Malignant field expression signatures in biopsy samples at diagnosis predict the likelihood of lethal disease in patients with localized prostate cancer

Abstract

Aim: Overtreatment of early-stage low-risk prostate cancer patients represents a significant problem in disease management and has significant socio-economic implications. Changes in prostate cancer screening and treatment practices in the United States have been associated with the recent decline in overall incidence and concomitant significant increase of the annual incidence of metastatic prostate cancer has been documented. Therefore, development of genetic and molecular markers of clinically significant disease in patients diagnosed with low grade localized prostate cancer would have a major impact in disease management. Methods: Identification of gene expression signatures (GES) associated with lethal prostate cancer has been performed using microarray analyses of biopsy specimens obtained at the time of diagnosis from 281 patients with Gleason 6 (G6) and G7 tumors in a Swedish watchful waiting cohort with up to 30 years follow-up. The performance of GES has been validated in independent cohort of 568 prostate cancer patients of the Cancer Genome Anatomy Project Prostate Cancer database. Results: GES comprising 98 genes identified 89% and 100% of all death events 4 years after diagnosis in G7 and G6 patients, respectively. At 6 years follow-up, 83% and 100% of all deaths events were captured in G7 and G6 patients, respectively. Remarkably, the 98-gene signature appears to perform successfully in patients stratification with as little as 2% of cancer cells in a specimen, strongly indicating that it captures a malignant field effect in human prostates harboring cancer cells of different degrees of aggressiveness. In G6 and G7 tumors from prostate cancer patients of age 65 or younger, GES identified 86% of all death events during the entire follow-up period. In G6 and G7 tumors from prostate cancer patients of age 70 or younger, GES identified 90% of all death events 6 years after diagnosis. Conclusion: Classification performance of the reported in this study 98-genes GES of lethal prostate cancer appeared suitable to meet design and feasibility requirements of a prospective 4 to 6 years clinical trial, which is essential for regulatory approval of diagnostic and prognostic tests in clinical setting. Prospectively validated GES of lethal PC in biopsy specimens of G6 and G7 tumors will help physicians to identify, at the time of diagnosis, patients who should be considered for exclusion from active surveillance programs and who would most likely benefit from immediate curative interventions.

Keywords

Gene expression signatures / lethal prostate cancer / localized prostate cancer / active surveillance / curative interventions / clinical management of early-stage prostate cancer / malignant field effect

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