Tai, Yi-Sheng Department of Urology, National Taiwan University Hospital

1. Tai, Yi-Sheng Department of Urology, National Taiwan University Hospital SMOKING INCREASED BLADDER TUMOR RECURRENCE RATE IN UPPER TRACT UROTHELIAL CARCINOMA吸菸增加上泌尿道泌尿上皮癌之膀胱復發

2. Background & Purpose • Cigarette smoking increases bladder recurrence in bladder UC patients. Smoking status is a risk factor for recurrence after transurethral resection of non-muscle-invasive bladder cancer. Eur Urol. 2011 • Stopping smoking decreases bladder recurrence in bladder UC patients. Stopping smoking might reduce tumour recurrence in nonmuscle-invasive bladder cancer. BJU Int. 2007 • Whether smoking also plays an important role on bladder recurrence in UUC patients?

3. Materials and Methods • Patient population: • Consecutive UUC patients from 2000~2011 • All received nephroureterectomies • Exclusion criteria • Arsenic endemic residency • Previous chemothrapy and radiotherapy for any reason • Insufficient tissue samples for etiology identification

4. Materials and Methods • Etiology identification • Questionnaire: cigarette smoking and herbs • Renal cortex: aristolactam-DNA adduct (aristolochic acid exposure) • Tumor: TP53 gene sequencing (signature mutation for aristolochic acid-induced UC)

5. Materials and Methods • Outcome measurement • Bladder recurrence: only tumor recurrence 3 months after nephroureterectomy • Tumor recurrence within 3 months was considered as synchronous bladder cancer  excluded from the analysis

6. Patient demographics Heavy smoker *: greater than 20 pack-year of smoking

7. Patient demographics stratified by smoking

8. Bladder tumor recurrence Non-heavy smoker Heavy smoker Log-rank p=0.034

9. Bladder tumor recurrence stratified by etiologies • AA-UUC: • signature p53 mutation and AL-DNA adduct

10. Prognostic factors for bladder tumor recurrence

11. Discussion • Cigarette smoking and bladder cancer • Cigarette smoking and UTUC • Smoking and bladder tumor recurrence in UUC

12. Cigarette smoking and bladder cancer • Current cigarette smokers have an approximately threefold higher risk of urinary tract cancer than nonsmokers. Cancer. 2000 Aug 1;89(3):630-9. • Ex- and current smoking result in significantly shorter recurrence-free survival than non-smoking Eur Urol 60 (2011) (713 - 720) • Chen et al. - Benefit of smoking cessation on bladder cancer recurrence. - Continued smokers have a 2.2-time increased risk than cessation BJU Int. 2007 Aug;100(2):281-6

13. Cigarette smoking and UTUC • Cigarette smoking : risk factor for the development of UTUC - 3.1-fold higher risk in smokers - 7.2-fold higher risk in long-term smokers CANCER RESEARCH 52, 254-257. January 15, 1992 • Associated with advanced disease stages, disease recurrence, and cancer-specific mortality in patients treated with RNU for UTUC. Eur Urol. 2012 Jun 22. • Smoking cessation >10 yr seems to mitigate some detrimental effects. Eur Urol. 2012 Jun 22.

14. Smoking and bladder tumor recurrence in UUC • Few published studies focued on the smoking as prognostic factors for bladder cancer recurrence after nephroureterectomy. • Terakawa et al. • Pathologic stage and tumor multifocality as independent predictors for recurrent bladder Urology. 2008 Jan;71(1):123-7 • Simsir et al. • smokers had higher cancer-specific mortality and bladder recurrence rates. • not provide a multivariable analysis Int Urol Nephrol. 2011 Dec;43(4):1039-45

15. Smoking and bladder recurrence in UUC: this study • Heavy smoking, TP53 mutation, DM and multiple tumor location are independent factors on bladder tumor recurrence after NUx • Aristolochic acid-related UUC: insignificant • Heavy smoking inversely associated with TP53 mutation.

16. Conclusions Heavy smokers UUC patients, > 20 pack-years, had more bladder tumor recurrence than non-smokers and aristolochic acid-related UUC patients Heavy smoking is an independent factor predicting bladder recurrence in UUC patients and inversely associated with TP53 mutation.

17. ThanksForYourAttention

18. A series of studies has demonstrated a significant association between the number of cigarettes smoked per day and p53 nuclear overexpression Cancer Epidemiol Biomarkers Prev. 1994 Jan-Feb;3(1):19-24as well as between the p53 point mutations and the number of years of smoking in bladder cancer. Carcinogenesis. 2000 Jan;21(1):101-6. • p53 mutation is associated with high-stage disease and p53 overexpression was correlated with advanced tumor stage and grade , and was forwarded as a significant negative predictor of survival . Int J Cancer 53 : 365-370 , J Natl Cancer Inst 85 : 53-58 , Science 252 : 706-709, Cancer, 82 (1998), pp. 715–723 • More recently, p53 nuclear accumulation in bladder carcinomas cells was found to correlate with the mitotic index and vascular invasion.  J. Urol., 162 (1999), pp. 1496–1501 • The detection of nuclear p53 was a independent predictor significantly associated with an increased risk of recurrence of bladder cancer  and with decreased overall survival.N Engl J Med. 1994 Nov 10;331(19):1259-64.

19. Rey et al. were the first to investigate the prognostic role of proteins involved in cell-cycle regulation in 83 patients with UTUC [100]. • The authors showed that the overexpression of p53 was significantly associated with tumor aggressiveness and patient survival, even after adjustment for several patient and disease characteristics. • More recently, the impact of p53 on survival was investigated by a Japanese single-center study (n = 66) and a European single-center study (n = 53) [101,102]. • According to these studies, while p53 was a predictor of survival in univariable analyses, it did not emerge as an independent prognostic factor after adjustment for other clinical and pathologic characteristics.

20. TP53 mutation (rate and pattern) in UUC patients(overall)