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Cervical cancer radiotherapy (RT) dose intensification with image guided interstitial brachytherapy (BT) has yielded excellent local control rates of 90% or higher. A high proportion of patients, however, develop distant metastases and die. Clinical trials of chemotherapy or molecular therapeutics have failed, in part because high risk patients cannot reliably be identified, and the drivers of metastases are poorly understood. To address this, we developed and validated an immune-based gene expression risk score for distant metastases after curative-intent treatment with RT/cisplatin.

Tumor biopsies were obtained from 81 cervical cancer patients at the Princess Margaret Cancer Centre prior to external beam RT/cisplatin and 2D BT with long-term follow-up and recording of sites of recurrence. Shallow whole genome DNA sequencing was performed for copy number alterations (CNA). Whole genome RNA sequencing was performed using an Illumina NextSeq500. Beginning with 4,723 immune-related genes, a 55 gene risk score for distant metastases was derived using Cox modelling and principal component analysis. It was validated in independent cohorts of 274 patients from the Norwegian Radium Hospital (NRH) and 206 patients from TCGA.

The 55 gene risk score was strongly predictive of distant metastatic recurrence (HR 2.7, p<0.0001) and lower cause specific survival (CSS) by univariate analysis (HR 2.0, p=0.0003). Similar results were seen (distant metastases HR 3.0, p<0.0001; CSS HR 2.2, p=0.0004) on multivariate analysis adjusted for clinical prognostic factors. The risk score validated as a predictor of distant metastatic recurrence (HR 1.4, p=0.05) and CSS (HR 1.48, p=0.013) in the NRH cohort and CSS (HR 1.4, p=0.03) in the TCGA cohort (sites of recurrence not available). There was no relationship with local recurrence. Higher risk scores were associated with higher CNA determined independently by DNA sequencing (p=0.001) and lower CIBERSORT estimates of tumor infiltrating immune cells, including CD8 T-cells and M1 and M2 macrophages (all p<0.001). Higher risk scores were also associated with lower expression (all p<0.001) of important chemokines (CXCL12, CXCR4), interferon regulated genes (IRF1, STAT1, IDO1) and immune checkpoint regulators (PD-1, PD-L1, CTLA-4).

The immune gene expression risk score addresses important clinical challenges in the treatment of cervical cancer – identifying patients at high risk of distant metastatic recurrence after RT and potential targets for mitigating this risk. The findings of this study indicate that high tumor mutational burden and an immune suppressed tumor microenvironment influence distant metastatic recurrence but not local recurrence, suggesting different biologic mechanisms for these two endpoints. Further validation of the risk score is require in a prospective clinical trial.