Combination of tumor asphericity and an extracellular matrix-related prognostic gene signature in non-small cell lung cancer patients

Abstract

One important aim of precision oncology is a personalized treatment of patients. This can be achieved by various biomarkers, especially imaging parameters and gene expression signatures are commonly used. So far, combination approaches are sparse. The aim of the study was to independently validate the prognostic value of the novel positron emission tomography (PET) parameter tumor asphericity (ASP) in non small cell lung cancer (NSCLC) patients and to investigate associations between published gene expression profiles and ASP. This was a retrospective evaluation of PET imaging and gene expression data from three public databases and two institutional datasets. The whole cohort comprised 253 NSCLC patients, all treated with curative intent surgery. Clinical parameters, standard PET parameters and ASP were evaluated in all patients. Additional gene expression data were available for 120 patients. Univariate Cox regression and Kaplan-Meier analysis was performed for the primary endpoint progression-free survival (PFS) and additional endpoints. Furthermore, multivariate cox regression testing was performed including clinically significant parameters, ASP, and the extracellular matrix-related prognostic gene signature (EPPI). In the whole cohort, a significant association with PFS was observed for ASP (p < 0.001) and EPPI (p = 0.012). Upon multivariate testing, EPPI remained significantly associated with PFS (p = 0.018) in the subgroup of patients with additional gene expression data, while ASP was significantly associated with PFS in the whole cohort (p = 0.012). In stage II patients, ASP was significantly associated with PFS (p = 0.009), and a previously published cutoff value for ASP (19.5%) was successfully validated (p = 0.008). In patients with additional gene expression data, EPPI showed a significant association with PFS, too (p = 0.033). The exploratory combination of ASP and EPPI showed that the combinatory approach has potential to further improve patient stratification compared to the use of only one parameter. We report the first successful validation of EPPI and ASP in stage II NSCLC patients. The combination of both parameters seems to be a very promising approach for improvement of risk stratification in a group of patients with urgent need for a more personalized treatment approach.

Figure 1

Kaplan Meier curves of all surgically treated patients stratified according to tumor asphericity.

Figure 2

Progression free survival of patients when stratified according to EPPI for all patients (A) and for patients stratified by PET measured ASP as low risk group (B). Additional stratification using combined risk factors (PET asphericity and EPPI risk score (C) and additional stratification benefit of patients stratified by EPPI risk score as high-risk with additional PET ASP information (D).

Figure 3

Kaplan Meier curves showing progression-free survival of all surgically treated UICC stage II patients stratified according to PET parameters. For each PET parameters the best cut-off value was applied, except ASP, here a previously published cut-off value was applied.

Figure 4

Patient stratification by EPPI in UICC II patients of the radiogenomics cohort that have been stratified by the PET parameter ASP into high risk and low risk groups.