Spatial and Temporal Heterogeneity in Clonal Evolution of Nonsmall-cell Lung Cancer: Implications for Therapy

Abstract Introduction Tumoral heterogeneity has been associated with treatment resistance and failure in patients with cancer. Tumoral heterogeneity can be either intertumoral (static variation of cancer cells) or intratumoral (spatial and temporal variation of cancer cells). Nonsmall-cell lung cancer (NSCLC) is considered a model disease for the study of tumoral heterogeneity, given the emerging evidence about the clinical implications of genetic variations among NSCLC subtypes. This review provides an overview of the etiology, detection, and management methods of intratumoral heterogeneity in NSCLC and discusses their clinical implications. Methods The authors searched biomedical databases (Medline, Scopus, Embase) for studies reporting on intratumoral heterogeneity in NSCLC. Results Intratumoral heterogeneity occurs in single tumors, multiple tumors in the same organs, primary tumors and metastases, and among distinct metastases. Genetic (selective pressure, clonal evolution, genomic instability) and nongenetic pathways (tumor metabolism, hypoxia) precipitate heterogeneity across the spatial and temporal progression of the disease. Proposed classifications are based either on cancer subtypes or mutations detected and metastasis sites. Liquid biopsies (cell-free DNA, circulating tumor cells) combined with imaging (computed tomographies (CTs), positron emission tomography/computed tomographies (PET/CTs)) have a major potential for the continuous minimally invasive monitoring of intratumoral heterogeneity in comparison to conventional biopsies. Targeted therapies have a higher likelihood to induce heterogeneity and resistance, while PD-L1 immunotherapy represents a promising therapeutic strategy. Conclusion Spatial and temporal intratumoral heterogeneity within a single patient sets additional challenges to personalized precision medicine, calling for continuous cellular and molecular-level surveillance and adequate adjustment of the treatment plan.