Real-world comprehensive genomic and immune profiling reveals distinct age- and sex-based genomic and immune landscapes in tumors of patients with non-small cell lung cancer

Wallen ZD, Ko H, Nesline MK, Hastings SB, Strickland KC, Previs RA, Zhang S, Pabla S, Conroy J, Jackson JB, Saini KS, Jensen TJ, Eisenberg M, Caveney B, Sathyan P, Severson EA, Ramkissoon SH. Real-world comprehensive genomic and immune profiling reveals distinct age- and sex-based genomic and immune landscapes in tumors of patients with non-small cell lung cancer. Front Immunol. 2024 Jun 21;15:1413956. doi: 10.3389/fimmu.2024.1413956. PMID: 38975340; PMCID: PMC11224431.

ABSTRACT

Younger patients with non-small cell lung cancer (NSCLC) (<50 years) represent a significant patient population with distinct clinicopathological features and enriched targetable genomic alterations compared to older patients. However, previous studies of younger NSCLC suffer from inconsistent findings, few studies have incorporated sex into their analyses, and studies targeting age-related differences in the tumor immune microenvironment are lacking. We performed a retrospective analysis of 8,230 patients with NSCLC, comparing genomic alterations and immunogenic markers of younger and older patients while also considering differences between male and female patients. We defined older patients as those ≥65 years and used a 5-year sliding threshold from <45 to <65 years to define various groups of younger patients. Additionally, in an independent cohort of patients with NSCLC, we use our observations to inform testing of the combinatorial effect of age and sex on survival of patients given immunotherapy with or without chemotherapy. We observed distinct genomic and immune microenvironment profiles for tumors of younger patients compared to tumors of older patients. Younger patient tumors were enriched in clinically relevant genomic alterations and had gene expression patterns indicative of reduced immune system activation, which was most evident when analyzing male patients. Further, we found younger male patients treated with immunotherapy alone had significantly worse survival compared to male patients ≥65 years, while the addition of chemotherapy reduced this disparity. Contrarily, we found younger female patients had significantly better survival compared to female patients ≥65 years when treated with immunotherapy plus chemotherapy, while treatment with immunotherapy alone resulted in similar outcomes. These results show the value of comprehensive genomic and immune profiling (CGIP) for informing clinical treatment of younger patients with NSCLC and provides support for broader coverage of CGIP for younger patients with advanced NSCLC.

DATA AVAILABILITY: 

De-identified, individual-level patient data, genomic variants, and individual immune gene expression data used in the manuscript can be found in this repository (https://zenodo.org/record/11396552). An R markdown file with R code used to perform the analyses and generate figures is also provided in the repository along with the data. All versions of software used are provided in the Methods section of the manuscript. Raw sequencing data were derived from routine clinical testing of real-world patients and cannot be shared publicly. Data for immune gene expression signatures are not publicly available due to a non‑provisional patent filing covering the methods used to generate and analyze these data but are available from the corresponding author on reasonable request.