Association of Molecular Profiles and Mutational Status With Distinct Histological Lung Adenocarcinoma Subtypes. An Analysis of the LACE-Bio Data

Prashanth Ashok Kumar , Maryam Karimi (1, 2, 3) , Alina Basnet , Lesley K. Seymour , Robert Arthur Kratzke , Élisabeth M. Brambilla (4, 5) , Thierry Le-Chevalier (1) , Jean-Charles Charles Soria (1) , Ken André Olaussen (6) , Siddhartha Devarakonda , Ramaswamy Govindan , Ming Sound Tsao , Frances Alice Shepherd , Stefan Michiels (1, 2, 7, 3) , Stephen L. Graziano

1 IGR - Institut Gustave Roussy
2 U1018 (Équipe 2) - Oncostat
3 CESP - Centre de recherche en épidémiologie et santé des populations
4 UGA - Université Grenoble Alpes
5 INSERM - Institut National de la Santé et de la Recherche Médicale
6 U981 - Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse
7 SBE - Service de biostatistique et d'épidémiologie

Background: Adjuvant chemotherapy (AC) is indicated for stage II and stage III lung adenocarcinomas (ADC). Using the LACE Bio II database, we analyzed the distribution of various mutations across the subtypes of ADCs and studied the prognostic and predictive roles of PD-L1, TMB, and Tumor Infiltrating Lymphocytes (TILs). Materials and Methods: Clinical and genomic data from the LACE Bio II data were extracted. Patients were divided into ADC subtypes, in which the grouping was done based on their known clinical behavior (Lepidic [LEP], Acinar/Papillary [ACI or PAP], Micropapillary/Solid [MIP or SOL], Mucinous [MUC] and Others). Kaplan-Meier (KM) and log-rank test were used to compare survival based on PD-L1, TMB, TILs and combinations of TMB with PD-L1 and TILs. Adjusted Hazard Ratios (HR) were analyzed with Overall Survival (OS), Disease-Free Survival (DFS) and Lung Cancer-Specific Survival (LCSS) as endpoints. Results: A total of 375 ADC patients were identified. MIP/SOL was the subtype most commonly positive for various biomarkers. PD-L1 Negative/high TMB was associated with better outcomes in terms of OS (HR = 0.46 [0.23-0.89], P = .021) and DFS (HR = 0.52 [0.30-0.90], P = .02), relative to PD-L1 Negative/low TMB. High TMB predicted worse outcome with AC use in terms of OS (ratio of hazard ratio rHR = 2.75 [1.07-7.04], P = .035). Marked TILs had better outcome with AC for DFS (rHR = 0.22 [0.06-0.87], P = .031 and LCSS (rHR = 0.08 [0.01-0.66], P = .019) respectively. There was also a beneficial effect of AC among patients with Marked TILs/low TMB in terms of DFS (rHR = 0.06 [0.01-0.53], P = .011). Conclusion: High TMB has a prognostic role in resectable lung ADC. The high TMB group had a poor outcome with AC, suggesting that this group may be better served with immune checkpoint therapy.

Mots clés: Lung adjuvant cisplatin evaluation (LACE); Non-small cell lung cancer (NSCLC); PD-L1; Tumor infiltrating lymphocytes (TIL); Tumor mutational burden (TMB)

Domaines: Sciences du Vivant [q-bio]

Prashanth Ashok Kumar, Maryam Karimi, Alina Basnet, Lesley K. Seymour, Robert Arthur Kratzke, et al.. Association of Molecular Profiles and Mutational Status With Distinct Histological Lung Adenocarcinoma Subtypes. An Analysis of the LACE-Bio Data. Clinical Lung Cancer, 2023, 24 (6), pp.528-540. ⟨10.1016/j.cllc.2023.06.002⟩. ⟨hal-04229530⟩