DNA ploidy and PTEN as biomarkers for predicting aggressive disease in prostate cancer patients under active surveillance

Background: Current risk stratification tools for prostate cancer patients under active surveillance (AS) may inadequately identify those needing treatment. We investigated DNA ploidy and PTEN as potential biomarkers to predict aggressive disease in AS patients. Methods: We assessed DNA ploidy by image cytometry and PTEN protein expression by immunohistochemistry in 3197 tumour-containing tissue blocks from 558 patients followed in AS at a Norwegian local hospital. The primary endpoint was treatment, with treatment failure (biochemical recurrence or initiation of salvage therapy) as the secondary endpoint. Results: The combined DNA ploidy and PTEN (DPP) status at diagnosis was associated with treatment-free survival in univariable- and multivariable analysis, with a HR for DPP-aberrant vs. DPP-normal tumours of 2.12 (p < 0.0001) and 1.94 (p < 0.0001), respectively. Integration of DNA ploidy and PTEN status with the Cancer of the Prostate Risk Assessment (CAPRA) score improved risk stratification (c-index difference = 0.025; p = 0.0033). Among the treated patients, those with DPP-aberrant tumours exhibited a significantly higher likelihood of treatment failure (HR 2.01; p = 0.027). Conclusions: DNA ploidy and PTEN could serve as additional biomarkers to identify AS patients at increased risk of developing aggressive disease, enabling earlier intervention for nearly 50% of the patients that will eventually receive treatment with current protocol

Tumor heterogeneity and the combined prognostic value of DNA ploidy and PTEN status in prostate cancer

Prostate cancer is the most frequently diagnosed cancer among Norwegian men. Currently available risk stratification tools are inadequate for differentiating between men who will develop a life-threatening disease that requires aggressive treatment, and those with a likely indolent disease who can avoid or postpone curative treatment through enrolment in active surveillance. Identification and application of additional biomarkers that could improve risk stratification is challenging due to tumor heterogeneity, the uneven distribution of a biomarker within a tumor. Tumor heterogeneity in prostate cancer has so far largely been ignored in existing biomarker studies. One aim of this study was to explore the extent of tumor heterogeneity and its effect on prognostic biomarkers in prostate cancer. We used Gleason score, DNA ploidy and PTEN (phosphatase and tensin homolog) status as representative biomarkers. Gleason score describes the morphology and architecture of tumor glands, DNA ploidy is a measure of cellular DNA content, and PTEN is a tumor suppressor. Furthermore, we studied the prognostic value of DNA ploidy and PTEN expression, separately and collectively, in multiple tumor samples from each patient in one large radical prostatectomy and one large active surveillance cohort. We demonstrated extensive tumor heterogeneity based on Gleason score, DNA ploidy and PTEN status in the majority of studied patients, suggesting that a single sample does not provide representative information of the tumor as a whole. DNA ploidy was a prognostic marker when multiple samples were analyzed, as opposed to when one randomly selected sample was used. Combined estimates of DNA ploidy and PTEN status provided better prognostic information than each marker independently. Our results suggest that the combined marker of DNA ploidy and PTEN status could be used in addition to Gleason score for earlier identification of patients with aggressive disease in the active surveillance setting