Integrated somatic subtypes of localized intermediate-risk prostate cancer.

Abstract

e560 Background: Approximately two thirds of intermediate risk prostate cancer patients are over- or under- treated because we cannot correctly prognose this risk group; therefore we require novel biomarkers to better direct patient therapies and avoid subjecting patients to side effects without benefit. One reason genomic biomarkers are not currently used in clinical settings is because they are notoriously difficult to validate in follow-up studies. Furthermore, the lack of clear prostate cancer subtypes prevents the development of subtype specific biomarkers as is standard practice in breast cancer. We aim to improve biomarker validation rates by defining prostate cancer subtypes that can be used to create subtype specific biomarkers. Methods: First, we assess large scale genomic patterns using whole genome sequencing and methylation data and create integrative subtypes for intermediate risk prostate cancer. Second, we assess associations between specific aberrations and subtypes, and determine whether certain types of molecular aberrations are more important background aberrations for subtype specific biomarker development. Finally, we assess biases in prognostic performance of the published Lalonde biomarker between groups associated with patient subtypes to show that subtype aware biomarkers are necessary. Results: We demonstrate that the Lalonde biomarker is biased by the cohorts’ proportion of TMPRSS2-ERG (T2E) aberrations illustrating the need to develop different biomarkers for patients with T2E and patients without T2E. Further, we suggest integrative subtypes can be used to select patients with similar genomic profiles for biomarker analysis to improve biomarker validation rates. Conclusions: This analysis provides direct guidance for future biomarker development and addresses an important barrier to clinical use of genomic biomarkers for prostate cancer.