<abstract xmlns="http://www.w3.org/1999/xhtml">

<sec><h3>Introduction</h3>
<p>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.</p>
</sec>
<sec><h3>Methods</h3>
<p>The authors searched biomedical databases (Medline, Scopus, Embase) for studies reporting on intratumoral heterogeneity in NSCLC.</p>
</sec>
<sec><h3>Results</h3>
<p>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.</p>
</sec>
<sec><h3>Conclusion</h3>
<p>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.</p>
</sec>
</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.

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

Forum of Clinical Oncology

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Introduction
Tumoral heterogeneity has been associated with treatment resistance and failure in patients with cancer. Tumoral heterogeneity can be either...

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

Article Category: Review

Published Online: Oct 12, 2023

Page range: 3 - 14

Received: Jun 20, 2023

Accepted: Jul 25, 2023

DOI: https://doi.org/10.2478/fco-2023-0005

Keywords
Nonsmall-cell lung cancer, NSCLC, heterogeneity, immunotherapy, targeted treatment

© 2023 A. Koulouris et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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

Article Category: Review

Published Online: Oct 12, 2023

Page range: 3 - 14

Received: Jun 20, 2023

Accepted: Jul 25, 2023

DOI: https://doi.org/10.2478/fco-2023-0005

KeywordsNonsmall-cell lung cancer, NSCLC, heterogeneity, immunotherapy, targeted treatment

© 2023 A. Koulouris et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords
Nonsmall-cell lung cancer, NSCLC, heterogeneity, immunotherapy, targeted treatment