Staging Endometrial caNcer Based on molEcular ClAssification
Conditions: Endometrial Cancer, Lymph Node Metastasis, Sentinel Lymph Node
Sponsor: Clinica Universidad de Navarra, Universidad de Navarra

Title: SENECA Study: Staging Endometrial caNcer based on molEcular ClAssification 
Principal Investigator  
Co-Principal Investigator 
Enrique Chacón MD  
Gyn Oncology Unit. Clinica Universidad 
de 
Navarra. 
Pamplona. 
Spain. 
echaconc@unav.es  
 
Luis Chiva MD, PhD 
Gyn Oncology Unit. Clinica Universidad de Navarra. 
Madrid. Spain. lchiva@unav.es  
Antonio González MD, PhD 
Gyn Oncology Unit. Clinica Universidad de Navarra. 
Madrid. Spain. agonzalezma@unav.es 
  
Co-investigators 
- Félix Boria MD. Gyn Oncology Unit. Clinica Universidad de Navarra. Madrid. Spain. 
F.boria.alegre@gmail.con 
-Luisa Sanchez Lorenzo MD, PhD. Gyn Oncology Unit. Clinica Universidad de Navarra. Madrid. 
Spain. lsanchezl@unav.es 
-José Ángel Mínguez MD, PhD. Gyn Oncology Unit. Clinica Universidad de Navarra. Pamplona. 
Spain. jaminguez@unav.es 
 
 
 
Version: 2.1 Date: 1/1/2023 
 
1. List of abbreviations 
 
EC: Endometrial Cancer 
LN: Lymph Node 
SLN: Sentinel lymph node mapping 
OS: Overal Survival 

DFS: Disease Free Survival 
OSNA: One Step Nucleic Acid Amplification 
ICG: Indocyanine green 
POLEmut: POLE exonuclease domain ultramutated 
p53abn: p53 abnormal 
MMRd: mismatch repair (MMR) proteins-deficient 
NSMP: no specific molecular profile 
 
2. Clinical study summary 
 
Study title: 
Staging Endometrial caNcer based on molEcular ClAssification (SENECA 
Trial) 
Study rationale: 
The management of endometrial cancer (EC) is currently undergoing 
a true revolution in terms of diagnosis and treatment. Since 2013 
and thanks to the TCGA project (The Cancer Genome Atlas), four 
distinct molecular subgroups (POLE, MMR-D, Copy number low, 
Copy number high) with distinct prognostic implications were 
identified.  
 
Currently, thanks to the retrospective analysis of the PORTEC-3 
cohort, we know that these four molecular subgroups may present 
differences in survival in high-risk patients.  
 
On the other hand, the surgical management of early EC (stage I/II) 
has been changing for some years now, especially at the level of 
nodal staging, from modulation of treatment depending on the risk 
group (pelvic lymphadenectomy +/- sentinel lymph node (SLN) for 
low and intermediate risk groups vs. aortopelvic lymphadenectomy 
+/- sentinel lymph node (SLN) for those at high risk) to a 
generalization of treatment based on detailed study of the SLN 

following the algorithm described by the group of Abu-Rustum NR 
et al.  
 
It remains unknown (or an open question) if it could be possible to 
tailor the type of lymph node staging in early EC (the most common 
and most frequent in our daily clinical practice) depending on the 
molecular subgroup. 
 
We therefore propose a study to evaluate the rate of lymph node 
involvement depending on the molecular subgroup in early-stage EC 
(I/II). 
Study design: 
International, retrospective, multicentre, observational study. 
Sites number: 
Not defined 
Objectives: 
 
Primary objective 
-To evaluate the lymph node involvement rate (sentinel) for each 
molecular subtype in patients with stage I/II EC 
Secondary objectives 
-To evaluate the lymph node involvement rate (sentinel and non-
sentinel) for each prognostic risk group in patients with stage I/II EC 
-To evaluate morbidity associated to SLN biopsy 
-To assess compliance of ESGO quality Indicators  
Study population: 
Patients with early-stage (FIGO stage I-II) EC that underwent surgical 
treatment with lymph node evaluation between January 2021 to 
December 2022, both included. 
 
A sample size of 1,032 patients may provide sufficient statistical 
power to evaluate the association between molecular subgroups 
and lymph node status. We assumed a 90% power for a 2-sided p-
value of 0.05 and a minimum difference of 4.4 percentage points in 
prevalence rates of positive lymph nodes. We anticipated a 
potential dropout rate of 10%. 

 
Inclusion criteria: 
 
-Age 18 years or older 
-Patient was operated during 2021-2022 
-Histological confirmation of Endometrial Cancer with endometrioid 
histology or high risk histology (serous, clear cell, carcinosarcoma 
and mixed histologies) 
-Preoperative FIGO stage I or II by MRI or US 
-Preoperative CT-Scan or PET-CT without evidence of local or distant 
disease (could be omitted in low-risk and intermediate risk 
endometrial carcinoma with low grade histology) 
-Surgical protocol according to ESGO/ESTRO/ESP guidelines 
-A detailed sentinel lymph node study protocol must be accredited, 
either by ultra-staging or OSNA 
-Molecular analysis performed on the pathology specimen 
according to ESGO/ESTRO/ESP guidelines (POLE mutation analysis 
could be omitted in low-risk and intermediate risk endometrial 
carcinoma with low grade histology). 
Exclusion criteria: 
-Pregnant women 
-Previous hysterectomy  
-Previous pelvic/para-aortic lymphadenectomy 
-Presence of extra-uterine disease (peritoneal, visceral or suspicious 
lymph node metastasis) 
-Past medical history of any invasive tumor 
-History of previous abdominal or pelvic radiotherapy of any type 
(including braquitherapy) 
-History of preoperative neoadjuvant chemotherapy 
Statistical 
considerations: 
Quantitative data will be presented as mean and standard deviation 
and qualitative variables with absolute values and percentages.  
Additionally, qualitative variables among groups will be compared 
by chi-square test or Fisher exact test; and quantitative variables 

with t-test and ANOVA test. For the multivariate analysis a logistic 
regression model will be used. Alpha error will be set at 5% 
 
3. BACKGROUND   
 
The management of endometrial cancer (EC) is currently undergoing a true revolution 
in terms of diagnosis and treatment. Since 2013 and thanks to the TCGA project1 (The 
Cancer Genome Atlas), four distinct molecular subgroups (POLE, MMR-D, Copy number 
low, Copy number high) with distinct prognostic implications were identified.  
 
Subsequently, PROMISE study2 brought this "new era" closer to daily clinical practice. 
These new findings led ESGO3 (European Society of Gynecologic Oncology) to decide to 
integrate this molecular classification into the definition of the different risk groups. 
 
Currently, thanks to the retrospective analysis of the PORTEC-3 cohort4,5, we know that 
these four molecular subgroups may present differences in survival in high-risk patients 
depending on the type of treatment proposed, chemoradiotherapy vs. adjuvant 
radiotherapy. This question will be answered by the RAINBO trial6 (Refining Adjuvant 
treatment IN endometrial cancer Based On molecular profile). 
 
On the other hand, the surgical management of early endometrial cancer (stage I/II) has 
been changing for some years now, especially with regard to nodal staging, from 
modulation of treatment depending on the risk group (pelvic lymphadenectomy +/- 
sentinel lymph node (SLN) for low and intermediate risk groups vs. aortopelvic 
lymphadenectomy +/- SLN for those at high risk) to a generalization of treatment based 
on detailed study of the sentinel node following the algorithm described by the group 
of Abu-Rustum NR et al7.  
 
Just as the RAINBO study will try to clarify the type of adjuvant treatment necessary for 
each molecular subgroup, we do not currently know if it could be possible to tailor the 
type of lymph node staging in early EC (the most common and most frequent in our daily 
clinical practice) depending on the molecular subgroup8,9. 

 
We therefore propose a study to evaluate the lymph node involvement rate depending 
on the molecular subgroup in early-stage EC (I/II). 
 
4. OBJECTIVES 
 
Primary objective 
-To evaluate the lymph node involvement rate (sentinel) for each molecular subtype in 
patients with stage I/II EC. 
 
Secondary objectives 
-To evaluate the lymph node involvement rate (sentinel and non-sentinel) for each 
prognostic risk group in patients with stage I/II EC. 
-To evaluate morbidity associated to SLN biopsy. 
-To assess compliance of ESGO quality Indicators. 
 
We consider that our study will help to:  
 Tailor the type of nodal staging depending on the molecular subgroup in early 
EC. 
 Take a snapshot of the morbidity in SLN.  
 Evaluate if the quality indicators described by ESGO are met. 
 Know the degree of correlation between the molecular classification of the 
preoperative and the definitive biopsy. 
 
5. STUDY GENERAL DESIGN 
 
STUDY GENERAL DESIGN 
The study is a retrospective multicentric international observational study reviewing 
data of patients diagnosed with early-stage (FIGO stage I-II) EC and underwent surgical 
treatment with lymph node evaluation between January 2021 to December 2022, both 
included. 
 

All data and records generated during this study will be kept confidential in accordance 
with Institutional policies and HIPAA on subject privacy. The Investigators and other site 
personnel will not use such data and records for any purpose other than conducting the 
study.  
 
This protocol will be reviewed by the IRB of Clinica Universidad de Navarra, and the data 
collection will not start until the IRB approval is obtained. Each institution will be 
responsible of obtaining its own IRB/EC approval.  
 
RECRUITMENT 
A sample size of 1,032 patients may provide sufficient statistical power to evaluate the 
association between molecular subgroups and lymph node status. We assumed a 90% 
power for a 2-sided p-value of 0.05 and a minimum difference of 4.4 percentage points 
in prevalence rates of positive lymph nodes. We anticipated a potential dropout rate of 
10%. 
 
Gynaecological Cancer Centres/Units and hospitals regularly performing elective 
surgeries for EC internationally will be invited to participate in this study. Invitations will 
be sent through international/national and informal networks. Participating sites will 
register with the central audit team at Clinica Universidad de Navarra and will be 
provided with unique user access credentials for the database. 
 
Each participating site (centre/unit/trust/hospital) will identify a principal investigator 
(PI) who will be responsible for coordinating data entry at their local site. The PI may 
have a bigger local reporting group/team with as many individuals as felt to be necessary 
to sustain the project. Team members may include gynaecological oncology 
trainees/fellows, medical/clinical oncologists, radiologists, pathologists, nurses, medical 
students, research staff, data managers. Each participating site will be provided a unique 
site code, individual username and password for database access. Inputting sites will 
only be able to access/see their own data and will not be able to see another site’s data. 
The central coordinating centre team will be able to see individual data from all sites. 
 

Study IDs are unique to each patient and will be automatically assigned when a patient 
is registered onto the database. Study IDs will be assigned centrally by the REDCap 
bespoke database. Only one study ID should be created for each patient and new data 
registered on the appropriate electronic case record file (eCRF). Individual centres will 
retain access to their patient data and not provide identifiable information on the 
international database. Local sites will retain information on patient identifiable data 
(name, date of birth, address, telephone number) in a separate file but not share this 
with the central audit team. This information/file that links the study ID to the patient 
identifiers will be kept on the local centre/unit/hospital server, in case further 
clarification of data is required. 
 
6. STUDY POPULATION 
 
INCLUSION CRITERIA 
A patient will be considered eligible for inclusion in this study if all the following criteria 
are met: 
-Age 18 years or older 
-Patient was operated during 2021-2022 
-Histological confirmation of Endometrial Cancer with endometrioid histology or high 
risk histology (serous, clear cell, carcinosarcoma and mixed histologies) 
-Preoperative FIGO stage I or II by MRI or US 
-Preoperative CT-Scan or PET-CT without evidence of local or distant disease (could be 
omitted in low-risk and intermediate risk endometrial carcinoma with low grade 
histology) 
-Surgical protocol according to ESGO/ESTRO/ESP guidelines 
-A detailed sentinel lymph node study protocol must be accredited, either by ultra-
staging or OSNA 
-Molecular 
analysis 
performed 
on 
the 
pathology 
specimen 
according 
to 
ESGO/ESTRO/ESP guidelines (POLE mutation analysis could be omitted in low-risk and 
intermediate risk endometrial carcinoma with low grade histology). 
EXCLUSION CRITERIA 
-Pregnant women 

-Previous hysterectomy  
-Previous pelvic/para-aortic lymphadenectomy 
-Presence of extra-uterine disease (peritoneal, visceral or suspicious lymph node 
metastasis) 
-Past medical history of any invasive tumor 
-History of previous abdominal or pelvic radiotherapy of any type (including 
braquitherapy) 
-History of preoperative neoadjuvant chemotherapy 
 
7. EVALUATION 
 
Definition of variables 
Sentinel lymph node: Defined as the first echelon lymph node where the tumor directly 
flows through the lymphatic duct. 
Isolated tumor cells: <0.2mm or less than 200 tumoral cells in a single histologic section 
Micrometastases: 0.2mm-0.2cm or more than 200 tumoral cells in a single histologic 
section. 
Macrometastases: Metastases >0.2cm 
 
Data to be abstracted:  
Medical history and demographic data will be reviewed. Patients will be grouped in 
group 1 (POLEmut), group 2 (MMRd), group 3 (NSMP), group 4 (p53abn),  depending on 
the molecular profile. Preoperative FIGO stage, modality of initial treatment, final 
pathology diagnosis, preoperative pathology analysis, type of surgery, perioperative 
details and adverse events will be reviewed. Follow up until the date will be reviewed as 
well. (Appendix).  
 
8. STATISTICAL ANALYSIS 
 
Quantitative data will be presented as mean and standard deviation and qualitative 
variables with absolute values and percentages.  Additionally, qualitative variables 
among groups will be compared by chi-square test or Fisher exact test; and quantitative 

variables with t-test and ANOVA test. For the multivariate analysis a logistic regression 
model will be used.  
 
Survival analysis will be performed using the Kaplan-Meier method and log-rank tests. 
Alpha error will be set at 5%. 
 
9. ETHICAL, LEGISLATIVE AND REGULATORY CONSIDERATIONS 
 
Ethical considerations 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual. All data will be collected on a customised, secure, password protected central 
REDCap database hosted by Clinica Unviersidad de Navarra. REDCap is used 
internationally to securely collect research data. All collected data will be transmitted 
and held anonymously. 
 
Investigator responsibilities 
The principal investigator of each site must conduct the study in accordance with the 
research protocol and with current regulations. 
The investigator should not implement any deviation from, or changes of the protocol 
without authorized in writing by the principal investigator and without the previous 
authorization of the Ethics Committee and competent authorities of proposed changes.  
The principal investigators are responsible of respecting the study confidentiality. 
 
Confidentiality of study documents and patient records 
The investigator must ensure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorised parties. On CRFs or other documents 
submitted to the principal investigator, patients should not be identified by their names, 
but by an identification code.  
 
Funding and conflict of interest 

This study has not received funding from any public or private for-profit entity, nor will 
it admit any during the development of the study. None of the investigators or patients 
will receive any financial or material compensation for the development of the study, 
nor do they have any financial conflict of interest in the conduct of the study. 
 
10. PUBLICATIONS 
 
We are currently in the design and approval phase of the study and expect to complete 
this phase by the end of 2022.  
 
Between January and February 2023 we will start the phase of dissemination of the 
project and recruitment of institutions wishing to participate in it, once the total number 
of participating centres is obtained, we will start recruiting between March and May 
2023. Throughout this process, several virtual meetings will be held to inform the heads 
of each institution of the status of the project as well as to resolve any doubts that may 
arise. In the same way, several reminder e-mails will be sent to ensure that the 
recruitment process is carried out on time.  
 
Once recruitment has been completed, we will proceed to the analysis of the data by 
our statistical team and the research committee. Preliminary results are intended to be 
presented at the ESGO Congress in ISTANBUL in October 2023.  
 
It will be the responsibility of the Principal Investigator to obtain and publish the results 
of this study in high impact journals indexed in the Journal Citation Report (Pubmed).  
The tentative deadlines for publication of the main results will be December 2023.    
    
 
With respect to authorship in the different papers, the following rules will be followed, 
the acceptance of which is considered implicit to participation in this study. 
We will 
always try to include the maximum number of authors, as well as the maximum number 
of participating centers, even those with the lowest participation, as follows: 
    
 
    

- The number of authors per publication will be a maximum of 20 authors (unless the 
journal is flexible, in which case the maximum allowed will be included). The general 
order of authors will be established by individual order of inclusion of cases in the study. 
If any author considers that another researcher from his/her institution should 
participate as a co-author in his/her place, this will be communicated in time for 
inclusion in the corresponding publication.     
    
- In case the limitation of authors makes it necessary to reduce the number of 
authorships, it will be reduced following the same rule of inclusion of cases in the study. 
  
- There will be 4 fixed positions in the publications corresponding to the persons in 
charge of the writing and elaboration of the articles (first and second author), 
coordination and development of the study (last author - PI), statistical study and 
methodology (penultimate author).     
 
-For the rest of the positions, half will correspond to the authors with the highest 
number of cases introduced in all the publications derived; and the other half 
consecutively to the authors of the institutions that follow them in number of cases. 
    
For example, in the case of 32 collaborating researchers arranged in order of 
participation and 3 articles to be written, the order of authorship would be:  
 
 Article 1: 4 fixed positions + authors centers of 1--8 + Authors 9-16  
 Article 2: 4 fixed positions + authors centers of 1--8 + Authors 17-24   
 Article 3: 4 fixed positions + authors centers of 1--8 + Authors 25-32 
    
 
    
In this way, the inclusion of the maximum and most varied number of authors will be 
encouraged while giving priority to the greatest participation and work of the study's 
collaborators.     
 
-At the end of the list of authors of each publication, "on behalf of SENECA group 
collaborative" will be written.  Authors who cannot be included as such in each 
publication will be included as collaborators or in the acknowledgements according to 
the possibilities of each journal. 
 

11. REFERENCES 
 
1. Kandoth C, Schultz N, Cherniack AD et al. Integrated genomic characterization of 
endometrial carcinoma. Nature 2013; 497(7447): 67–73. 
2. Talhouk A, McConechy MK, Leung S et al. A clinically aplicable molecular-based 
classification for endometrial cancers. Br J Cancer 2015; 113(2): 299–310 
3. Concin N, Matias-Guiu X, Vergote I et al. ESGO/ESTRO/ESP guidelines for the 
management of patients with endometrial carcinoma. Int J Gynecol Cancer. 2021 
Jan;31(1):12-39. doi: 10.1136/ijgc-2020-002230. Epub 2020 Dec 18. PMID: 
33397713. 
4. León-Castillo A, de Boer SM, Powell ME et al. Molecular Classification of the 
PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and 
Benefit From Adjuvant Therapy. J Clin Oncol. 2020 Oct 10;38(29):3388-3397. doi: 
10.1200/JCO.20.00549. Epub 2020 Aug 4. PMID: 32749941; PMCID: 
PMC7527156. 
5. León‐Castillo  A, Gilvazquez  E, Nout  R , et al . Clinicopathological and molecular 
characterisation 
of 
‘multiple‐classifier’ 
endometrial 
carcinomas. J 
Pathol 2020;250:312–22 
6. https://clinicaltrials.gov/ct2/show/NCT05255653 
7. Abu-Rustum NR. Sentinel lymph node mapping for endometrial cancer: a modern 
approach to surgical staging. J Natl Compr Canc Netw. 2014 Feb;12(2):288-97. 
doi: 10.6004/jnccn.2014.0026. PMID: 24586087. 
8. Moloney K, Janda M, Frumovitz M, et al. Development of a surgical competency 
assessment tool for sentinel lymph node dissection by minimally invasive surgery 
for endometrial cancer. Int J Gynecol Cancer. 2021 May;31(5):647-655. doi: 
10.1136/ijgc-2020-002315. Epub 2021 Mar 4. PMID: 33664126. 
9. Betella I, Fumagalli C, Rafaniello Raviele P, et al A novel algorithm to implement 
the molecular classification according to the new ESGO/ESTRO/ESP 2020 
guidelines for endometrial cancer International Journal of Gynecologic 
Cancer 2022;32:993-1000. 
 
11. APPENDICES:  

 
Figure 1 Operation guide 
 
 
Figure 
2 Memorial 
Sloan-Kettering 
Cancer 
Center’s 
Pathologic 
Ultrastaging Algorithm for Sentinel Lymph Nodes