Medical Student Research Fellowship for Summer 2008

Mentor: Dr. Yair Lotan
Department: Urology
Room number: J8.112
Mail Code: 9110
Phone number: 214-648-0389
E-mail: Yair.Lotan@utsouthwestern.edu
Project title: Prospective Study on the Significance of Altered Molecular Markers in Patients with High Grade/Stage Bladder Cancer

Human subjects IRB approved project number (where applicable): IRB # 0503-307
Animal subjects IRB approved project number (where applicable):

Project Type: patient-based

Brief Description of Project:

An estimated 67,160 new cases of bladder cancer and 13,750 deaths from bladder cancer are expected in 2007 in the United States.(1) Approximately 25% of patients present with muscle-invasive disease, and radical cystectomy is the preferred standard definitive therapy. Unfortunately, even patients with locally invasive disease (pathologic stages T1-T3a, node negative) recur up to 25% at 5-years with most dying of their disease.(2;3) Although bladder cancer is chemo-responsive, treatment of grossly metastatic disease offers minimal prolongation of survival.(4) Neoadjuvant chemotherapy has been found to improve survival in several studies in patients with locally advanced bladder cancer,(5;6) but is often withheld because of attendant risks, patient co-morbidities, and concerns of over treatment in node-negative patients. The results for adjuvant chemotherapy trials have been mixed with several trials demonstrating no clear benefit.(7-9) Other trials showed some survival benefits(10-12), but have been criticized for major deficiencies in terms of sample size, early stopping of patient entry, and confusing statistical analyses.(13)
One reason for the significant variability of outcomes for chemotherapy trials is the heterogeneity among muscle-invasive bladder cancers. Most clinical trials thus far have randomized patients based on standard staging criteria using TNM staging. These trials did not utilize molecular markers to help stratify risk of recurrence or bladder cancer-specific survival. Factors such as lymphovascular invasion status(3) and status of molecular markers such as cell cycle regulators (p53, pRB, p21, p27) are known independent predictors of recurrence and survival.(14-16) At UTSW, we evaluated whether a panel of 5 common molecular alterations (p53, pRB, p21, p27 and cyclin E1) can improve the ability to predict recurrence and bladder-cancer specific survival in patients who underwent cystectomy with node negative status and no evidence of metastases. We analyzed the added benefit of marker status to standard staging criteria, as well as lymphovascular invasion status and created nomograms to predict recurrence and bladder cancer-specific survival after cystectomy.(17)
We evaluated 191 patients who underwent cystectomy and bilateral pelvic lymphadenectomy at our institution with pathologic stages T1-T3 with no lymph node involvement and no metastatic disease. We found that 19% recurred and 16% died of their disease after a mean follow-up of 51 months. Patients with lymph node involvement or metastatic disease are usually counseled in favor of chemotherapy. Yet the majority of patients who undergo cystectomy have locally advanced disease (stages T1-T3) with negative lymph nodes and these patients are rarely provided with multi-modality therapy. In 2 large contemporary series of patients undergoing cystectomy, only 26% of patients received adjuvant chemotherapy and this was primarily given to patients with node positive disease.(2;3) However, it is clear that up to 20% of patients with negative lymph nodes have systemic disease and could potentially benefit from adjuvant therapies. The problem with the current staging system is that it does not provide sufficient information to identify which patients will recur and die of their disease.
Our panel of 5 markers provided discriminatory information that significantly improved the ability to predict which patients will recur and have bladder cancer specific mortality. Molecular alterations in cell cycle regulators (p53, pRB, p21, and p27) and cyclin E1 were common and 82% of patients had at least one altered marker, 20% had 3 marker alterations and 16% had 4 or 5 altered markers. Patients with 3 or greater altered markers had a 4 to 10 times greater risk of recurrence and death of disease. Despite the fact that only 19% of patients recurred after cystectomy, less than 10% of patients with less than 3 altered markers recurred at 5 years as compared with 30% and 65% of patients with 3 and 4-5 alterations, respectively. Another analysis found that Ki-67, a marker of proliferation, was an independent predictor of survival and recurrence after cystectomy.(18)
Due to the limitations of retrospective reviews, we developed a protocol to confirm our findings prospectively. Starting in January 2007, all patients at our institution who have invasive or high grade bladder cancer had their specimens evaluated with a molecular marker panel. The goals of this study are to validate the significance of altered molecular markers in patients with high grade/stage bladder cancer. We will also evaluate the correlation of the number of altered markers with stage and grade of tumors. Furthermore, in patients with endoscopic resection of tumors, we will determine if the molecular status of transurethrally resected tumors correlates with the cystectomy specimen.

REFERENCES

1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007 Jan-2007 Feb 28;57(1):43-66.
2. Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001 Feb 1;19(3):666-75.
3. Silverman DT, Hartge P, Morrison AS, Devesa SS. Epidemiology of bladder cancer. Hematol Oncol Clin North Am 1992 Feb;6(1):1-30.
4. Sternberg CN, Yagoda A, Scher HI, Watson RC, Ahmed T, Weiselberg LR, Geller N, Hollander PS, Herr HW, Sogani PC, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 1985 Mar;133(3):403-7.
5. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003 Aug 28;349(9):859-66.
6. Sherif A, Holmberg L, Rintala E, Mestad O, Nilsson J, Nilsson S, Malmstrom PU. Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies. Eur Urol 2004 Mar;45(3):297-303.
Notes: CORPORATE NAME: Nordic Urothelial Cancer Group.
7. Studer UE, Bacchi M, Biedermann C, Jaeger P, Kraft R, Mazzucchelli L, Markwalder R, Senn E, Sonntag RW. Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial. J Urol 1994 Jul;152(1):81-4.
8. Otto T, Börgermann C, Krege S, Rübben H. Adjuvant chemotherapy in locally advanced bladder cancer [pT3/pT4a,pN1-2,M0]- a phase III study. Eur Urol 39 (Suppl. 2):147.
9. Pianezza O, Meneguelo M, Merlo F. et al. Adjuvant chemotherapy in locally advanced bladder cancer. Long-term follow-up of a multicenter study. J Urol 169 (Suppl.):337.
10. Skinner DG, Daniels JR, Russell CA, Lieskovsky G, Boyd SD, Nichols P, Kern W, Sakamoto J, Krailo M, Groshen S. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 1991 Mar;145(3):459-64; discussion 464-7.
11. Freiha F, Reese J, Torti FM. A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 1996 Feb;155(2):495-9; discussion 499-500.
12. Stockle M, Meyenburg W, Wellek S, Voges G, Gertenbach U, Thuroff JW, Huber C, Hohenfellner R. Advanced bladder cancer (stages pT3b, pT4a, pN1 and pN2): improved survival after radical cystectomy and 3 adjuvant cycles of chemotherapy. Results of a controlled prospective study. J Urol 1992 Aug;148(2 Pt 1):302-6; discussion 306-7.
13. Sylvester R, Sternberg C. The role of adjuvant combination chemotherapy after cystectomy in locally advanced bladder cancer: what we do not know and why. Ann Oncol 2000 Jul;11(7):851-6.
14. Esrig D, Elmajian D, Groshen S, Freeman JA, Stein JP, Chen SC, Nichols PW, Skinner DG, Jones PA, Cote RJ. Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 1994 Nov 10;331(19):1259-64.
15. Sarkis AS, Dalbagni G, Cordon-Cardo C, Zhang ZF, Sheinfeld J, Fair WR, Herr HW, Reuter VE. Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst 1993 Jan 6;85(1):53-9.
16. Shariat SF, Tokunaga H, Zhou J, Kim J, Ayala GE, Benedict WF, Lerner SP. p53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer. J Clin Oncol 2004 Mar 15;22(6):1014-24.
17. Shariat SF, Karakiewicz PI, Ashfaq R, Lerner SP, Palapattu GS, Cote RJ, Sagalowsky AI, Lotan Y. Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy. Cancer 2008 Jan 15;112(2):315-25.
18. Margulis V, Shariat SF, Ashfaq R, Sagalowsky AI, Lotan Y. Ki-67 is an independent predictor of bladder cancer outcome in patients treated with radical cystectomy for organ-confined disease. Clin Cancer Res 2006 Dec 15;12(24):7369-73.

Previous Research Activities or Publications with Medical Students:

Bensalah K, Raman JD, Bagrodia A, Marvin A, Lotan Y.Does Obesity Impact the Costs of Partial and Radical Nephrectomy?J Urol. 2008 Mar 14
Yair Lotan1, Karim Bensalah1, Timothy Ruddell1, Shahrokh F. Shariat1, Arthur Sagalowsky1, Raheela Ashfaq2.
Prospective Evaluation of the Clinical Utility of Reflex Fluorescent In Situ Hybridization Assay in Patients with Atypical Cytology for Detection of Urothelial Carcinoma of the Bladder. J urol in press
Svatek RS, Lee D, Lotan Y. Correlation of Office-Based Cystoscopy and Cytology with Histologic Diagnosis: How Good is the Gold Standard? Urology. 2005 Jul;66(1):65-8.
Shariat SF, Herman MP, Casella R, Lotan Y, Karam JA, Stenman UH. Urinary Levels of Tumor-Associated Trypsin Inhibitor (TATI) in the Detection of Transitional Cell Carcinoma of the Urinary Bladder. Eur Urol. 2005 Sep;48(3):424-31
Anderson JK, Murdock A, Cadeddu JA, Lotan Y. Cost Comparison of Laparoscopic versus Radical Retropubic Prostatectomy. Urology. 2005 Sep;66(3):557-60.
Svatek RS, Herman MP, Lotan Y, Casella R, Hsieh JT, Sagalowsky AI, Shariat SF. Soluble Fas-A promising novel urinary marker for the detection of recurrent superficial bladder cancer. Cancer. 2006 Mar 15.
Park S, Jaffer O, Lotan Y, Saboorian H, Roehrborn CG, Cadeddu JA. Contemporary laparoscopic and open radical retropubic prostatectomy: pathologic outcomes and Kattan postoperative nomograms are equivalent. Urology. 2007 Jan;69(1):118-22.