A 6-gene signature for loco-regional control prognosis in HNSCC patients treated by PORT-C


A 6-gene signature for loco-regional control prognosis in HNSCC patients treated by PORT-C

Patil, S.; Linge, A.; Grosser, M.; Gudziol, V.; Nowak, A.; Tinhofer, I.; Budach, V.; Sak, A.; Stuschke, M.; Balermpas, P.; Rödel, C.; Schäfer, H.; Grosu, A.; Abdollahi, A.; Debus, J.; Ganswindt, U.; Belka, C.; Pigorsch, S.; Combs, S. E.; Mönnich, D.; Zips, D.; Baretton, G. B.; Baumann, M.; Krause, M.; Löck, S.

Purpose: The aim of this study was to identify and validate a gene signature combining machine learning approaches and biological information in order to predict loco-regional control (LRC) in patients with HPV-negative, locally advanced HNSCC who received postoperative radio(chemo)therapy (PORT(-C)).
Materials and methods: Gene expression analysis was performed using the GeneChip Human Transcriptome Array 2.0 on a multicentre retrospective training cohort of 128 patients and an independent validation cohort of 114 patients of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG) treated with PORT(-C) (figure A). Genes were filtered based on differential gene expression analysis and Cox regression. The identified gene signature was combined with clinical features and with previously identified genes related to cancer stem cells [1-2] and hypoxia [3]. Model performance was evaluated by the concordance index (ci) and Kaplan-Meier analyses.

Results:

We identified a 6-gene signature consisting of four individual genes CAV1, GPX8, IGLV3-25, TGFBI and one metagene combining the highly correlated genes INHBA and SERPINE1. A multivariable Cox model combining the 6-gene classifier and clinical parameters was fit to the training data (ci=0.81) and was successfully validated (ci=0.66). It stratified patients into two risk groups that significantly differed in the primary endpoint LRC in training (p<0.001) and in validation (p=0.039) (figure B, C). In addition, the corresponding gene classifier was successfully validated on a TCGA dataset with a validation ci of 0.59 for the endpoint OS (figure D, E). Extending the 6-gene signature with the putative cancer stem cell marker CD44 [1-2] and the 15 genes of a hypoxia-associated signature [3] further improved performance on the validation cohort (ci=0.70) as well as patient stratification (p<0.001) (figure F, G).
Conclusion: We identified and validated a novel 6-gene signature for patients with HPV-negative HNSCC treated by PORT(-C) that is prognostic for LRC. After successful prospective validation the signature could be applied in clinical trials to further individualize radiotherapy.

References:

[1] Linge et al. Clin Cancer Res 22: 2639 (2016).
[2] Linge et al. Clin Transl Radiat Oncol 1: 19 (2016).
[3] Toustrup et al. Cancer Res 7: 5923 (2011).

Keywords: head and neck squamous cell carcinoma; gene signature; postoperative radiotherapy; hypoxia; cancer stem cells; feature selection; model building

  • Contribution to proceedings
    European Society Radiation Oncology (ESTRO) 2021, 27.-31.08.2021, Online Congress, Online Congress

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Publ.-Id: 34122