Molecular Signature From Tumor to Lymph Nodes (N2-3S)

Molecular Signature From Tumor to Lymph Nodes: How to Identify the Right Candidate for IIIA-N2 Lung Cancer Surgery?

Mediastinal lymph node (LN) involvement (N2) in non-small cell lung cancer (NSCLC) concerns 15% of resectable tumors and is associated with a poor prognosis and an overall survival reaching 9 to 49%. Literature fails to provide any definitive consensus regarding the management of these patients, except for the platinum-based doublet chemotherapy. The N2 involvement remains a matter of debate because of its not yet well-classified heterogeneity. Regarding anatomy, the Mountain and Dresler's regional LN classification for lung cancer staging remains the reference. Different studies classified IIIA-N2 disease into 4 groups, in addition to the skip-N2 phenomenon: minimal-N2, N2 single station, N2 multiple stations, and bulky-N2. Other subgroups were recently proposed for the 8th edition of the TNM: N2a1 - single station skip, N2a2 - single station non-skip, N2b - multiple stations.

The French National Cancer Institute (INCa) proposed guidelines, but in case of cN2 staging without mediastinal infiltration, guidelines remained imprecise ("resectability should be discussed for each case") and suggested surgery first, or induction chemotherapy, or concomitant chemoradiation.

Thus, optimal management of cIIIA-N2 remains controversial but complete tumor resection can be related to long-term survival in some patients, including 10 years after surgery [1]. In this situation, the identification of markers that will help select IIIA-N2 patients who will benefit from surgical resection is mandatory.

Study Overview

• Status: Recruiting
• Conditions: Lung Cancer; Stage IIIA-cN2; Operated With Curative Intent; Primary Tumor Tissue Available; Node Tumor Tissue Available

Detailed Description

We planned a comprehensive molecular characterization of tumors and lymph nodes to evaluate the impact of molecular signatures and molecular heterogeneity on disease-free survival after surgery in IIIA-N2 NSCLC patients. Identification of specific molecular profiles in primary tumors and evolution profiles in nodes might provide clues to the potential risk of metastatic evolution and trigger specific management.

For patients included prospectively, we planned to analyze cell free circulating tumor DNA (ctDNA) as prognostic marker. Because multiple biopsies are not always available in care settings, ctDNA could also be analyzed as a surrogate marker of molecular heterogeneity. Next generation sequencing (NGS) that was validated in our lab to screen ctDNA using a specific bio-informatics workflow allows accurate and cost effective ctDNA screening

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

• Study Contact: Name: Antoine LEGRAS, MD PhD; Phone Number: 33 2 47474747; Email: antlegras@gmail.com
• Study Contact Backup: Name: Liliane HAMMANI-BERKANI, MSc; Phone Number: 33 156093762; Email: liliane.berkani@aphp.fr

Study Locations

• France
  • Bordeaux, France
    • Not yet recruiting
    • Hôpital du Haut-Lévêque, CHU de Bordeaux
    • Contact: Jacques JOUGON, Pr
  • Clamart, France
    • Not yet recruiting
    • Hopital Militaire Percy
    • Contact: Bertrand GRAND, Dr
  • Marseille, France
    • Not yet recruiting
    • Hôpital Nord
    • Contact: Pascal THOMAS, Pr
  • Nice, France
    • Not yet recruiting
    • Hôpital Pasteur, CHU de Nice
    • Contact: Jérome MOUROUX, Pr
  • Paris, France, 75015
    • Recruiting
    • Hôpital Européen Georges-Pompidou
    • Contact: Françoise LE PIMPEC-BARTHES, Pr
  • Paris, France
    • Not yet recruiting
    • Hôpital Cochin
    • Contact: Marco ALIFANO, Pr
  • Paris, France
    • Not yet recruiting
    • Hôpital Bichat
    • Contact: Pierre MORDANT, Dr
  • Paris, France, 75015
    • Active, not recruiting
    • Hegp-Aphp
  • Rennes, France
    • Not yet recruiting
    • Hôpital PONTCHAILLOU, CHU de RENNES
    • Contact: Bertrand RICHARD DE LA TOUR, PR
  • Strasbourg, France
    • Not yet recruiting
    • Hôpitaux universitaires de Strasbourg
    • Contact: MASSARD Gilbert, Pr
  • Toulouse, France
    • Not yet recruiting
    • Hôpital Larrey, CHU de Toulouse
    • Contact: Laurent BROUCHET, Pr
  • Tours, France
    • Not yet recruiting
    • CHRU de Tours
    • Contact: Antoine LEGRAS, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

230 patients in 11 French centers in order to have 200 eligible patients. Objectives are 120 patients recruited retrospectively and 110 prospectively.

Inclusion criteria are: all consecutive patients operated with a curative intent for an IIIA-cN2 NSCLC.

Description

Inclusion Criteria:

• Adult patient, men and women age >18 years
• Patients operated with a curative intent for an IIIA-cN2 NSCLC
• Social security affiliation
• Written informed consent for patient included in part 2 (prospective) or not opposing the use of this data for patient included in part 1 (retrospective)

Exclusion Criteria:

• Patient with T4, R1 or R2 surgical resection, sublobar resection, no radical lymphadenectomy
• Patient under protectives measures
• Pregnancy or breast-feeding

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year disease-free survival	To identify a molecular signature based on a comprehensive molecular analysis at genomic and transcriptomic levels linked to 3-year disease-free survival in resected IIIA-N2 NSCLC.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-year disease-free survival	To identify a molecular signature based on a comprehensive molecular analysis at genomic and transcriptomic levels linked to 5-year disease-free survival in resected IIIA-N2 NSCLC.	5 years
pathological architectural patterns WHO 2015 classification	To evaluate the impact of the pathological architectural patterns WHO 2015 classification on the 5-year cancer-specific survival and the 5-year overall survival	5 years
anatomical lymphatic spread	To identify tumor molecular patterns associated with specific anatomical lymphatic spread subgroups.	at the end of molecular analyses
ctDNA	To assess ctDNA prognostic impact, before and after surgery.	3 years

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Ministry of Health, France; National Cancer Institute, France; Université de Paris
• Investigators: Principal Investigator: Helene BLONS, PharmD PhD, Hôpital Européen Georges-Pompidou

Publications and helpful links

General Publications

• Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting recommendations for tumor marker prognostic studies (REMARK): explanation and elaboration. BMC Med. 2012 May 29;10:51. doi: 10.1186/1741-7015-10-51.
• Legras A, Mordant P, Arame A, Foucault C, Dujon A, Le Pimpec Barthes F, Riquet M. Long-term survival of patients with pN2 lung cancer according to the pattern of lymphatic spread. Ann Thorac Surg. 2014 Apr;97(4):1156-62. doi: 10.1016/j.athoracsur.2013.12.047. Epub 2014 Feb 26.
• Lin IF, Chang WP, Liao YN. Shrinkage methods enhanced the accuracy of parameter estimation using Cox models with small number of events. J Clin Epidemiol. 2013 Jul;66(7):743-51. doi: 10.1016/j.jclinepi.2013.02.002. Epub 2013 Apr 6.
• Peduzzi P, Concato J, Feinstein AR, Holford TR. Importance of events per independent variable in proportional hazards regression analysis. II. Accuracy and precision of regression estimates. J Clin Epidemiol. 1995 Dec;48(12):1503-10. doi: 10.1016/0895-4356(95)00048-8.
• Tapak L, Saidijam M, Sadeghifar M, Poorolajal J, Mahjub H. Competing risks data analysis with high-dimensional covariates: an application in bladder cancer. Genomics Proteomics Bioinformatics. 2015 Jun;13(3):169-76. doi: 10.1016/j.gpb.2015.04.001. Epub 2015 Apr 20.
• Um SW, Joung JG, Lee H, Kim H, Kim KT, Park J, Hayes DN, Park WY. Molecular Evolution Patterns in Metastatic Lymph Nodes Reflect the Differential Treatment Response of Advanced Primary Lung Cancer. Cancer Res. 2016 Nov 15;76(22):6568-6576. doi: 10.1158/0008-5472.CAN-16-0873. Epub 2016 Sep 13.
• Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol. 2007 Mar 15;165(6):710-8. doi: 10.1093/aje/kwk052. Epub 2006 Dec 20.
• Pecuchet N, Rozenholc Y, Zonta E, Pietrasz D, Didelot A, Combe P, Gibault L, Bachet JB, Taly V, Fabre E, Blons H, Laurent-Puig P. Analysis of Base-Position Error Rate of Next-Generation Sequencing to Detect Tumor Mutations in Circulating DNA. Clin Chem. 2016 Nov;62(11):1492-1503. doi: 10.1373/clinchem.2016.258236. Epub 2016 Sep 13.

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2021
• Primary Completion (Anticipated): November 1, 2023
• Study Completion (Anticipated): November 1, 2027

Study Registration Dates

• First Submitted: December 15, 2020
• First Submitted That Met QC Criteria: December 15, 2020
• First Posted (Actual): December 21, 2020

Study Record Updates

• Last Update Posted (Estimate): January 9, 2023
• Last Update Submitted That Met QC Criteria: January 6, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: NSCLC; prognosis; N2; molecular profile
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms; Lung Neoplasms
• Other Study ID Numbers: D20180155 (Other Identifier: Assistance Publique - Hôpitaux de Paris); 2019-A02635-52 (Other Identifier: N° IDRCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared.
• IPD Sharing Time Frame: Two years after the last publication

IPD Sharing Access Criteria

Data sharing must be accepted by the sponsor and the PI based on a scientific project and scientific involvement of the PI team. Collaboration will be fostered.

Teams wishing obtain IPD must meet the sponsor and IP team to present scientifics (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractualization. Processing of shared data must comply with European General Data Protection Regulation (GDPR).

• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No