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. 2024 Jul 30;13(7):1481-1494.
doi: 10.21037/tlcr-24-226. Epub 2024 Jul 17.

Differential impact of intratumor heterogeneity (ITH) on survival outcomes in early-stage lung squamous and adenocarcinoma based on tumor mutational burden (TMB)

Stanislav Fridland  1 , Hye Sung Kim  1 , Young Kwang Chae  1   2
Affiliations

Differential impact of intratumor heterogeneity (ITH) on survival outcomes in early-stage lung squamous and adenocarcinoma based on tumor mutational burden (TMB)

Stanislav Fridland et al. Transl Lung Cancer Res. .

Abstract

Background: Molecular biomarkers are reshaping patient stratification and treatment decisions, yet their precise use and best implementation remain uncertain. Intratumor heterogeneity (ITH), an area of increasing research interest with prognostic value across various conditions, lacks defined clinical relevance in certain non-small cell lung cancer (NSCLC) subtypes. Exploring the relationship between ITH and tumor mutational burden (TMB) is crucial, as their interplay might reveal distinct patient subgroups. This study evaluates how the ITH-TMB dynamic affects prognosis across the two main histological subtypes of NSCLC, squamous cell and adenocarcinoma, with a specific focus on early-stage cases to address their highly unmet clinical needs.

Methods: We stratify a cohort of 741 early-stage NSCLC patients from The Cancer Genome Atlas (TCGA) based on ITH and TMB and evaluate differences in clinical outcomes. Additionally, we compare driver mutations and the tumor microenvironment (TME) between high and low ITH groups.

Results: In lung squamous cell carcinoma (LUSC), high ITH predicts an extended progression-free survival (PFS) (median: 21 vs. 14 months, P=0.01), while in lung adenocarcinoma (LUAD), high ITH predicts a reduced PFS (median: 15 vs. 20 months, P=0.04). This relationship is driven by the low TMB subset of patients. Additionally, we found that CD8 T cells were enriched in better-performing subgroups, regardless of histologic subtype or ITH status.

Conclusions: There are significant differences in clinical outcomes, driver mutations, and the TME between high and low ITH groups among early-stage NSCLC patients. These differences may have treatment implications, necessitating further validation in other NSCLC datasets.

Keywords: Non-small cell lung cancer (NSCLC); intratumor heterogeneity (ITH); molecular biomarkers; tumor mutational burden (TMB).

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-226/coif). Y.K.C. reports that he received grants or contracts from AbbVie, BMS, Biodesix, Freenome, PictureHealth, and Predicine; consulting fees from Roche/Genentech, AstraZeneca, Foundation Medicine, Neogenomics, Guardant Health, Boehringer Ingelheim, Biodesix, ImmuneOncia, Lilly Oncology, Merck, Takeda, Lunit, Jazz Pharmaceutical, Tempus, BMS, Regeneron, NeoImmunTech, Esai; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche/Genentech, AstraZeneca, Foundation Medicine, Neogenomics, Guardant Health, Boehringer Ingelheim, Biodesix, ImmuneOncia, Lilly Oncology, Merck, Takeda, Lunit, Jazz Pharmaceutical, Tempus, BMS, Regeneron, NeoImmunTech, Esai. The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
TMB and ITH distributions for patients with early-stage NSCLC. The vertical axis and horizontal axes represent the sample count with a given TMB or ITH value. LUSC and LUAD are plotted next to each other. (A) TMB sample distribution; (B) ITH sample distribution. NSCLC, non-small cell lung cancer; TMB, tumor mutational burden; ITH, intratumor heterogeneity; mut/Mb, mutations per Megabase of DNA; LUSC, lung squamous cell carcinoma; LUAD, lung adenocarcinoma.
Figure 2
Figure 2
Survival outcomes in patients with early-stage NSCLC stratified by ITH alone and with low TMB. Kaplan-Meier survival plots of early-stage NSCLC patients stratified by ITH and low TMB at selected cutoffs based on output from the maxStat R package. Below each Kaplan-Meier plot is a risk table showing the number of at risk individuals in each group over time. P values were adjusted when multiple comparisons were performed using the false discovery control rate via SciPy Stats python package and are labeled Padj on the plot. (A) Early-stage LUSC: PFS stratified by ITH >1.4. (B) Early-stage LUSC: OS stratified by ITH >1.4. (C) Early-stage LUAD: PFS stratified by ITH >2.7. (D) Early-stage LUAD OS: stratified by ITH >2.7. (E) Early-stage LUSC with low TMB (TMB ≤9): PFS stratified by ITH >1.4. (F) Early-stage LUSC with low TMB (TMB ≤9): OS stratified by ITH >1.4. (G) Early-stage LUAD with low TMB (TMB ≤6): PFS stratified by ITH >2.7. (H) Early-stage LUAD with low TMB (TMB ≤6): OS stratified by ITH >2.7. P values based on log-rank test and adjusted with false discovery rate control. LUSC, lung squamous cell carcinoma; LUAD, lung adenocarcinoma; PFS, progression-free survival; OS, overall survival; TMB, tumor mutational burden; ITH, intratumor heterogeneity; NSCLC, non-small cell lung cancer.
Figure 3
Figure 3
Survival outcomes in patients with early-stage LUAD, low TMB, and without EGFR driver mutations, stratified by ITH. Kaplan-Meier survival plots of early-stage LUAD patients without EGFR mutations stratified by ITH and low TMB at selected cutoffs based on output from the maxStat R package. Below each Kaplan-Meier plot is a risk table showing the number of at risk individuals in each group over time. Since only one comparison was made, P values were not adjusted. (A) Early-stage LUAD with low TMB (TMB ≤6): PFS stratified by ITH >2.7. (B) Early-stage LUAD with low TMB (TMB ≤6): OS stratified by ITH >2.7. P values based on log-rank test. LUAD, lung adenocarcinoma; PFS, progression-free survival; OS, overall survival; TMB, tumor mutational burden; ITH, intratumor heterogeneity.
Figure 4
Figure 4
Immune cell enrichment in patients with early-stage NSCLC with low TMB, stratified by selected ITH cutoffs. For LUSC, the selected cutoffs were 9 and 1.4, respectively. For LUAD, the cutoffs were 6 and 2.7 for TMB and ITH, respectively. Plots were generated by the ssGSEA. ROC module within the Genepattern tool kit. The vertical axis represents the enrichment scores, and the horizontal axis displays the two groups of interest: LTHI and LTLI. The line within each box represents the median of the distribution. The top and bottom of each box represent the 3rd and 1st quartile of the distribution, respectively. The vertical lines extending to horizontal lines represent 1.5 the interquartile range. Empty circles beyond the horizontal lines are considered represent distributional outliers. The Wilcox P value is located below the horizontal axis labels. A total of 1 LUSC LTLI, 2 LUAD LTHI, and 1 LUAD LTLI patients were excluded from the analysis due to insufficient RNASeq data. (A) Type 2 helper T cells LUSC LTHI vs. LTLI enrichment plot. (B) CD8 T cells LUSC LTHI vs. LTLI enrichment plot. (C) CTLA4 LUSC LTHI vs. LTLI enrichment plot. (D) PDCD1 LUSC LTHI vs. LTLI enrichment plot. (E) Type 1 helper T cells LUAD LTHI vs. LTLI enrichment plot. (F) CD8 T cells LUAD LTHI vs. LTLI enrichment plot. (G) B cells LUAD LTHI vs. LTLI enrichment plot. P values were calculated using the two-sided Wilcoxon test. NSCLC, non-small cell lung cancer; LUSC, lung squamous cell carcinoma; LUAD, lung adenocarcinoma; ssGSEA, single sample gene set enrichment analysis; ITH, intratumor heterogeneity; TMB, tumor mutational burden; LTHI, low TMB high ITH; LTLI, low TMB low ITH; ROC, receiver operating characteristic.
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