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.

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

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

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.

Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared.

Two years after the last publication

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).