Development and validation of a quantitative reactive stroma biomarker (qRS) for prostate cancer prognosis

Abstract

To develop and validate a new tissue-based biomarker that improves prediction of outcomes in localized prostate cancer by quantifying the host response to tumor. We use digital image analysis and machine learning to develop a biomarker of the prostate stroma called quantitative reactive stroma (qRS). qRS is a measure of percentage tumor area with a distinct, reactive stromal architecture. Kaplan Meier analysis was used to determine survival in a large retrospective cohort of radical prostatectomy samples. qRS was validated in two additional, distinct cohorts that include international cases and tissue from both radical prostatectomy and biopsy specimens. In the developmental cohort (Baylor College of Medicine, n = 482), patients whose tumor had qRS > 34% had increased risk of prostate cancer-specific death (HR 2.94; p = 0.039). This result was replicated in two validation cohorts, where patients with qRS > 34% had increased risk of prostate cancer-specific death (MEDVAMC; n = 332; HR 2.64; p = 0.02) and also biochemical recurrence (Canary; n = 988; HR 1.51; p = 0.001). By multivariate analysis, these associations were shown to hold independent predictive value when compared to currently used clinicopathologic factors including Gleason score and PSA. qRS is a new, validated biomarker that predicts prostate cancer death and biochemical recurrence across three distinct cohorts. It measures host-response rather than tumor-based characteristics, and provides information not represented by standard prognostic measurements.

Keywords: Biomarker; Cancer; Host response; Prostate; Stroma.

Figure 1:. Study design –

A training cohort of 50 patients was used to train the tissue segmentation software to recognize tissue components. This algorithm was used to quantify reactive stroma in the Baylor College of Medicine cohort. An optimal biomarker cutoff was established as qRS 34%, which was used in two validation cohorts.

Figure 2:. Segmented Tissue -

Hematoxylin and eosin deconvoluted images on the left. Corresponding segmented images on the right. Smooth muscle fibers are colored in red while reactive stroma is colored purple. Individual cell nuclei and cytoplasm are identified in each compartment.

Figure 3:. BCM-TMA Survival Curve and Logistic regression –

(A) Patients whose tumors have qRS > 34% have shorter disease-specific survival compared to patients with less reactive stroma in the tumor microenvironment. (B) Multivariate analysis confirms statistical significance that is independent of other standard clinicopathologic variables.

Figure 4:. Validation in VA and Canary Cohorts -

(A) Patients from the VA cohort whose tumors have qRS > 34% have shorter disease-specific survival compared to patients with qRS less than 34%. (B) This risk is confirmed by multivariate analysis. (C) Patients from the Canary cohort whose tumors have qRS > 34% have shorter time to biochemical recurrence (PSA > 0.02 ng/ml) than patients with qRS less than 34%. (D) This risk is confirmed with multivariate analysis.