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|Biomarkers - Prognostic and Predictive Indicators|
The research continues to show promising results, yet no biomarker has yet to be used in clinical, everyday practice.
Of note: Predictive value of cell cycle biomarkers in nonmuscle invasive bladder transitional cell carcinoma.
Updates Dec. 2004- Usefulness of CA 125 as a preoperative prognostic marker for transitional cell carcinoma of the bladder- see below
The study of biomarkers, or chromosomal abnormalities that can possibly predict how a person’s disease may progress or respond to treatment, falls under the category of chemoprevention as scientists hope that the end result of these studies will provide an aid in early detection and screening, which could hopefully make a dent in the statistics re: bladder cancer specific deaths. The biomarker must be expressed differently in normal and high-risk tissue, with clear evidence of progression from normal tissue to biomarker to cancer and, ideally, should appear early in carcinogenesis. If the use of biomarkers proves to be a tool for achieving successful preventive intervention, this would support the possibility that a preventive agent that could reverse these molecular events (or suppress their consequences) for one tumor site may be effective in preventing a variety of tumors. The development and validation of biomarkers are important to the success of testing chemopreventive agents. 1
Examples of biomarkers include include genetic markers (eg, nuclear aberrations [such as micronuclei], gene amplification, and mutation), cellular markers (eg, differentiation markers and measures of proliferation, such as thymidine labeling index), histologic markers (eg, premalignant lesions, such as leukoplakia and colonic polyps), and biochemical and pharmacologic markers (eg, ornithine decarboxylase activity). 1
This aspect of urology/oncology is currently one of intense research efforts. The ultimate goal is to find a marker that can reliably detect occult disease.2At the present time none of the markers tested is elevated in more than 50% of patients. The use of biomarkers has not yet been incorporated into standard staging procedures, and although great headway is being made in the field of biomarker studies, at this point in time pathological assessment of stage and grade is still the best index of prognosis in common use.
The most discussed chromosomal biomarker of all is the p53 protein, a tumor suppressor gene on chromosome 17p. Between 1993 and 1996 over 4,000 articles on this subject were published.8 A wealth of studies seems to confirm that the p53 protein, if mutated and overexpressed in cancerous cells, is an indication of a potentially aggressive condition. 9
It’s been shown that both grade and stage of (invasive) bladder cancer are related to p53 alterations.10 Mutations in the p53 gene are observed in 65% of CIS cases and 51% of muscle invasive TCC, while only 3% of papillary Ta tumors show mutations. 11
Mutations in the p53 gene can be detected in tissue sections by immunohistochemistry. Since the wild-type p53 gene has a short life, immunostaining of normal urothelium with p53 monoclonal antibodies is negative. When mutations in the p53 gene occur, the mutated proteins aggregate in tetrameric and pentameric macromolecules of longer life. The result is an accumulation of p53 protein that provides a positive immunostaining reaction. The reaction is observed in the nuclei of tumor cells affected by these events. The role of the immune system in neutralizing the invasive potential of CIS is unknown but may explain why a significant proportion of CIS fails to invade.11
The function of p53 is critical to the way that many cancer treatments kill cells since radiotherapy and chemotherapy act in part by triggering cell suicide in response to DNA damage. This successful response to therapy is greatly reduced in tumours where p53 is mutant so these tumours are often particularly difficult to treat. It is hoped that better understanding of p53 can guide the developement of new treatments for cancer. Scientists are beginning to unravel some of the mysteries and in the test tube at least, are beginning to find ways to make these damaged p53s work again. Such discoveries could potentially offer a powerful and selective new way of treating cancer.12
How should P53 status be used during decision making for patients with superficial transitional cell carcinoma of the bladder?
New data coming in regarding another biomarker, the p21 gene, is showing that people with p21-positive tumors have a decreased probability of tumor recurrence.13
The research team from USC/Norris Comprehensive Cancer Center conducted a study on 242 patients with locally confined bladder tumors who were followed for an average of 8.5 years. Analysis was done of of the p21 protein and it’s interaction with the p53 protein. Results of the study indicated that patients with p21-positive tumours survived disease-free significantly longer than those patients with p21-negative tumours. Furthermore, it was shown that the way the p21 and p53 proteins interact with each other can give a very good indication of which patients must be considered at high risk for recurrence.
The article stated that p53 is known to be a primary regulator of p21, since genetic changes in p53 may lead to loss of p21 expression and function. This in turn leads to unregulated cell growth, and is thought to contribute to the aggressive behaviour of some tumours. "We reasoned that if p21 is [positively] expressed despite alterations in p53, then cell cycle control might be maintained and the tumours would be less likely to progress," said Dr. Richard Cote, M.D., Ass. Prof. of Pathology and Urology, and researcher at Norris. "Our hypothesis seems confirmed by this study.”
Patients with p53- altered/p21-negative tumors demonstrated a higher rate of recurrence and worse survival compared with those with p53-altered/p21-positive tumors. Patients with p53-altered/p21-positive tumors demonstrated a similar rate of recurrence and survival as those with p53-wild type tumors.13
John Stein, M. D., Assistant Professor of Urology, an expert on surgical approaches to bladder cancer and a colleague of Cote’s at USC stated; "Molecular markers will allow us to manage patients with a clearer idea of the benefits of treatment in that individual. This represents a greatadvantage to physicians and patients.”
Memorial Sloan Kettering Cancer Center in NYC has also conducted a study on the usefulness of p53 to guide treatment approaches. The findings of Herr and colleagues in published 1999 suggest that the bladder may be preserved for up to 10 years in patients with tumors confined to the bladder (stage T2) who lack detectable p53 if they respond completely to neoadjuvant chemotherapy. The authors conclude that patients with T3 bladder tumors or T2 p53 positive tumors are best treated currently with cystectomy. 14
The loss of expression of the retinoblastoma gene (Rb) on chromosome 13q (3) has also been associated with malignancies including bladder cancer.
In 1992 Logothetis and fellow researchers from MD Anderson concluded that “The high frequency of Rb alteration in locally advanced bladder carcinomas, plus the fact that a significant correlation could not be found between the Rb status and other known prognostic markers in this preliminary study, suggests that altered RB expression may be an independent prognostic marker of tumor progression in bladder cancer.”15
In 1998, Cote and associates at Norris concluded that tumors altered in both p53 and pRb have significantly increased rates of recurrence and lower survival compared to those with no alterations in either p53 or pRb; patients with alterations in only one of these proteins had intermediate rates of recurrence and survival. These results suggested that: (a) bladder cancers with high pRb expression do not show the tumor suppressor effects of the protein; and (b) alteration in both p53 and pRb may act in cooperative or synergistic ways to promote tumor progression.16
Another biomarker, bcl-2, is an apoptosis regulator; when production of bcl-2 is deregulated, overexpression acts to prevent apoptosis and the cells prolonged survival provides additional opportunity to acquire futher abnormalities. Recent findings from Dr. Mayake's team in Japan suggest that, if it is overexpressed, Bcl-2 prolongs cell survival under unfavourable conditions encountered in the metastatic process, resulting in the enhanced metastatic potential of bladder cancer.17
The same researchers have reported other findings which suggest that the expression of Bcl-2 in bladder cancer cells interferes with the therapeutic effects of cisplatin through the inhibition of the apoptotic pathway.18
Memorial Sloan - Kettering Cancer Center-July 2000: MSK investigators have pinpointed a protein that may identify which patients with bladder cancer are likely to fare well with standard treatment, as opposed to those who might need more aggressive therapy. The protein, E2F-1, may be a useful marker to help doctors determine the most effective course of treatment for each patient. MSK physicians are also using a new combination chemotherapy -- with ifosfamide, taxol and platinum, also known as TIC-- that appears to be more effective and have fewer side effects that M-VAC, the standard therapy.
MDR-1 (Multiple Drug Resistance) expression in cancer cells is associated with resistance to natural product chemotherapeutic agents such as Taxol, Doxorubicin, and Etoposide, and detection of MDR-1 can play a critical role in the selection of a treatment regimen. Benson and colleagues from Columbia University stated that the ability of flow cytometry to detect and quantify the expression of MDR-1 may allow for the early detection of chemotherapy resistance in TCC patients treated with systemic and intravesical therapy.19
Another important predictive marker is MRP. This marker is associated with resistance to commonly used drugs in treatment of bladder cancer such as platinum analogs, vinblastine, etoposide, doxorubicin, and other drugs which may be conjugated with glutathione.20
Kubo and fellow researchers from Japan reported that ‘The intrinsic or acquired resistance of urothelial cancer to chemotherapy is one major obstacle to successful treatment’. Their study showed that 17 of 33 bladder tumors (51.5%) expressed more than 2-fold the MRP mRNA levels of drug-sensitive human KB cells, and they concluded that MRP may be one mechanism responsible for intrinsic drug resistance in low-grade urothelial cancer.21
A recent article by Hemstreet and colleagues from the University of Oklahoma discussed the use of DMSO to modulate biomarker expression of G-actin, DNA aneuploidy, and p300 tumor antigen, which were evaluated prior to and immediately following treatment with BCG on 25 people. Excluding patients who did not respond to BCG recurrence correlated with persistent abnormal G- actin findings. Of patients who were G-actin negative following therapy, only 25% recurred during follow-up in contrast to 67% in patients who were positive. The authors concluded that Cytosolic G-actin levels can be an important intermediate end point marker for chemoprevention. 6
Superficial, low grade papillary tumors are not routinely tested for biomoarkers, as it isn’t considered cost effective (not proven to save lives in the long run) and the efficacy is questioned. The testing of biomarkers is not routine and still considered experimental, although the flood of data on p53 has started to influence even the most isolated urologists.
If a tumor has been determined to be poorly differentiated and high grade, no matter the stage, you might want to ask about what kind of patholgy tests were done, what they showed, whether the Rb, p53 and p21 or any other prognostic/predictive indicators have been analyzed, whether this could or should effect treatment strategy.
Larger prospective studies are needed to evaluate further the independent value of these biological markers in superficial bladder cancer management. It is important that the analysis of the p53 and other biomarkers be done properly, and not all urologists and pathologists are able to interpret the findings correctly.
Biomarkers are also being tested in private labs. For a look at what they are doing for bladder cancer there is a website www.IMPATH.com which has labs in New York, LA and Pheonix. IMPATH is a resource for pathologists, as well as patients. Some of the biomarkers used for analysis of bladder tumors are the Ki-67, bcl-2, MDR-1, the Lewis X blood group antigen, proteins p21 and p53, the retinoblastoma gene and DNA ploidy.
“For poorly differentiated tumors, morphological assessment alone errs so often (in nearly 50 percent of cases overall), that failure to perform immunohistologic studies is difficult to defend ethically or legally. In cases of poorly differentiated carcinomas of prostate/bladder area; Prostate cancer may invade the bladder, and bladder tumors may invade the prostate, but the therapies for these two entities differ markedly. Incorrect therapy resulting from misdiagnosis may lead to fatal spread of the disease” Source; Impath website.
Many patients feel that by educating themselves (and perhaps even their doctor in the process), they can be assured that they will get the best odds in the long run. On the other hand, you have to take into consideration what this information would mean to you, will it change anything in your treatment? Could you rest easy knowing that you have an aggressive condition that needs careful monitoring? If you have put yourself in the hands of a competent team of doctors that you have confidence and trust in, this is also a valid approach. Each individual must find the path that helps him or her cope in the best way possible. For some, it’s knowing every angle no matter how scary. Others may be less comfortable with this information.
In the face of bladder cancer patients advocating for more clinical trials, studies and use of these tests, hopefully more funding will be allocated and we will soon get the clear answers we are wating for.
Here are a couple of links to p53 sites;
A useful book to help lay people understand the process of a cell’s mutations;"One renegade cell", by Robert A Weinberg. Basic Books; ISBN: 0465072755
Links and book recommended by Steve Miley
Tumor Marker for Bladder Cancer
Increased CA 125 was seen in approximately 11% of patients with high grade or invasive TCC preoperatively. It was more commonly found in patients with locally advanced and lymph node positive disease, and it was associated with overall survival. However, recurrence-free survival was not associated with CA 125. Further studies are required to define the exact role of CA 125 in bladder cancer.
From the Departments of Urology (AC, GM, DS, JPS) and Biostatistics (JC, SG), University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. CHANG, ANDY; CAI, JIE; MIRANDA, GUS; GROSHEN, SUSAN; SKINNER, DONALD; STEIN, JOHN P. Journal of Urology. 172(6, Part 1 of 2):2182-2186, December 2004. PubMedReferences
1. Cancer Prevention: The Roles of Diet and Chemoprevention; Peter Greenwald, MD, DrPH, Sharon S. McDonald, MS,Division of Cancer Prevention and Control at the National Cancer Institute, Bethesda, Md (PG) and The Scientific Consulting Group, Inc, Gaithersburg, Md (SSM)http://www.moffitt.usf.edu/pubs/ccj/v4n2/article2.html
2. Bladder Cancer: Twenty Years of Progress and the Challenges That Remain. Donald L. Lamm, M.D. CAJournal for Clinicians, Guest Editorial 1998 http://www.ca-journal.org/articles/48/5/263-268/48_263-268_frame.htm
3. Predicting prognosis in patients with superficial bladder cancer. de Vere White RW, Stapp E Department of Urology, University of California, Davis, Sacramento. Oncology (Huntingt) 1998 Dec;12(12):1717-23; discussion 1724-6
4. Prognostic markers in bladder cancer: a contemporary review of the literature. Stein JP; Grossfeld GD; Ginsberg DA; Esrig D; Freeman JA; Figueroa AJ; Skinner DG; Cote RJ Department of Urology, Kenneth Norris, Jr. Comprehensive Cancer Center, University of Southern California, Los Angeles, USA. J Urol 1998;160(3 Pt 1):645-59 UI: 98385469
6. Biomarkers in monitoring for efficacy of immunotherapy and chemoprevention of bladder cancer with dimethylsulfoxide.Hemstreet GP 3rd; Rao J; Hurst RE; Bonner RB; Mellott JE; Rooker GMDepartment of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, USA.Cancer Detect Prev 1999;23(2):163-71 PMID: 10101598 UI: 99201814
7. The role of Ki67 proliferation assessment in predicting local control in bladder cancer patients treated by radical radiation therapy. Lara PC; Rey A; Santana C; Afonso JL; Diaz JM; Gonzalez GJ; Apolinario R Department of Radiation Oncology, Hospital Nuestra Senora del Pino, Las Palmas de Gran Canaria, Spain. Radiother Oncol 1998 Nov;49(2):163-7 PMID: 10052882 UI: 99160247
10. p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Esrig D; Spruck CH 3d; Nichols PW; Chaiwun B; Steven K; Groshen S; Chen SC; Skinner DG; Jones PA; Cote RJ Urologic Cancer Research Laboratory, University of Southern California, Los Angeles 90033. Am J Pathol 1993 Nov;143(5):1389-97 PMID: 7901994 UI: 94056661
11. Two molecular pathways to transitional cell carcinoma of the bladder. Spruck CH 3rd; Ohneseit PF; Gonzalez-Zulueta M; Esrig D; Miyao N; Tsai YC; Lerner SP; Schmutte C; Yang AS; Cote R; et al Kenneth Norris Jr. Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Southern California, School of Medicine, Los Angeles 90033. Cancer Res. 1994;54:784-788.
From; Cancer Control: Journal of the Morffitt Cancer Center; Pathology Update: Pathobiology of Preinvasive Utothelial Neoplasia Author: Jose I. Diaz, MD, Pathology Service, H. Lee Moffitt Cancer Center & Research Institute http://www.moffitt.usf.edu/pubs/ccj/v3n6/patholog.html 3(6):552-556, 1996. © 1996 Moffitt Cancer Center & Research Institute] Article can also be found at http://www.medscape.com/
12. David P. Lane FRS, FRSE, FRCPath, Ph.D.
13. Effect of p21WAF1/CIP1 expression on tumor progression in bladder cancer Stein JP; Ginsberg DA; Grossfeld GD; Chatterjee SJ; Esrig D; Dickinson MG; Groshen S; Taylor CR; Jones PA; Skinner DG; Cote RJ Department of Pathology, University of Southern California School of Medicine and Kenneth Norris Jr. Comprehensive Cancer Center, Los Angeles 90033, USA. J Natl Cancer Inst 1998 Jul 15;90(14):1072-9 PMID: 9672255 UI: 98335999
14. Can p53 help select patients with invasive bladder cancer for bladder preservation?
15. Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer
16. Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cote RJ; Dunn MD; Chatterjee SJ; Stein JP; Shi SR; Tran QC; Hu SX; Xu HJ; Groshen S; Taylor CR; Skinner DG; Benedict WF Department of Pathology, University of Southern California School of Medicine/Norris Comprehensive Cancer Center, Los Angeles 90033, USA. Cancer Res 1998 Mar 15;58(6):1090-4 PMID: 9515785 UI: 98175538
17. Overexpression of Bcl-2 enhances metastatic potential of human bladder cancer cells. Miyake H; Hara I; Yamanaka K; Gohji K; Arakawa S; Kamidono S Department of Urology, Kobe University School of Medicine, Japan. Br J Cancer 1999 Apr;79(11-12):1651-6 PMID: 10206273 UI: 99221114
18. Overexpression of Bcl-2 in bladder cancer cells inhibits apoptosis induced by cisplatin and adenoviral-mediated p53 gene transfer.
19. Flow cytometric determination of the multidrug resistant phenotype in transitional cell cancer of the bladder: implications and applications. Benson MC; Giella J; Whang IS; Buttyan R; Hensle TW; Karp F; Olsson CA Department of Urology, Columbia University College of Physicians and Surgeons, New York, New York. J Urol 1991 Oct;146(4):982-6; discussion 986-7 PMID: 1680203 UI: 91374690
20. Oncotech biotech laboraty; www.oncotech.com
21. Expression of the multidrug resistance-associated protein (MRP) gene in urothelial carcinomas. Kubo H; Sumizawa T; Koga K; Nishiyama K; Takebayashi Y; Chuman Y; Furukawa T; Akiyama S; Ohi Y Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Japan. Int J Cancer 1996 Dec 20;69(6):488-94 PMID: 8980253 UI: 97134693
22. Correlation and prognostic significance of p53, p21WAF1/CIP1 and Ki-67 expression in patients with superficial bladder tumors treated with bacillus Calmette-Guerin intravesical therapy Zlotta AR; Noel JC; Fayt I; Drowart A; Van Vooren JP; Huygen K; Simon J; Schulman CC Department of Urology, Erasme University Hospital, Brussels, Belgium. J Urol 1999 Mar;161(3):792-8 PMID: 10022686 UI: C
23. Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette- Guerin therapy: correlation to clinical outcome. Lacombe L; Dalbagni G; Zhang ZF; Cordon-Cardo C; Fair WR; Herr HW; Reuter VE Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021-6356, USA. J Clin Oncol 1996 Oct;14(10):2646-52 PMID: 8874323 UI: 97028309
Bladder Cancer: State of the Art Care Michael J. Droller M.D.
|Last Updated ( Friday, 14 November 2008 )|