A146

Background: Superficial (papillary) bladder cancer comprises a spectrum of pre- or early malignant disorders incorporated into the concept of intraepithelial neoplasia, which is considered an important target for the development of new agents designed to reduce both cancer incidence and death. Despite the efficacy of prophylactic BCG3 immunotherapy in prolonging recurrence and progression-free survival, a substantial proportion of cases are destined to recur anywhere in the urothelial lining, as a result of field cancerization effect. However, no reliable quantitative biomarkers that predict progression and death from the target organ have been identified. Recent studies have shown that DNA aneuploidy in papillary tumor tissue predicts the subsequent risk of invasive cancer. Methods: We analyzed the long-term prognostic effect of DNA flow-cytometry in bladder washings from 93 subjects with resected Ta/T1 superficial bladder cancer who participated in a randomized chemoprevention trial of the synthetic retinoid fenretinide. The DNA index (DI) was evaluated as the ratio of the DNA content of G0-G1 aneuploid cells to the DNA content of diploid G0-G1 cells. Kaplan-Meier analysis and Cox regression were used to determine the prognostic effect of DNA aneuploidy on cancer progression and mortality adjusting for conventional confounding (age, sex, smoking habits) and clinical factors (fenretinide treatment, tumor stage, tumor grade, tumor history) after a median of 11.5 years (IQ range, 9.5-11.7 years). Results: Overall, 58 of 93 (62%) specimens were DNA aneuploid at baseline. A history of recurrent tumors and previous intravesical BCG were associated with a DNA aneuploid washing. Of the 11 progressions to invasive bladder cancer, 10 (91%) had a DNA aneuploid washing (HR = 10.5; 95%CI, 0.9-126.1; LRtest p = 0.03). Stage T1 exhibited a greater risk of progression than Ta tumors (HR = 31.6, 95%CI, 2.6-386.1; p < 0.001). Twenty-two of the 27 deaths (82%) were DNA aneuploid, and the risk of death was greater for DNA aneuploid washings (HR = 2.8, 95%CI, 0.9-9.0; p = 0.05) and stage T1 tumors (HR = 2.6, 95%CI, 1.04-6.7; p = 0.04). All bladder cancer deaths were DNA aneuploid. Fenretinide had no significant effect on cancer progression and death. Conclusions: DNA aneuploidy in washings from apparently normal bladder is a significant predictor of progression and death in addition to tumor stage. This biomarker may help to identify and monitor a high-risk group who may benefit from a chemoprevention intervention.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]