Heidi Lyng

MRI-guided dynamic risk assessment in cervical cancer based on tumor hypoxia at diagnosis and volume response at brachytherapy

Improvements in treatment outcome for patients with locally advanced cervical cancer (LACC) require a better classification of patients according to their risk of recurrence. We investigated whether an imaging-based approach, combining pretreatment hypoxia and tumor response during therapy, could improve risk classification. Ninety-three LACC patients with T2-weigthed (T2W)-, dynamic contrast enhanced (DCE)- and diffusion weighted (DW)-magnetic resonance (MR) images acquired before treatment, and T2W- and, for 64 patients, DW-MR images, acquired at brachytherapy, were collected. Pretreatment hypoxic fraction (HF HF The combination of pretreatment hypoxia and volume regression at brachytherapy improved patient risk classification. Integration of ADC with volume regression showed promise as a new tumor response parameter.

Combining imaging- and gene-based hypoxia biomarkers in cervical cancer improves prediction of chemoradiotherapy failure independent of intratumour heterogeneity

Emerging biomarkers from medical imaging or molecular characterization of tumour biopsies open up for combining the two and exploiting their synergy in treatment planning of cancer patients. We generated a paired data set of imaging- and gene-based hypoxia biomarkers in cervical cancer, appraised the influence of intratumour heterogeneity in patient classification, and investigated the benefit of combining the methodologies in prediction of chemoradiotherapy failure. Hypoxic fraction from dynamic contrast enhanced (DCE)-MR images and an expression signature of six hypoxia-responsive genes were assessed as imaging- and gene-based biomarker, respectively in 118 patients. Dichotomous biomarker cutoff to yield similar hypoxia status by imaging and genes was defined in 41 patients, and the association was validated in the remaining 77 patients. The two biomarkers classified 75% of 118 patients with the same hypoxia status, and inconsistent classification was not related to imaging-defined intratumour heterogeneity in hypoxia. Gene-based hypoxia was independent on tumour cell fraction in the biopsies and showed minor heterogeneity across multiple samples in 9 tumours. Combining imaging- and gene-based classification gave a significantly better prediction of PFS than one biomarker alone. A combined dichotomous biomarker optimized in 77 patients showed a large separation in PFS between more and less hypoxic tumours, and separated the remaining 41 patients with different PFS. The combined biomarker showed prognostic value together with tumour stage in multivariate analysis. Combining imaging- and gene-based biomarkers may enable more precise and informative assessment of hypoxia-related chemoradiotherapy resistance in cervical cancer. Norwegian Cancer Society, South-Eastern Norway Regional Health Authority, and Norwegian Research Council.

Targeted Therapy on the Screen: Do We Hit the Target?

Summary A phase II trial, investigating whether the antidiabetic drug metformin could reduce hypoxia in cervical cancer, used imaging to preselect patients and test the biological hypothesis behind the drug effect. This trial design would be of importance for the implementation of targeted treatment in the clinic. See related article by Han et al., p. 5263

miR‐200a/b/‐429 downregulation is a candidate biomarker of tumor radioresistance and independent of hypoxia in locally advanced cervical cancer

Many patients with locally advanced cervical cancer experience recurrence within the radiation field after chemoradiotherapy. Biomarkers of tumor radioresistance are required to identify patients in need of intensified treatment. Here, the biomarker potential of miR‐200 family members was investigated in this disease. Also, involvement of tumor hypoxia in the radioresistance mechanism was determined, using a previously defined 6‐gene hypoxia classifier. miR‐200 expression was measured in pretreatment tumor biopsies of an explorative cohort (n = 90) and validation cohort 1 (n = 110) by RNA sequencing. Publicly available miR‐200 data of 79 patients were included for the validation of prognostic significance. A score based on expression of the miR‐200a/b/‐429 (miR‐200a, miR‐200b, and miR‐429) cluster showed prognostic significance in all cohorts. The score was significant in multivariate analysis of central pelvic recurrence. No association with distant recurrence or hypoxia status was found. Potential miRNA target genes were identified from gene expression profiles and showed enrichment of genes in extracellular matrix organization and cell adhesion. miR‐200a/b/‐429 overexpression had a pronounced radiosensitizing effect in tumor xenografts, whereas the effect was minor in vitro. In conclusion, miR‐200a/b/‐429 downregulation is a candidate biomarker of central pelvic recurrence and seems to predict cell adhesion‐mediated tumor radioresistance independent of clinical markers and hypoxia.

An Immune Gene Expression Risk Score for Distant Metastases after Radiotherapy for Cervical Cancer

Abstract Purpose: To develop an immune-based gene expression risk score to identify patients with cervical cancer at increased risk of distant metastases (DM). Experimental Design: Tumor biopsies were obtained from 81 patients prior to chemoradiotherapy. Whole-transcriptome RNA sequencing was performed (Illumina NextSeq500). Beginning with 4,723 immune-related genes, a 55-gene risk score for DM was derived using Cox modeling and principal component analysis. It was validated in independent cohorts of 274 patients treated at the Norwegian Radium Hospital (NRH) and 206 patients from The Cancer Genome Atlas (TCGA). Results: The risk score was predictive of DM (HR, 2.7; P < 0.0001) and lower cause-specific survival (CSS) by univariate analysis (HR, 2.0; P = 0.0003) and multivariate analysis adjusted for clinical factors (DM HR, 3.0; P < 0.0001; CSS HR, 2.2; P = 0.0004). The risk score predicted DM (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 TCGA cohort. Higher risk scores were associated with 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 associated with lower expression (all P < 0.001) of important chemokines (CXCL12, CXCR4), IFN-regulated genes (IRF1, STAT1, IDO1), and immune checkpoint regulators (PD-1, PD-L1, CTLA-4). Conclusions: The immune metastatic risk score addresses important challenges in the treatment of cervical cancer—identifying patients at high risk of DM after radiotherapy. The findings of this study indicate that high tumor mutational burden and a “cold,” immune-excluded tumor microenvironment influence distant metastatic recurrence. Further validation of the risk score is needed.