13 (43%)
NEEC
8 (22%)
24 (31%)
0.35

14. Results: distant recurrence
L1CAM - + p
Stage I EEC
27 (3%)
12 (13%)
<0.01
Stage II-IV EEC
20 (15%)
9 (30%)
0.04
NEEC
6 (17%)
20 (26%)
0.29

16. Main findings
L1CAM expression (> 10%), is an independent predictor in stage I EEC for overall-, and disease-free survival
L1CAM expression is significantly more frequent expressed in non-endometrioid type endometrial carcinomas
(68% versus 11%)
L1CAM expression is mainly predictive for distant metastasis in both endometrioid and non-endometrioid endometrial carcinomas

17. Reflection on data
L1CAM expression compared to previous published studies
Zeimet et al. Stage I EEC: 17% L1CAM +
Bosse et al. Stage I EEC / PORTEC 1&2: 6% L1CAM +
ENITEC Stage I EEC: 10% L1CAM +
Overall survival in L1CAM+ Stage I EEC
Zeimet et al. HR 34.07, CI
Bosse et al. HR 2.1, CI
ENITEC HR HR 2.9, CI
L1CAM expression related to NEEC
Observed in both studies
Specific related to distant recurrence
Ten aanzien van 1e punt verschil in lymfklierdissectie in zeimet studie 50%, geen verschil in de groep die WEL /GEEN lymfklierdissectgie heeft gehad
Hoe is het percentage lymfklierdissectie in onze groep ?
Zeimet AG. J Natl Cancer Inst. 2013; 105(15):
Bosse T. Eur J Cancer. 2014; 50(15):

18. Univariate disease free survival analyses according to L1CAM expression in patients with FIGO stage I, type I endometrial cancers
Hazard Ratio DFS: 3.8 ( )
Univariate survival analyses according to L1CAM expression in 1021 patients with Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stage I, type I endometrial cancers. A) Disease-free survival. B) Overall survival. Differences in survival between L1CAM positive (pos; ie, immunostaining in ≥10% of the tumor cells) and L1CAM negative (neg; ie, immunostaining in <10% of the tumor cells) groups were assessed by the two-sided log-rank test. The numbers of patients at risk are given below the graphs.
HR 3.1 ( )
A. Alain G. Zeimet et al. JNCI J Natl Cancer Inst 2013;105:
B. ENITEC validation study
© The Author Published by Oxford University Press. All rights reserved. For Permissions, please

19. Univariate overall survival analyses according to L1CAM expression in patients with FIGO stage I, type I endometrial cancers
HR 2.9 ( )
Univariate survival analyses according to L1CAM expression in 1021 patients with Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stage I, type I endometrial cancers. A) Disease-free survival. B) Overall survival. Differences in survival between L1CAM positive (pos; ie, immunostaining in ≥10% of the tumor cells) and L1CAM negative (neg; ie, immunostaining in <10% of the tumor cells) groups were assessed by the two-sided log-rank test. The numbers of patients at risk are given below the graphs.
A. ENITEC validation study
B. Alain G. Zeimet et al. JNCI J Natl Cancer Inst 2013;105:
© The Author Published by Oxford University Press. All rights reserved. For Permissions, please

20. Strength and limitations of the ENITEC L1CAM validation study
Strenght
Multicenter study
Well defined cohort with large number of patients
Reflection of clinical practice
Limitations
Not all patients underwent lymphadenectomy (up to 70%)
Slides are not centrally reviewed
Adjuvant treatment not standardized

21. Challenges in European Network studies

22. Challenges in this ENITEC study
ENITEC Members sending slides
IHC of L1CAM & building database
1st scoring
Nijmegen
2nd scoring Barcelona
Freiburg
Data analysis

23. Challenges in coordination of L1CAM study
Communication
Transportation
Time schedule & managing expectations

24. Future plans with L1CAM within ENITEC
Evaluation of L1CAM expression in the preoperative tumor tissue
Correlation between preoperative and postoperative L1CAM expression
Proper cut-off in preoperative samples
Can L1CAM be used in preoperative risk selection ?
How does L1CAM contribute to distant metastasis ?
What are the possibilities for targeted therapy ?
Other suggestions ?

25. Collaborators
Xavier Matias-Guiu, Maria Santacana, Universitat de Lleida, Barcelona
Eva Colas, Vall D'Hebron research Institute, Barcelona Spain
Francesc Alameda, Hospital del Mar, Barcelona, Barcelona, Spain
Jone Trovik, Helga Salvesen, Univeristy hosptial, Bergen, Norway
Jutta Huvila, Dept Pathology, University of Turku, Finland
Marc Hirschfield, Jasmin Boas, Peter Bronsert, University Hospital Freiburg, Germany
Martin Koskas, Francine Walker, Bichat University Hospital Paris, France
Stefanie Schrauwen, Frederic Amant, University Hospital Leuven, Belgium
Vit Weinberger, University Hospital, Brno, Czech Republic
Koen van de vijver, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands
Hans Bulten, Nicole Visser, Leon Massuger, Louis van der Putten, Radbouduniversity Medical Center, Nijmegen, The Netherlands

26. Conclusion
L1CAM expression in FIGO stage I EEC is an independent predictor of recurrence, mainly distant recurrence.
L1CAM expression is associated with non-endometrioid histology (NEEC)
L1CAM expression is also associated with poor outcome in advanced stage EEC and NEEC
Understanding the tumor driving pathway of L1CAM might contribute to tumor targeted therapy

27. Conclusion
Translational studies within the ENTEC group are feasible, and support collaboration and future trials

28. Future ENITEC studies starting in Nice !
Merci pour l'attention

29. Questions ?