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MP61-17 ASSOCIATIONS OF PROGRESSION IN T1G3 BLADDER CANCERS AND MUTATION HETEROGENEITY IN 20 CANCER-RELATED GENES
THE JOURNAL OF UROLOGYâ
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BCG treatment. A total of 13 patients (7 BCG responders and 6 non responders) were included. BCG response was defined by no recurrence neither progression for at least 24 month after therapy. Hematoxilin-eosin (HE) and immunohistochemical stains were performed at the pathology department, using monoclonal antibodies specific either for the Th2 associated transcription factor GATA-3(L50-823) or the Th1-associated transcription factor T-bet (H-210). Number of peritumoral GATA-3+ and T-bet + were determined. The ratio Th2/ Th1(GATA -3+/T-bet +) was calculated. Results obtained from these metric were correlated with response to treatment. Statistical analysis for comparisions between groups was performed. The median values were compared using a nonparametric Mann Whitney test. RESULTS: Variable lymphocytic response was found in peritumoral stroma in all cases. Patients who responded to BCG (R) had a higher Th2 infiltration (GATA 3+ cells) than patients who did not respond (NR) (median149.534 and 91.7018 cells, respectively) and a minor presence of Th1 cells (T-bet +) (median 30.33 8.9 and 48.608.7 cells, respectively). The GATA 3+/T-bet + (Th2/Th1) ratio was higher in responders than in non responders (4.9 and 2.3, respectively). CONCLUSIONS: The presence of an infiltrating Th-1 type immune response in peritumoral tissue before BCG therapy may be associated with lack of response to treatment. Determining the immune polarization (Th1 vs Th2) could be useful as a prognostic marker to BCG therapy in these patients. Source of Funding: none
MP61-17 ASSOCIATIONS OF PROGRESSION IN T1G3 BLADDER CANCERS AND MUTATION HETEROGENEITY IN 20 CANCER-RELATED GENES Karsten Salomo*, Doreen Huebner, Jana Hahm, Joern Meinel, Vladimir Novotny, Manja Boehme, Susanne Fuessel, Manfred P. Wirth, Dresden, Germany INTRODUCTION AND OBJECTIVES: With about 70-80% nonmuscle-invasive bladder cancers (NMIBC) are by far the most common urothelial carcinomas at the time of diagnosis. NMIBC are characterized by a high level of clinical and pathological heterogeneity. Especially high grade NMIBC of stage T1 are prone to progress to an aggressive disease. Therefore, biomarkers to differentiate the progression risk in T1G3 bladder cancers would be greatly beneficial. As muscle-invasive bladder cancers (MIBC) are characterized by mutations, e.g. in TP53 and RB1, which differ from mutations in NMIBC, e.g. in FGFR3 and RAS, a set of mutations might exist to better stratify the risk of progression in T1G3 tumors. METHODS: We assessed the mutation status of 20 bladder cancer-associated genes in tumor and corresponding tumor-free formalin-fixed paraffin-embedded (FFPE) bladder tissues (23x
Vol. 195, No. 4S, Supplement, Monday, May 9, 2016
tumor stage and progress. Of the PIK3CA mutations, E545K was the most frequent one (6-17%). CONCLUSIONS: Mutation heterogeneity and a particular set of mutations seem to be related to the risk of progression in T1G3 bladder cancers. Preliminary results show that on average 10% of all mutations found enriched in T1G3 bladder cancers are significantly related with tumor stage and grade, progression or recurrence. Furthermore, highly abundant mutations may be potential candidates for urine-based bladder cancer diagnosis. Source of Funding: Saxon Ministry of Science and the Fine Arts (SMWK)
MP61-18 A NOVEL FORMULATION OF DOCETAXEL WITH ACTIVITY IN MUSCLE INVASIVE BLADDER CANCER XENOGRAFTS Clement Mugabe, Richard Liggins, Igor Moskalev, Michael Parr, Jayachandran Kizhakkedathu, Don Brooks, Helen Burt, Alan So*, Vancouver, Canada INTRODUCTION AND OBJECTIVES: Bladder cancer is a significant public health problem responsible for more than 130,000 deaths annually word-wide. Approximately, 70-80% of patients initially present with non-muscle invasive bladder cancer (NMIBC). The rate of recurrence of NMIBC, after standard of care surgery followed by locally administered chemotherapy (mitomycin C, MMC) is 55%. Overall, 30% of patients will ultimately progress toward muscle invasive disease, which is terminal unless treated by radical cystectomy. We have developed a functionalized nanoparticle formulation of docetaxel to improve treatment outcomes of intravesical chemotherapy. Based on hyperbranched polyglycerol (HPG) technology, our new formulation (DTX/HPG-NH2): a) solubilises the drug without micelle forming surfactants which limit drug bioavailability in the bladder, b) is mucoadhesive, to prolong drug residence time after bladder voiding, c) enhances drug uptake into the bladder wall d) has demonstrated safety in preclinical models, and e) has shown promising efficacy in treating non-muscle invasive bladder tumors in mouse xenograft models. The objective of this study was to investigate the effectiveness of docetaxel formulations in a new mouse model of muscle invasive bladder cancer. METHODS: Female nude mice were inoculated with UM-UC3luc using ultrasound-guided intramural injection and tumor growth was measured by bioluminescence imaging twice a week. On day 8 posttumor inoculation, mice with established muscle invasive bladder tumors were grouped into 3 treatment groups and were instilled with 50 mL of PBS (control), or 50 mg of docetaxel in Polysorbate 80 (Taxotereâ), or 50 mg of docetaxel formulated in HPG-NH2 nanoparticles. RESULTS: All mice developed bladder tumors and the success of tumor implantation was confirmed by bioluminescence and ultrasound imaging. Intravesical therapy with docetaxel HPGNH2 formulation significantly (p<0.001, two-way ANOVA, Bonferroni post-hoc test) inhibited tumor growth compared to the Taxotereâ treatment group. There was no significant difference between the Taxotereâ treated group and the PBS control group. All subjects tolerated the treatments with no signs of toxicity observed in either group. CONCLUSIONS: A novel formulation of docetaxel based on the HPG technology was found to be safe and effective when given intravesically to treat muscle invasive tumors in mice. To our knowledge, this is a first report on intravesical therapy for muscle invasive bladder tumor. Source of Funding: The above work was supported by funding from Genome BC PoC, CIHR PoP II and CDRD CVI.
e810
BCG treatment. A total of 13 patients (7 BCG responders and 6 non responders) were included. BCG response was defined by no recurrence neither progression for at least 24 month after therapy. Hematoxilin-eosin (HE) and immunohistochemical stains were performed at the pathology department, using monoclonal antibodies specific either for the Th2 associated transcription factor GATA-3(L50-823) or the Th1-associated transcription factor T-bet (H-210). Number of peritumoral GATA-3+ and T-bet + were determined. The ratio Th2/ Th1(GATA -3+/T-bet +) was calculated. Results obtained from these metric were correlated with response to treatment. Statistical analysis for comparisions between groups was performed. The median values were compared using a nonparametric Mann Whitney test. RESULTS: Variable lymphocytic response was found in peritumoral stroma in all cases. Patients who responded to BCG (R) had a higher Th2 infiltration (GATA 3+ cells) than patients who did not respond (NR) (median149.534 and 91.7018 cells, respectively) and a minor presence of Th1 cells (T-bet +) (median 30.33 8.9 and 48.608.7 cells, respectively). The GATA 3+/T-bet + (Th2/Th1) ratio was higher in responders than in non responders (4.9 and 2.3, respectively). CONCLUSIONS: The presence of an infiltrating Th-1 type immune response in peritumoral tissue before BCG therapy may be associated with lack of response to treatment. Determining the immune polarization (Th1 vs Th2) could be useful as a prognostic marker to BCG therapy in these patients. Source of Funding: none
MP61-17 ASSOCIATIONS OF PROGRESSION IN T1G3 BLADDER CANCERS AND MUTATION HETEROGENEITY IN 20 CANCER-RELATED GENES Karsten Salomo*, Doreen Huebner, Jana Hahm, Joern Meinel, Vladimir Novotny, Manja Boehme, Susanne Fuessel, Manfred P. Wirth, Dresden, Germany INTRODUCTION AND OBJECTIVES: With about 70-80% nonmuscle-invasive bladder cancers (NMIBC) are by far the most common urothelial carcinomas at the time of diagnosis. NMIBC are characterized by a high level of clinical and pathological heterogeneity. Especially high grade NMIBC of stage T1 are prone to progress to an aggressive disease. Therefore, biomarkers to differentiate the progression risk in T1G3 bladder cancers would be greatly beneficial. As muscle-invasive bladder cancers (MIBC) are characterized by mutations, e.g. in TP53 and RB1, which differ from mutations in NMIBC, e.g. in FGFR3 and RAS, a set of mutations might exist to better stratify the risk of progression in T1G3 tumors. METHODS: We assessed the mutation status of 20 bladder cancer-associated genes in tumor and corresponding tumor-free formalin-fixed paraffin-embedded (FFPE) bladder tissues (23x
Vol. 195, No. 4S, Supplement, Monday, May 9, 2016
tumor stage and progress. Of the PIK3CA mutations, E545K was the most frequent one (6-17%). CONCLUSIONS: Mutation heterogeneity and a particular set of mutations seem to be related to the risk of progression in T1G3 bladder cancers. Preliminary results show that on average 10% of all mutations found enriched in T1G3 bladder cancers are significantly related with tumor stage and grade, progression or recurrence. Furthermore, highly abundant mutations may be potential candidates for urine-based bladder cancer diagnosis. Source of Funding: Saxon Ministry of Science and the Fine Arts (SMWK)
MP61-18 A NOVEL FORMULATION OF DOCETAXEL WITH ACTIVITY IN MUSCLE INVASIVE BLADDER CANCER XENOGRAFTS Clement Mugabe, Richard Liggins, Igor Moskalev, Michael Parr, Jayachandran Kizhakkedathu, Don Brooks, Helen Burt, Alan So*, Vancouver, Canada INTRODUCTION AND OBJECTIVES: Bladder cancer is a significant public health problem responsible for more than 130,000 deaths annually word-wide. Approximately, 70-80% of patients initially present with non-muscle invasive bladder cancer (NMIBC). The rate of recurrence of NMIBC, after standard of care surgery followed by locally administered chemotherapy (mitomycin C, MMC) is 55%. Overall, 30% of patients will ultimately progress toward muscle invasive disease, which is terminal unless treated by radical cystectomy. We have developed a functionalized nanoparticle formulation of docetaxel to improve treatment outcomes of intravesical chemotherapy. Based on hyperbranched polyglycerol (HPG) technology, our new formulation (DTX/HPG-NH2): a) solubilises the drug without micelle forming surfactants which limit drug bioavailability in the bladder, b) is mucoadhesive, to prolong drug residence time after bladder voiding, c) enhances drug uptake into the bladder wall d) has demonstrated safety in preclinical models, and e) has shown promising efficacy in treating non-muscle invasive bladder tumors in mouse xenograft models. The objective of this study was to investigate the effectiveness of docetaxel formulations in a new mouse model of muscle invasive bladder cancer. METHODS: Female nude mice were inoculated with UM-UC3luc using ultrasound-guided intramural injection and tumor growth was measured by bioluminescence imaging twice a week. On day 8 posttumor inoculation, mice with established muscle invasive bladder tumors were grouped into 3 treatment groups and were instilled with 50 mL of PBS (control), or 50 mg of docetaxel in Polysorbate 80 (Taxotereâ), or 50 mg of docetaxel formulated in HPG-NH2 nanoparticles. RESULTS: All mice developed bladder tumors and the success of tumor implantation was confirmed by bioluminescence and ultrasound imaging. Intravesical therapy with docetaxel HPGNH2 formulation significantly (p<0.001, two-way ANOVA, Bonferroni post-hoc test) inhibited tumor growth compared to the Taxotereâ treatment group. There was no significant difference between the Taxotereâ treated group and the PBS control group. All subjects tolerated the treatments with no signs of toxicity observed in either group. CONCLUSIONS: A novel formulation of docetaxel based on the HPG technology was found to be safe and effective when given intravesically to treat muscle invasive tumors in mice. To our knowledge, this is a first report on intravesical therapy for muscle invasive bladder tumor. Source of Funding: The above work was supported by funding from Genome BC PoC, CIHR PoP II and CDRD CVI.