Pre-Treatment [F-18]FDG-PET SUVmax as a Prognostic and Radiogenomic Marker in Cervical Cancer

Abstract

We previously identified primary tumor [F-18]fluorodeoxyglucose-positron emission tomography ([F-18]FDG-PET) maximum standardized uptake value (SUVmax) as a candidate prognostic marker in cervical cancer patients treated with definitive radiation therapy (RT). We hypothesize that high SUVmax is associated with targetable biologic pathways. This work aims to identify and validate a prognostic cut point for SUVmax in cervical cancer, and define associated biologic pathways. Two cohorts were used for this study. Cohort 1 consisted of all patients with cervical cancer treated at our institution between 2006-2015 who underwent a pre-treatment [F-18]FDG-PET, were treated with curative intent RT, and completed all prescribed RT (N=331). Cohort 2 consisted of patients enrolled on a prospective tumor banking study with sufficient RNA for whole transcriptome sequencing (N=68). An optimal SUVmax prognostic for freedom from progression (FFP) was determined in cohort 1 using outcome-oriented cut point methodology. This SUVmax was validated with a bootstrap Cox multivariate analysis (MVA) using 1000 random samplings from cohort 1. SUVmax, stage, [F-18]FDG-PET lymph node status, age, and histology were included in the MVA. Stratified Kaplan-Meier (KM) analysis was also performed on cohort 1 subgroups of stage and lymph node status. Gene set enrichment analysis was then performed on RNA samples from cohort 2 to identify pathways associated with high SUVmax. Using cohort 1, the optimal SUVmax cut point prognostic of FFP was 11.41 (p = 0.002 by log-rank). This was also prognostic for cancer specific survival (p = 0.02 by log-rank), but not overall survival. In the bootstrap Cox MVA validation, SUVmax >11.41 was a significant prognostic factor for FFP in 46.1% of the cohort 1 samples (median hazard ratio (HR) 1.91), stage in 75.1% (median HR 1.08 for stage II vs. I, 2.23 for stage III vs. I, and 2.57 for stage IV vs. I), and [F-18]FDG-PET positive lymph nodes in 99.1% (median HR 1.30 for pelvic nodes vs none, 3.23 for para-aortic nodes vs. none). On stratified KM analysis, SUVmax was prognostic of FFP in stage I cancers (p = 0.002), and in patients with positive pelvic nodes on pretreatment [F-18]FDG-PET (p = 0.006) and maintained significance on MVA in these subgroups (p = 0.003 and 0.03, respectively). Whole transcriptome profiling identified gene sets associated with the NF-κB (p < 3e-16, false discovery rate (FDR) = 7.2e-5) and JAK/STAT3 (p < 3e-16, FDR = 8.6e-4) pathways, and an inflammatory phenotype associated with immunosuppressive M2 tumor associated macrophages (p < 3e-16, FDR < 3e-16) in tumors with SUVmax > 11.41. Pre-treatment [F-18]FDG-PET SUVmax > 11.41 is prognostic in cervical cancer, particularly in stage I cancers and patients with PET-positive pelvic nodes. High SUVmax is associated with NF-κB and JAK/STAT3 pathway activation and an inflammatory but immunosuppressive phenotype.