A prognostic hypoxia gene signature with low heterogeneity within the dominant tumour lesion in prostate cancer patients.

BACKGROUND: Gene signatures measured in a biopsy have been proposed as hypoxia biomarkers in prostate cancer. We assessed a previously developed signature, and aimed to determine its relationship to hypoxia and its heterogeneity within the dominant (index) lesion of prostate cancer. METHODS: The 32-gene signature was assessed from gene expression data of 141 biopsies from the index lesion of 94 patients treated with prostatectomy. A gene score calculated from the expression levels was applied in the analyses. Hypoxic fraction from pimonidazole immunostained whole-mount and biopsy sections was used as reference standard for hypoxia. RESULTS: The gene score was correlated with pimonidazole-defined hypoxic fraction in whole-mount sections, and the two parameters showed almost equal association with clinical markers of tumour aggressiveness. Based on the gene score, incorrect classification according to hypoxic fraction in whole-mount sections was seen in one third of the patients. The incorrect classifications were apparently not due to intra-tumour heterogeneity, since the score had low heterogeneity compared to pimonidazole-defined hypoxic fraction in biopsies. The score showed prognostic significance in uni-and multivariate analysis in independent cohorts. CONCLUSIONS: Our signature from the index lesion reflects tumour hypoxia and predicts prognosis in prostate cancer, independent of intra-tumour heterogeneity in pimonidazole-defined hypoxia.

Stability of metabolic tumor volume may enable radiotherapy dose painting in anal cancer.

PURPOSE: To evaluate the variability of the 18F-FDG-PET/CT-based metabolic tumor volume (MTV) in anal cancers during fractionated chemoradiotherapy (CRT), and assess the impact of this variability on dosimetric accuracy in MTV-targeted dose painting. METHODS: Eleven patients with anal squamous cell carcinoma who received fractionated chemoradiotherapy with curative intent were included. 18F-FDG PET/CT images were acquired at pre- and mid-treatment. Target volumes and organs at risk (OARs) were contoured manually on both image series. The MTV was generated from the PET images by thresholding. Treatment plans were retrospectively optimized for both image series using volumetric modulated arc therapy (VMAT). Standard plans prescribed 48.6 Gy, 54 Gy and 57.5 Gy in 27 fractions to elective regions, lymph node metastases and primary tumor, respectively. Dose painting plans included an extra dose level of 65 Gy to the MTV. Pre-treatment plans were transferred and re-calculated at mid-treatment basis. RESULTS: MTV decreased from pre- to mid-treatment in 10 of the 11 patients. On average, 71 % of MTVmid overlapped with MTVpre. The median and mean doses to the MTV were robust against anatomical changes, but the transferred dose painting plans had lower D98% values than the original and re-optimized plans. No major differences were found between standard and dose painting plans for OARs. CONCLUSIONS: Despite volumetric changes in the MTV, adequate dose coverage was observed in most dose painting plans. The findings indicate little or no need for adaptive dose painting at mid-treatment. Dose painting appears to be a safe treatment alternative with similar dose sparing of OARs.

Prostate cancer radiogenomics reveals proliferative gene expression programs associated with distinct MRI-based hypoxia levels.

BACKGROUND AND PURPOSE: The biology behind individual hypoxia levels in patient tumors is poorly understood. Here, we used radiogenomics to identify associations between magnetic resonance imaging (MRI)-based hypoxia levels and biological processes derived from gene expression data in prostate cancer. MATERIALS AND METHODS: For 85 prostate cancer patients, MRI-based hypoxia images were constructed by combining diffusion-weighted images reflecting oxygen consumption and supply. The ability to differentiate hypoxia levels in these images was verified by comparison with matched biopsy sections stained for the hypoxia marker pimonidazole. For MRI-defined hypoxia levels, corresponding hypoxic fractions were calculated and correlated with biopsy gene expression profiles. Biological processes were predicted by gene set enrichment analysis (GSEA) and validated by immunohistochemistry (Ki67 proliferation marker, reactive stroma grade) and RT-PCR (MYC). RESULTS: Genes with correlation between expression level and hypoxic fraction were identified for 56 MRI-based hypoxia levels. At all levels, GSEA identified proliferation as the predominant biological process enriched among the correlating genes. Two independent proliferative gene signatures were developed. The Peak1 signature, upregulated at moderate/severe hypoxia, reflected MYC upregulation and high Ki67-proliferation index of cancer cells in pimonidazole-positive regions. The Peak2 signature, upregulated at mild to non-hypoxic levels, was associated with fibroblast gene signature and reactive stroma grade. High scores of both Peak1 and Peak2 indicated elevated risk of biochemical recurrence in multiple cohorts. CONCLUSION: Radiogenomics identified two gene expression programs activated at different hypoxia levels, reflecting proliferation of cancer cells and stroma cells. Genes involved in these programs could be candidate targets for intervention.

Integrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance.

Human papillomavirus (HPV)-associated cervical cancer is a leading cause of cancer deaths in women. Here we present an integrated multi-omic analysis of 643 cervical squamous cell carcinomas (CSCC, the most common histological variant of cervical cancer), representing patient populations from the USA, Europe and Sub-Saharan Africa and identify two CSCC subtypes (C1 and C2) with differing prognosis. C1 and C2 tumours can be driven by either of the two most common HPV types in cervical cancer (16 and 18) and while HPV16 and HPV18 are overrepresented among C1 and C2 tumours respectively, the prognostic difference between groups is not due to HPV type. C2 tumours, which comprise approximately 20% of CSCCs across these cohorts, display distinct genomic alterations, including loss or mutation of the STK11 tumour suppressor gene, increased expression of several immune checkpoint genes and differences in the tumour immune microenvironment that may explain the shorter survival associated with this group. In conclusion, we identify two therapy-relevant CSCC subtypes that share the same defining characteristics across three geographically diverse cohorts.