Abstract
B37
Background: Digital nuclear morphometric analysis can detect and quantify subtle changes of chromatin patterns, thus allowing to better identify high-risk subjects and to study progression of dysplasia towards malignancy. Moreover, it may serve as a surrogate endpoint biomarker for drug efficacy. >Purpose: Within a phase I-II biomarker trial on the activity of weekly low-dose bicalutamide in subjects at high risk for prostate cancer, we investigated whether treatment was able to modify karyometric parameters of normal secretory cells obtained through needle core-biopsy. >Methods: High-risk subjects with elevated PSA (> 4 ng/ml) and negative initial biopsy were sequentially and non-randomly assigned to either low-dose Bic (50 or 100 mg weekly) or no treatment for 6 months. A second biopsy was performed after 6 months to assess morphological and morphometrical changes induced by treatment. Blood samples were obtained before and after treatment to assess changes in circulating biomarkers (PSA and PAP). Morphometric, DNA, and chromatin texture analyses were performed on nuclei of normal secretory cells using a CAS 200 image analyzer and the “Cell Sheet” software, evaluating up to 41 features on each nucleus of a mean of 200 cells per subject. >Results: 80 subjects were enrolled. There was a significant regression of high-grade prostatic intraepithelial neoplasia (HG-PIN) (p=0.03) and a significant decrease of both PSA and PAP (p<0.001 and p=0.03, respectively) in treated vs. control subjects. Image analysis at baseline and on end-of-study biopsy was available on 74 and 70 subjects, respectively, and revealed a significant trend to an increase of both densitometric and Markovian chromatin texture features in normal secretory cells. Specifically, DNA optical density (OD) increased significantly by 1% on treatment and decreased by 3% in control subjects (estimated mean changes are 2.15 vs. -0.71 respectively, p for interaction time*treatment = 0.005), suggesting a reduced transcriptional activity in the nucleus of normal secretory cells on treatment with bicalutamide, consistent with a significant decrease of both PSA and PAP observed on treatment. >Conclusions: Nuclear morphometry appears to be feasible on prostate needle biopsies. Treatment with bicalutamide induced significant karyometric changes, supporting further investigation of this procedure as a surrogate biomarker of treatment effect in chemoprevention trials.
Sixth AACR International Conference on Frontiers in Cancer Prevention Research-- Dec 5-8, 2007; Philadelphia, PA