Early Postoperative Plasma Transforming Growth Factor-β1 is a Strong Predictor of Biochemical Progression After Radical Prostatectomy

Purpose: Blood levels of transforming growth factor-β1, interleukin-6 and interleukin-6 soluble receptor have been associated with aggressive primary and metastatic prostate cancer. We hypothesized that patients with increased plasma levels of transforming growth factor-β1, interleukin-6 and/or interleukin-6 soluble receptor after radical prostatectomy would be more likely to harbor occult metastases, leading to disease progression despite effective local control of disease. Materials and Methods: Plasma transforming growth factor-β1, interleukin-6 and interleukin-6 soluble receptor were measured 6 to 8 weeks after surgery in 291 consecutive patients treated with radical prostatectomy for clinically localized disease. Discrimination and validation of multivariate Cox regression models targeting time to biochemical progression were used to quantify the added value of these markers to predictive accuracy (concordance index) after internal validation with 200 bootstrap resamples. Results: On multivariate analysis adjusting for standard postoperative features postoperative plasma transforming growth factor-β1 was the only biomarker independently associated with biochemical progression (p <0.001). The addition of postoperative transforming growth factor-β1 improved the accuracy of the standard postoperative model from 78.4% to 84.1%, representing a 5.7% gain (p <0.001). Of patients who experienced biochemical progression postoperative transforming growth factor-β1 was significantly higher in those with features of aggressive disease progression, ie development of metastasis, prostate specific antigen doubling time less than 10 months and/or failure to respond to local salvage radiation therapy (p <0.001). Conclusions: Postoperative interleukin-6 and interleukin-6 soluble receptor have limited clinical usefulness in prostate cancer. In contrast, postoperative plasma transforming growth factor-β1 measured 6 to 8 weeks after surgery is a strong predictor of biochemical progression, presumably due to an association with early low volume occult metastases that are at the threshold of clinical progression.