Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study

Abstract

Movember Foundation, Prostate Cancer Canada, Ontario Institute for Cancer Research, Canadian Institute for Health Research, NIHR Cambridge Biomedical Research Centre, The University of Cambridge, Cancer Research UK, Cambridge Cancer Charity, Prostate Cancer UK, Hutchison Whampoa Limited, Terry Fox Research Institute, Princess Margaret Cancer Centre Foundation, PMH-Radiation Medicine Program Academic Enrichment Fund, Motorcycle Ride for Dad (Durham), Canadian Cancer Society.

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

“…Similarly, in ovarian cancers the percentage of stromal cells (assessed from hematoxylin and eosin slides) was significantly associated with poor overall and progression free-survival, even after controlling for clinical parameters including surgical debulking status and age (Natrajan et al, 2016). In prostate cancers, a measure of genomic instability coupled with intratumoral hypoxia was found to be able to significantly improve prognostic accuracy, beyond conventional clinical parameters (Lalonde et al, 2014). A landmark study in melanoma, which sequenced over 4,500 single cells from 19 patients (including malignant, immune, stromal and epithelial cells), identified therapy resistance tumor subpopulations present prior to treatment, which may have been missed with bulk-sequencing, as well as a relationship between cancer-associated fibroblasts and preferential expression of an AXLhigh/MITF-low transcriptional program (Tirosh et al, 2016).…”

Application of a Clinical Whole-Transcriptome Assay for Staging and Prognosis of Prostate Cancer Diagnosed in Needle Core Biopsy Specimens

“…15 Use of this expression array protocol also allows for evaluation of various combinations of PSRs, and thus permits one to simultaneously assess other expression marker panels and data sets, 10,16,17 as well as evaluate new ones. To explore the transcriptomic differences between prostate biopsy and matched RP samples, and evaluate the effects of heterogeneity, we compared transcriptomic data generated using Human Exon arrays obtained from 158 different prostate tissue samples from 33 patients seen at three different institutions.…”

Clinical development of new drug–radiotherapy combinations

“…Given the potential for mechanistic interactions between novel drugs and radiotherapy, preclinical studies should be used to carefully assess combination regimens, using tumour models that are linked to a clinical development strategy. Clinically derived 'signatures' of prognosis following radical radiotherapy, on the basis of genomic and microenvironmental indices, might also be considered for use in patient selection once these biomarkers have been validated in prospective clinical trials 98,99 . Finally, it is important to verify that the PD biomarkers being used for drug evaluation are not adversely influenced by radiotherapy treatment.…”