Exploring Genomic Biomarkers for Pembrolizumab Response: A Real-World Approach and Patient Similarity Network Analysis Reveal DNA Response and Repair Gene Mutations as a Signature

Marco Filetti; Mario Occhipinti; Alessio Cirillo; Fabio Scirocchi; Alessio Ugolini; Raffaele Giusti; Pasquale Lombardi; Gennaro Daniele; Andrea Botticelli; Giuseppe Lo Russo; Filippo De Braud; Paolo Marchetti; Marianna Nuti; Elisabetta Ferretti; Lorenzo Farina; Aurelia Rughetti; Manuela Petti

doi:10.3390/cancers16233955

Exploring Genomic Biomarkers for Pembrolizumab Response: A Real-World Approach and Patient Similarity Network Analysis Reveal DNA Response and Repair Gene Mutations as a Signature

Cancers (Basel). 2024 Nov 26;16(23):3955. doi: 10.3390/cancers16233955.

Authors

Marco Filetti^{1

2}, Mario Occhipinti^{2

3}, Alessio Cirillo^{2

4}, Fabio Scirocchi^{2

5}, Alessio Ugolini^{2

6}, Raffaele Giusti⁷, Pasquale Lombardi¹, Gennaro Daniele¹, Andrea Botticelli⁴, Giuseppe Lo Russo³, Filippo De Braud⁸, Paolo Marchetti⁹, Marianna Nuti², Elisabetta Ferretti², Lorenzo Farina¹⁰, Aurelia Rughetti², Manuela Petti¹⁰

Affiliations

¹ Phase 1 Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy.
² Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
³ Thoracic Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
⁴ Department of Radiology, Oncological and Anatomo-Pathological Science, Sapienza University of Rome, 00161 Rome, Italy.
⁵ Department of Onco-Hematology, Gene and Cell Therapy, Bambino Gesù Children's Hospital-IRCCS, 00165 Rome, Italy.
⁶ Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
⁷ Department of Medical Oncology, St. Andrea Hospital, 00189 Rome, Italy.
⁸ Oncology and Hemato-Oncology Department, University of Milan, 20133 Milan, Italy.
⁹ Istituto Dermopatico dell'Immacolata IDI-IRCCS, 00167 Rome, Italy.
¹⁰ Department of Computer, Control, and Management Engineering, Sapienza University of Rome, 00161 Rome, Italy.

Abstract

Purpose: Single-agent immune checkpoint inhibitor (IO) therapy is the standard for non-oncogene-addicted advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score ≥ 50%. Smoking-induced harm generates high tumor mutation burden (H-TMB) in smoking patients (S-pts), while never-smoking patients (NS-pts) typically have low TMB (L-TMB) and are unresponsive to IO. However, the molecular characterization of NS-pts with H-TMB remains unclear. Experimental design: Clinical data of 142 aNSCLC patients with PD-L1 ≥ 50% treated with first line pembrolizumab were retrospectively collected. Next-generation sequencing was performed using the FoundationOne^®CDx assay to correlate genomic alterations with clinical characteristics and response outcomes. Detected mutations were classified into eleven main pathways and enrichment analysis identified patient subgroups based on mutated pathways. Additionally, a patient similarity network was constructed to analyze molecular characterization. Results were validated using data from 853 aNSCLC patients in POPLAR and OAK trials. Results: Among the patients, S-pts had higher TMB than NS-pts. Interestingly, 11 (8%) NS-pts exhibited H-TMB and were enriched in β-catenin/Wnt and DDR pathway mutations. DDR pathway mutations were confirmed to be enriched in NS-pts with H-TMB using data from POPLAR and OAK trials. In the real-world cohort, the NS/H-TMB subgroup with DDR pathway mutations demonstrated improved IO outcome. Patient similarity network analysis confirmed the clustering of NS/H-TMB patients with DDR mutations and their association with improved overall survival in both the real-world cohort and the trials. Conclusions: The DDR signature has a potential role as an additional generator of H-TMB in NS-pts. This subgroup of IO-responsive NS-pts may have better prognosis. Our findings suggest that DDR-based mutational profiling may help identify NS-pts who could benefit from IO therapy.

Keywords: DNA damage response and repair; immunotherapy; network analysis; never-smoker; non-small cell lung cancer.

Grants and funding

This work was partially supported by funding to MF (Sapienza research grant number: AR12218166B9BEFB).