Transcriptomics in Tumor and Normal Tissues and Precision Oncology Algorithms Identify Early-Stage NSCLC Patients with High Risk of Post-Surgery Recurrence Who May Benefit from Adjuvant Therapies

Background: The prognosis of patients with non-small cell lung cancer (NSCLC) is traditionally determined by anatomic staging using the Tumor, Node, Metastasis (TNM) staging system. TNM staging neglects the biological features of the tumor that may be important in determining patient outcome and guiding therapeutic interventions. Identifying NSCLC patients at increased risk of recurrence after curative-intent surgery remains an important unmet need as adjuvant therapies are available that may reduce the risk of recurrence and improve patient survival.  Methods: Digital Display Precision Predictor (DDPP), based on differential RNA expression in tumor versus normal tissue, was used to interrogate gene sets to determine their association with disease-free survival (DFS) in patients with non-small cell lung cancer (NSCLC) who underwent curative-intent surgery. Findings: Low versus high DDPP score was significantly associated with shorter DFS (highest recurrence risk): HR=1.88, 95% CI [1.2-2.9] (p=0.006) in all patients (n=120) and in patients with TNM stages 1-2 (p= 0.00051) (n=83). For patients with stages 1-2 and low DDPP (n=29), adjuvant chemotherapy was associated with improved DFS (p= 0.0041).  High co-overexpression of  CTLA-4, PD-L1 and ICOS in normal lung (28 of 120 patients), hypothesized to reflect the host immune status, was also significantly associated with decreased DFS (p= 0.0013) suggesting an immune tolerance to tumor neoantigens in some patients. Patients with DDPP low and immunotolerant normal tissue had the shortest DFS (p=2.12E-11).  Interpretation: We identified stage 1-2 NSCLC patients with high risk of recurrence who benefitted from adjuvant chemotherapy.  Furthermore, identified a subset of NSCLC patients who may have poor post-surgery outcome related to an immunotolerant normal tissue profile that might be amenable to modulation by specific checkpoint blockade immunotherapies.  Funding: European Union Frame Pprogram 6-funded project (Chemores FP6 Health, Grant 37 665). Declaration of Interest: Dr. Vladimir Lazar, Catherine Bresson, are full time employees of Worldwide Innovative Network (WIN) Association - WIN Consortium. Worldwide Innovative Network (WIN) Association - WIN Consortium is the owner of the patent family entitled Digital Display. The inventors are Dr. Vladimir Lazar, and Shai Magidi. Dr. Jean-Francois Martini, is a full-time employee and stockholder of Pfizer Inc. Dr. Susan Galbraith is a full-time employee and stockholder of AstraZeneca. Dr. Benjamin Solomon received honorarium for Advisory Board from AstraZeneca and Bayer. Shai Magidi receives consultancy from Worldwide Innovative Network (WIN) Association. Dr. Amir Onn receives consulting fees from Roche Israel, MSD Israel, Boehringer Ingelheim 552 and AstraZeneca. Dr. Enriqueta Felip receives advisory board and/or speaker’s bureau fee from Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffman-LaRoche, Glaxi Smith Kline, Janssen, Medical Trends, Medscape, Merck Sharp & Dohme, Merck Serono, Peptomyc, Peervoice, Pfizer, Puma, Regeneron, Sanofi, Springer, Syneos Health, Takeda, Touch Medical; on the board of Grifols, Independent member. Receives research funding from Fundacion Merck Salud, Grant for Oncology Innovation (GOI) EMD Serono. Dr. Josep Tabernero declares scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics. Dr. Gerald Batist collaborates in formal clinical trial contracts, IITs and in joint grants funded by Canadian and Quebec governments with Roche, Merck, Novartis, Astra-Zeneca, Bayer, Esperas, Aurka, Caprion, MRM. Pr. Angel Porgador declares scientific consultancy role for PiNK Biopharma. Dr. Razelle Kurzrock has received research funding from Genentech, Merck Serono, Pfizer, Boehringer Ingelheim, TopAlliance, Takeda, Incyte, Debiopharm, Medimmune, Sequenom, Foundation Medicine, Konica Minolta, Grifols, Omniseq, and Guardant, as well as consultant and/or speaker fees and/or advisory board for X-Biotech, Neomed, Pfizer, Actuate Therapeutics, Roche, Turning Point Therapeutics, TD2/Volastra, Bicara Therapeutics, Inc., and Biological Dynamics, has an equity interest in IDbyDNA and CureMatch Inc, serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. Dr. Richard L. Schilsky’s institution (ASCO) receives research grants in support of a clinical trial that he directs from the following companies: AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Genentech, Lilly, Merck, Pfizer. Dr. Schilsky reports being a consultant to Cellworks, Clarify Precision Medicine, Bryologx, EQRx and Scandion Oncology. The remaining authors declare no competing interests. Ethical Approval: The bio-banking study was approved by the IMM’s Ethics Committee.