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Prognostic and Predictive Factors in Bladder Cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology. (Experimentell Urologi)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Prognostic and Predictive Factors in Bladder Cancer (English)
Abstract [en]

Bladder cancer is a potentially curable malignancy; however in regards to the state of current therapy regimens, a plateau has been reached in both the non-muscle and muscle invasive types. To obtain effective treatment, and consequently a decreased mortality, it has become imperative to test and understand aspects affecting therapy response. The aim of this thesis is to illustrate a better understanding of clinical factors affecting therapy response using new drug combinations and new tumor markers alongside established risk criteria. In Paper I we reported the 5 year follow up from a multicenter, prospectively randomized study and we evaluated the 5-year outcomes of BCG alone compared to a combination of epirubicin and interferon-a2b in the treatment of patients with T1 bladder cancer. Treatment, tumor size and tumor status at second resection were independent variables associated with recurrence. Concomitant Cis was not predictive of failure of BCG therapy. Independent factor for treatment failure was remaining T1 stage at second resection. In Paper II &III we investigated the validity of emmprin, survivin and CCTα proteins as biomarkers for response and survival before neoadjuvant cisplatin chemotherapy. Bladder tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry (IHC). Patients in the chemotherapy cohort with negative emmprin and CCTα expression had significantly better overall survival (OS) than those with positive expression. In Paper IV primary end point was examining STMN1 as prognostic factor in bladder cancer.  Analysis was performed on three bladder cancer patient cohorts using IHC, western blot and a bladder cancer cell line. High levels of STMN1, expression correlated to shorter disease-specific survival and the growth and migration of the cells were significantly reduced when transfecting the cells with STMN1 siRNA. Conclusion Risk assessment and predictors of outcomes could help in individualized treatment and follow up.  Biomarkers will become more important for treatment choices in bladder cancer management.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 113 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1207
Keyword [en]
bladder cancer, BCG, cisplatin, STMN1, emmprin, survivin, CCTα, biomarker, immunohistochemistry, IHC, tissue microarray, TMA
National Category
Urology and Nephrology
Identifiers
URN: urn:nbn:se:uu:diva-282607ISBN: 978-91-554-9544-2 (print)OAI: oai:DiVA.org:uu-282607DiVA: diva2:917242
Public defence
2016-05-30, Enghoffhall, Akademiska University Hospital, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2016-05-02 Created: 2016-04-05 Last updated: 2016-05-12
List of papers
1. Five year outcome of a randomized prospective study comparing bacillus Calmette-Guerin with epirubicin and interferon α 2b in patients with T1 bladder cancer
Open this publication in new window or tab >>Five year outcome of a randomized prospective study comparing bacillus Calmette-Guerin with epirubicin and interferon α 2b in patients with T1 bladder cancer
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2014 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 191, no 5, 1244-1249 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

In a multicenter, prospectively randomized study we evaluated the five-year outcome of bacillus Calmette-Guérin (BCG) alone compared to a combination of epirubicin and interferon α 2b in the treatment of patients with T1 bladder cancer.

MATERIAL AND METHODS:

The transurethral resection was followed by a second resection and bladder mapping. Stratification was for grade and cancer in situ. Follow-up entailed regular cystoscopy and cytology during the first 5 years. The end points assessed in this analysis were recurrence-free survival, time to failure of the treatment and progression, cancer-specific survival, and prognostic factors.

RESULTS:

The study recruited 250 eligible patients.The five years recurrence-free survival were 38% in the combination arm and 59% in the BCG arm (p=0.001). The corresponding rates for the other endpoints were not significantly different; free of - progression 78 and 77%, - treatment failure 75 and 75% and cancer-specific survival 90 and 92%. The type of treatment, size and tumour status at second resection were independent variables associated with recurrence. Concomitant carcinoma in situ was not predictive of failure of BCG therapy. Independent factor for treatment failure was remaining T1 stage at second resection.

CONCLUSIONS:

BCG therapy was more effective than the tested combination. Presently recommended management with second resection and three week maintenance BCG entails a low risk of cancer specific death. More aggressive treatment in patients with infiltrative tumours at second resection might improve these results. In particular, concomitant carcinoma in situ was not a predictive factor for poor outcome after BCG therapy.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-211159 (URN)10.1016/j.juro.2013.11.005 (DOI)000335147100010 ()24231843 (PubMedID)
Available from: 2013-11-20 Created: 2013-11-20 Last updated: 2017-12-06Bibliographically approved
2. Emmprin Expression Predicts Response and Survival following Cisplatin Containing Chemotherapy for Bladder Cancer: A Validation Study.
Open this publication in new window or tab >>Emmprin Expression Predicts Response and Survival following Cisplatin Containing Chemotherapy for Bladder Cancer: A Validation Study.
2015 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 194, no 6, 1575-1581 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Neoadjuvant chemotherapy before cystectomy is recommended. To our knowledge the subset of patients likely to benefit has not been identified. We validate emmprin and survivin as markers of chemotherapy response.

MATERIALS AND METHODS: Tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry.

RESULTS: Expression was categorized according to predefined cutoffs reported in the literature. Data were analyzed with the Kaplan-Meier method and Cox models. Patients in the chemotherapy cohort with negative emmprin expression had significantly higher down staging overall survival than those with positive expression (71% vs 38%, p <0.001). The values for cancer specific survival were 76% and 56%, respectively (p <0.027). In the cystectomy only cohort emmprin expression was not associated with overall survival (46% vs 35%, p = 0.23) or cancer specific survival (55% vs 51%, p = 0.64). Emmprin negative patients had an absolute risk reduction of 25% in overall survival (95% CI 11-40) and a number needed to treat of 4 (95% CI 2.5-9.3). Survivin expression was not useful as a biomarker in this study. Limitations were the retrospective design and heterogeneity coupled with the time difference between the trials.

CONCLUSIONS: Patients with emmprin negative tumors have a better response to neoadjuvant chemotherapy before cystectomy than those with positive expression.

Keyword
urinary bladder neoplasms; antigens, CD147; drug therapy; cystectomy; biological markers
National Category
Medical and Health Sciences Urology and Nephrology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-266544 (URN)10.1016/j.juro.2015.06.085 (DOI)000365985900012 ()26119672 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2015-11-10 Created: 2015-11-10 Last updated: 2017-12-01Bibliographically approved
3. Choline Phosphate Cytidylyltransferase-α (CCT-α) a Novel Predictor of Response to Cisplatin Neoadjuvant Chemotherapy in Urothelial Cancer of the Bladder
Open this publication in new window or tab >>Choline Phosphate Cytidylyltransferase-α (CCT-α) a Novel Predictor of Response to Cisplatin Neoadjuvant Chemotherapy in Urothelial Cancer of the Bladder
(English)Manuscript (preprint) (Other academic)
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-282609 (URN)
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2016-05-12
4. The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer
Open this publication in new window or tab >>The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer
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2014 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 111, no 6, 1180-1187 p.Article in journal (Refereed) Published
Abstract [en]

Background:The oncoprotein-18/stathmin 1 (STMN1), involved in cell progression and migration, is associated with clinical outcome in breast cancer. Here we aim to investigate its clinical significance in urinary bladder cancer and its possibilities as a therapeutic target.Methods:Immunohistochemical analyses of STMN1 protein expression were performed in three patient cohorts: cohort I (n=115 Ta, n=115 T1, n=112 T2-4 stages), cohort II, based on randomised controlled trials (n=239 T1-T4), and cohort III of primary tumour/matched metastasis (n=90 T1-T4). The effects of STMN1 on cell proliferation and migration were evaluated in the urinary bladder cancer cell line, T24, by inhibiting STMN1-cellular expression using siRNA.Results:In cohort I, high STMN1 expression correlated to shorter disease-specific survival hazard ratio (HR)=2.04 (95% confidence interval (CI) 1.13-3.68; P=0.02), elevated p53- (P<0.001) and Ki67-protein levels (P<0.001). The survival result was validated in cohort II: HR=1.76 (95% CI 1.04-2.99; P=0.03). In the metastatic bladder cancer material, 70% of the patients were STMN1-positive in both the primary tumour and matched metastases. In vitro, the growth and migration of the T24 cells were significantly reduced (P<0.01, P<0.0001, respectively), when transfecting the cells with STMN1-siRNA.Conclusions:STMN1 protein expression has prognostic significance but is primarily a potential treatment target in urinary bladder cancer. 

National Category
Medical and Health Sciences Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-231186 (URN)10.1038/bjc.2014.427 (DOI)000341910900018 ()25072257 (PubMedID)
Funder
Swedish Cancer Society
Note

De två första författarna delar första författarskapet.

Available from: 2014-09-05 Created: 2014-09-05 Last updated: 2017-12-05Bibliographically approved

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