- Email: [email protected]
Molecular Profiling of Small Cell Bladder Cancer Reveals Gene Expression Determinants of an Aggressive Phenotype
E254
International Journal of Radiation Oncology Biology Physics
2606
Materials/Methods: Under IRB approvals, de-identified data from the two cohorts were analyzed. The first comprised 1,214 men treated with imageguided PT using implanted fiducials from 2006 to 2010 to a dose of 78 Gy(RBE) in 39 fractions. The second comprised 301 men treated with image-guided IMRT using transabdominal ultrasound from 2000 to 2005 to a dose of 75.6 Gy in 42 fractions. Median age and follow-up were 66 yrs and 5.6 yrs for PT and 74 yrs and 7.2 yrs for IMRT. Hormone therapy (ADT) was used with PT and IMRT, respectively, in 7% and 3% of lowrisk, 9.9% and 25% of intermediate-risk, and 57.8% and 91% of high-risk patients. Comparative endpoints were age-stratified 5-year (5Y) survival (OS), grade (GR) 3 gastrointestinal (GI) and urologic (GU) toxicity, and 5Y freedom from biochemical progression (FFBP). Results: The rates of GR 3 GU and GI events were low in both groups. Prevalence rates of GR 3 toxicity at last follow-up were lower in the PT cohort compared to the IMRT cohort for both GI toxicity (0.1% vs 1.3%; pZ0.0065) and GU toxicity (0.1% vs 4.3%; p<0.0001). In the PT and IMRT cohorts, OS rates were 88.7% and 90.8% in men 75 yrs (pZ0.4083). In men <75, OS rates were better with PT compared to IMRT for both low-risk (97.5% vs 91.6%, pZ0.003) and intermediate-risk patients (95.5% vs 92.1%; p Z 0.0535) but similar for high-risk patients (90.0% vs 92.0%; pZ0.4975). FFBP rates were better with PT compared to IMRT for both low-risk (98.9% vs 92.2%, p<0.0001) and intermediate-risk patients (94.5% vs 87.3%, pZ0.0226), and similar in high-risk patients (74.4% vs 80.3%, pZ0.5154) despite the more frequent and longer duration of ADT use in the IMRT cohort. Conclusion: In this retrospective comparison of outcomes in cohorts of men treated with IMRT and PT for prostate cancer, FFBP rates were better with PT for men with low- and intermediate-risk disease and similar in men with high-risk disease, despite longer and more frequent use of ADT in the IMRT cohort. It is notable that toxicity was less in the PT cohort despite the use of a higher median dose. While this study identified some difficulties in comparing retrospective series (differences in age, RT dose and fraction size, and ADT use between cohorts), the magnitude of improvement with PT is intriguing and warrants prospective testing. Author Disclosure: N.P. Mendenhall: None. W.W. Wong: None. C.M. Bryant: None. S.A. Vora: None. R.H. Henderson: None. S.R. Keole: None. B.S. Hoppe: Employee; Stanford University. helped develop protocol and am a Co-chair; RTOG. Secretary, PI on Lung trial; Proton Collaborative Group. Develop appropriateness criteria; American College of Radiology. C. Vargas: None. R. Nichols: None. T.B. Daniels: None. W.M. Mendenhall: Employee; University of Florida. C.G. Morris: None. S.E. Schild: Research Grant; Alliance. Travel Expenses; Alliance.
Trends and Clinico-Sociodemographic Determinants of Stereotactic Body Radiation Therapy Use for Localized Prostate Cancer B.A. Mahal,1 R. Sethi,2 Y.W. Chen,3 D.L. Casey,4 D.D. Yang,5 V. Muralidhar,6 A.R. Mahal,7 P.F. Orio III,6 P.L. Nguyen,8 and J.B. Yu9; 1 Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA, 2Harvard Radiation Oncology Program, Boston, MA, 3Cleveland Clinic, Cleveland, OH, 4Memorial Sloan Kettering Cancer Center, New York, NY, 5Harvard Medical School, Boston, MA, 6Brigham and Women’s Hospital, Boston, MA, 7Yale School of Medicine, New Haven, CT, 8 Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 9 Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT Purpose/Objective(s): Stereotactic body radiotherapy (SBRT) represents an emerging and cautiously guideline-approved definitive therapy option for prostate cancer, though long-term data on efficacy and toxicity is still pending. Herein, we sought to determine contemporary national SBRT trends and clinico-sociodemographic determinants associated with its use in prostate cancer. Materials/Methods: The National Cancer Data Base (NCDB) was queried to identify 181,544 patients diagnosed with localized prostate cancer from 2004-2012 who received external beam radiotherapy. Multivariable logistic regression adjusted for sociodemographic and clinical factors was used to identify independent determinants of SBRT use. Results: Rate of SBRT use for localized prostate cancer increased from 0.05% in 2004 to 4.87% in 2012 (Ptrend<0.001). SBRT was more likely to be delivered at academic centers, to patients with Medicare, and to patients who were white, younger, healthier, from wealthier and more educated zipcodes, and who had lower risk disease features (all P<0.001). Relative to Whites, men from more affluent zipcodes, or men with low stage or grade prostate cancer, Blacks, Hispanics, and men from less affluent zipcodes and men with high stage or grade prostate cancer were less likely to receive SBRT after multivariable adjustment, with adjusted hazard ratios of 0.66, 0.35, 0.33, 0.07, and 0.21, respectively (all P<0.001). Conclusion: The absolute national rate of SBRT use as definitive therapy for prostate cancer has increased nearly 100-fold over the last decade. Men who are White, younger, healthier, from more affluent zipcodes and with favorable disease characteristics are more likely to receive an emerging form of radiotherapy with unknown long-term efficacy and toxicity. Author Disclosure: B.A. Mahal: None. R. Sethi: None. Y. Chen: None. D.L. Casey: None. D.D. Yang: None. V. Muralidhar: None. A.R. Mahal: None. P.F. Orio: Honoraria; CR BARD. Consultant; Augmenix; American Brachytherapy Society, ASTRO. P.L. Nguyen: Consultant; GI Windows, Infinity Pharmaceuticals, Nanobiotix. Advisory Board; Dendreon, Ferring, Genome DX, Medivation. ; Genitourinary Cancers Symposium. J.B. Yu: None.
2607 Potential Improved Outcomes with Proton Therapy in Prostate Cancer: a Comparison of IMRT and Proton Cohorts N.P. Mendenhall,1 W.W. Wong,2 C.M. Bryant,1 S.A. Vora,2 R.H. Henderson,1 S.R. Keole,2 B.S. Hoppe,1 C. Vargas,2 R.C. Nichols Jr,1 T.B. Daniels,2 W.M. Mendenhall,1 C.G. Morris,1 and S.E. Schild2; 1 University of Florida Health Proton Therapy Institute, Jacksonville, FL, 2 Mayo Clinic Arizona, Phoenix, AZ Purpose/Objective(s): The ProtecT trial underscores the importance of definitive treatment in men with prostate cancer who have life expectancies >10 years and the validity of radiation therapy (RT) as a treatment option. RT can be given with photons or protons. To shed light on the controversy of which is better, clinical outcomes of proton therapy (PT) and photonbased intensity-modulated RT (IMRT) cohorts from two institutions were directly compared.
2608 Molecular Profiling of Small Cell Bladder Cancer Reveals Gene Expression Determinants of an Aggressive Phenotype P. Grivas,1 V.S. Koshkin,1 J. Pettiford,1 L. Atkins,1 P. Elson,1 J. Reynolds,2 C. Magi-Galluzzi,2 J. McKenney,2 K. Isse,3 L.R. Saunders,3 M. Hu,1 A.F. Fergany,4 G.P. Haber,4 J.A. Garcia,1 B. Rini,1 A.J. Stephenson,4 R.D. Tendulkar,5 M. Abazeed,5 and O.Y. Mian5; 1Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, 2Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, 3AbbVie Stemcentrx, San Francisco, CA, 4Cleveland Clinic Glickman Urology and Kidney Institute, Cleveland, OH, 5Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH Purpose/Objective(s): SCBC is a rare variant of bladder cancer with relatively poor outcomes. Treatment options are often extrapolated from other anatomic sites. We performed molecular profiling to better characterize unique features in SCBC with the goal of identifying novel therapeutic targets and biomarkers for risk stratification. Materials/Methods: A retrospective analysis of 63 patients with biopsyconfirmed SCBC treated with radiotherapy, chemotherapy, and surgery at a single high volume academic center between 1994-2015. Small cell histology (SC%) was quantitatively determined by independent pathologic review. DLL3 and PD-L1 protein expression were measured by IHC in 53 patients. Formalin fixed and paraffin embedded tumor tissue was available
Volume 99 Number 2S Supplement 2017 for gene expression analysis in 39/63 primary tumors (median SC% Z100%), 1 metastatic sample, and 6 adjacent normal samples (nZ46 total) using the HTG EdgeSeq OBP assay with probes for 2568 genes. An average of 1.1x107mRNA probes were sequenced per sample and analyzed using the RNAseq workflow in the Partek Genomics Suite. Results: Median age was 71 (nZ63, range 39-90), 83% were men, SC% range was 5-100%, estimated median OS was 22.8 months. Unsupervised hierarchical clustering of gene expression patterns from 46 samples produced 4 distinct clusters; independent consensus clustering confirmed 4 stable and well-demarcated gene clusters. Patients with tumors in cluster 1 (where 5 of 6 normal samples were located) did not have metastases at diagnosis and did not develop distant recurrence, both of which were over-represented in the other 3 clusters. Kaplan-Meier analysis revealed a trend towards longer overall survival in cluster 1 patients (log rank p Z 0.065). Higher gene expression of PRC1, NCAM1 (CD56) and DLL3 correlated with higher SC%, as did lower gene expression of ERBB2, PD-L1 and HPGD (p < 0.01). PD-L1 protein expression determined by IHC (1% cells) was noted in 30% of patients but did not correlate with outcome, SC%, DLL3 protein expression (IHC), or PDL1 gene expression. DLL3 protein expression (1% cells) was noted in 68% of patients and DLL3 > 10% correlated with decreased OS (p Z 0.03). Higher DLL3 protein expression correlated with DLL3 gene expression (Spearman r Z 0.70, p < .01) and with SC% (r Z 0.33, p Z 0.01). Conclusion: This is the first study to reveal distinct gene expression patterns that define aggressive behavior, metastatic potential and outcomes in SCBC. The prognostic value of differential gene expression networks and the presence of underlying genetic and epigenetic alterations is the subject of ongoing prospective validation in a larger cohort. Author Disclosure: P. Grivas: Consultant; Genentech, Dendreon, Bayer, Clovis, Bristol-Myers Squibb, AstraZeneca. V.S. Koshkin: None. J. Pettiford: None. L. Atkins: None. P. Elson: None. J. Reynolds: None. C. Magi-Galluzzi: None. J. McKenney: None. K. Isse: None. L.R. Saunders: None. M. Hu: None. A.F. Fergany: None. G. Haber: None. J.A. Garcia: None. B. Rini: Research Grant; Pfizer. Consultant; Pfizer, Merck, BMS, Roche. A.J. Stephenson: None. R.D. Tendulkar: None. M. Abazeed: None. O.Y. Mian: None.
2609 Long-Term PSA Outcomes in a Single Institution, Prospective Randomized 131Cs / 125I Permanent Prostate Brachytherapy Trial B.J. Moran Jr and M.H. Braccioforte; Prostate Cancer Foundation of Chicago, Westmont, IL Purpose/Objective(s): To evaluate biochemical (PSA) outcomes in a prospectively enrolled group of patients diagnosed with low to intermediate risk, localized prostate cancer randomized to undergo permanent iodine-125 (I-125) or cesium-131 (Cs-131) brachytherapy. Materials/Methods: Between 4/5/2007 and 6/16/2008, 140 patients were randomized by random number assignment to I-125 (nZ70) or Cs-131 (nZ70) monotherapy at a single institution. Patients were treated to a minimum prostatic dose of 144 Gy for I-125 and 115 Gy for Cesium-131. Sources were delivered via a pre-planned, template-based, pre-loaded needle technique. Biochemical relapse-free survival (BRFS) was estimated using the Kaplan-Meier method and the Phoenix definition (“nadir plus 2 ng/ml”) was used to identify failures. PSA failure times were assigned “at call”. Results: Low risk patients made up 81.4% of the overall group, while 18.6% were intermediate risk. Average age was 61 years. There was no difference in either risk composition or age between the isotopes used. A total of 1,474 serum PSA measurements were obtained on the 140 patients (average 10.5 per patient). Median follow-up was 95 months. There were a total of 10 failures (7%): 6 (8.6%) in the I-125 group and 4 (5.7%) in the Cs-131 group. At nine years, with 19 patients (14%) at risk, BRFS was 89% for the I-125 group and 86% for the Cs-131 group, log rank pZ0.45. Conclusion: Permanent, low dose rate brachytherapy provides excellent PSAbased outcomes for low to intermediate risk patients. No significant difference in BRFS between these two isotopes has been detected at this point in follow-up. Author Disclosure: B.J. Moran: None. M.H. Braccioforte: None.
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2610 A Phase 1/2 Trial of Stereotactic Body Radiation Therapy for Prostate Cancer With a Simultaneous Integrated Boost to MRI-Identified Regions of High Tumor Volume (NCT02470897) B.A. Morris,1,2 R.A.B. Bayliss,1 N. Anger,1 Z.S. Morris,1 and M.A. Ritter1; 1Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI, 2University of Wisconsin School of Medicine and Public Health, Madison, WI Purpose/Objective(s): Stereotactic body radiation therapy (SBRT) is a promising treatment option for low- and intermediate- risk prostate carcinoma. Dose escalation beyond currently standard SBRT regimens may further improve outcomes, particularly for bulkier tumors, but could be limited by adjacent organ dose constraints. However, selective dose escalation to identified regions of high tumor burden may offer a safer approach than uniform dose escalation. Therefore, this ongoing prospective study seeks to test the planning and delivery feasibilities and the tolerability of treating patients with a modest dose escalation to the entire prostate and a simultaneous integrated boost (SIB) to MRI-identified lesions. Materials/Methods: Low- or intermediate- risk prostate cancer patients (Gleason score 7, PSA 20, T stage 2b) are eligible and treated based on ability to undergo pre-treatment pelvic MRI. Patients enrolled to date undergoing MRI (nZ10) received LINAC-based prostate SBRT (5 x 8.0 Gy delivered every other day) with urethral, anterior rectal wall and bladder base doses constrained to 7.25 Gy/fraction. MRI-identified PI-RADS 4 or 5 lesions received a SIB to 8.5 - 9.0 Gy/fraction. Patients not undergoing MRI imaging (nZ6) received a uniform SBRT dose (5 x 7.5 Gy) with the same normal tissue constraints. Intra-fractional shifts were monitored with a repeat alignment scan after half of the fractional dose was delivered. Acute bowel and bladder toxicity was assessed using RTOG toxicity scales and the IPSS. Urinary, bowel and sexual quality of life will be assessed at regular intervals using the expanded prostate cancer index composite (EPIC-26) questionnaire. Results: Median follow up was 8 months with a range of 2-16 months. Dosimetric evaluation of planned and delivered dose indicates that prostate SBRT including both a dose constraint applied to the urethra, anterior rectum and bladder base as well as a SIB to MRI-identified tumor subvolumes can be reproducibly planned and delivered. There were no grade 3 or 4 acute or late GI or GU toxicities and only two patients reported acute grade 2 urinary symptoms (2/16 or 12.5%). Average IPSS scores increased only modestly from pretreatment baseline scores of 8.2 to 6 week scores of 10.4 (pZ0.02). Conclusion: This ongoing trial employs a simultaneous integrated boost to MRI-detected lesions during SBRT while constraining doses to immediately bordering normal organ subvolumes. Results to date indicate that this approach is dosimetrically feasible and deliverable, while preliminary outcomes find it to be well tolerated acutely. Additional accrual and follow up for this ongoing trial will be required to assess longer term conventional and patient reported toxicity outcomes as well as tumor control. Author Disclosure: B.A. Morris: Employee; Epic. R.B. Bayliss: None. N. Anger: None. Z.S. Morris: None. M.A. Ritter: None.
2611 The Analysis of Radioactive Implant Migration in Patients Treated With Iodine-125 Seeds for Permanent Prostate Brachytherapy with Median Lobe Hyperplasia K. Muraki,1 E. Ogo,1 H. Suefuji,2 H. Eto,1 C. Hattori,1 C. Tsuji,1 Y. Miyata,1 H. Himuro,1 S. Hayashi,1 K. Chikui,1 M. Nakiri,1 T. Igawa,1 and T. Abe1; 1Kurume University, Kurume, Japan, 2Ion Beam Therapy Center, SAGA HIMAT Foundation, Tosu, Japan Purpose/Objective(s): Prostate cancer with MLH is a relative contraindication of PPB, because of the increased risk of post-implant dysuria and the technical difficulties of stability while implanting intravesical tissue. We examined that the treatment outcome, seed migration, and urination disorders after treatment in MLH patients who received PPB. The purpose of our research concerns is to what degree MLH implants could be stabilized.
International Journal of Radiation Oncology Biology Physics
2606
Materials/Methods: Under IRB approvals, de-identified data from the two cohorts were analyzed. The first comprised 1,214 men treated with imageguided PT using implanted fiducials from 2006 to 2010 to a dose of 78 Gy(RBE) in 39 fractions. The second comprised 301 men treated with image-guided IMRT using transabdominal ultrasound from 2000 to 2005 to a dose of 75.6 Gy in 42 fractions. Median age and follow-up were 66 yrs and 5.6 yrs for PT and 74 yrs and 7.2 yrs for IMRT. Hormone therapy (ADT) was used with PT and IMRT, respectively, in 7% and 3% of lowrisk, 9.9% and 25% of intermediate-risk, and 57.8% and 91% of high-risk patients. Comparative endpoints were age-stratified 5-year (5Y) survival (OS), grade (GR) 3 gastrointestinal (GI) and urologic (GU) toxicity, and 5Y freedom from biochemical progression (FFBP). Results: The rates of GR 3 GU and GI events were low in both groups. Prevalence rates of GR 3 toxicity at last follow-up were lower in the PT cohort compared to the IMRT cohort for both GI toxicity (0.1% vs 1.3%; pZ0.0065) and GU toxicity (0.1% vs 4.3%; p<0.0001). In the PT and IMRT cohorts, OS rates were 88.7% and 90.8% in men 75 yrs (pZ0.4083). In men <75, OS rates were better with PT compared to IMRT for both low-risk (97.5% vs 91.6%, pZ0.003) and intermediate-risk patients (95.5% vs 92.1%; p Z 0.0535) but similar for high-risk patients (90.0% vs 92.0%; pZ0.4975). FFBP rates were better with PT compared to IMRT for both low-risk (98.9% vs 92.2%, p<0.0001) and intermediate-risk patients (94.5% vs 87.3%, pZ0.0226), and similar in high-risk patients (74.4% vs 80.3%, pZ0.5154) despite the more frequent and longer duration of ADT use in the IMRT cohort. Conclusion: In this retrospective comparison of outcomes in cohorts of men treated with IMRT and PT for prostate cancer, FFBP rates were better with PT for men with low- and intermediate-risk disease and similar in men with high-risk disease, despite longer and more frequent use of ADT in the IMRT cohort. It is notable that toxicity was less in the PT cohort despite the use of a higher median dose. While this study identified some difficulties in comparing retrospective series (differences in age, RT dose and fraction size, and ADT use between cohorts), the magnitude of improvement with PT is intriguing and warrants prospective testing. Author Disclosure: N.P. Mendenhall: None. W.W. Wong: None. C.M. Bryant: None. S.A. Vora: None. R.H. Henderson: None. S.R. Keole: None. B.S. Hoppe: Employee; Stanford University. helped develop protocol and am a Co-chair; RTOG. Secretary, PI on Lung trial; Proton Collaborative Group. Develop appropriateness criteria; American College of Radiology. C. Vargas: None. R. Nichols: None. T.B. Daniels: None. W.M. Mendenhall: Employee; University of Florida. C.G. Morris: None. S.E. Schild: Research Grant; Alliance. Travel Expenses; Alliance.
Trends and Clinico-Sociodemographic Determinants of Stereotactic Body Radiation Therapy Use for Localized Prostate Cancer B.A. Mahal,1 R. Sethi,2 Y.W. Chen,3 D.L. Casey,4 D.D. Yang,5 V. Muralidhar,6 A.R. Mahal,7 P.F. Orio III,6 P.L. Nguyen,8 and J.B. Yu9; 1 Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA, 2Harvard Radiation Oncology Program, Boston, MA, 3Cleveland Clinic, Cleveland, OH, 4Memorial Sloan Kettering Cancer Center, New York, NY, 5Harvard Medical School, Boston, MA, 6Brigham and Women’s Hospital, Boston, MA, 7Yale School of Medicine, New Haven, CT, 8 Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 9 Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT Purpose/Objective(s): Stereotactic body radiotherapy (SBRT) represents an emerging and cautiously guideline-approved definitive therapy option for prostate cancer, though long-term data on efficacy and toxicity is still pending. Herein, we sought to determine contemporary national SBRT trends and clinico-sociodemographic determinants associated with its use in prostate cancer. Materials/Methods: The National Cancer Data Base (NCDB) was queried to identify 181,544 patients diagnosed with localized prostate cancer from 2004-2012 who received external beam radiotherapy. Multivariable logistic regression adjusted for sociodemographic and clinical factors was used to identify independent determinants of SBRT use. Results: Rate of SBRT use for localized prostate cancer increased from 0.05% in 2004 to 4.87% in 2012 (Ptrend<0.001). SBRT was more likely to be delivered at academic centers, to patients with Medicare, and to patients who were white, younger, healthier, from wealthier and more educated zipcodes, and who had lower risk disease features (all P<0.001). Relative to Whites, men from more affluent zipcodes, or men with low stage or grade prostate cancer, Blacks, Hispanics, and men from less affluent zipcodes and men with high stage or grade prostate cancer were less likely to receive SBRT after multivariable adjustment, with adjusted hazard ratios of 0.66, 0.35, 0.33, 0.07, and 0.21, respectively (all P<0.001). Conclusion: The absolute national rate of SBRT use as definitive therapy for prostate cancer has increased nearly 100-fold over the last decade. Men who are White, younger, healthier, from more affluent zipcodes and with favorable disease characteristics are more likely to receive an emerging form of radiotherapy with unknown long-term efficacy and toxicity. Author Disclosure: B.A. Mahal: None. R. Sethi: None. Y. Chen: None. D.L. Casey: None. D.D. Yang: None. V. Muralidhar: None. A.R. Mahal: None. P.F. Orio: Honoraria; CR BARD. Consultant; Augmenix; American Brachytherapy Society, ASTRO. P.L. Nguyen: Consultant; GI Windows, Infinity Pharmaceuticals, Nanobiotix. Advisory Board; Dendreon, Ferring, Genome DX, Medivation. ; Genitourinary Cancers Symposium. J.B. Yu: None.
2607 Potential Improved Outcomes with Proton Therapy in Prostate Cancer: a Comparison of IMRT and Proton Cohorts N.P. Mendenhall,1 W.W. Wong,2 C.M. Bryant,1 S.A. Vora,2 R.H. Henderson,1 S.R. Keole,2 B.S. Hoppe,1 C. Vargas,2 R.C. Nichols Jr,1 T.B. Daniels,2 W.M. Mendenhall,1 C.G. Morris,1 and S.E. Schild2; 1 University of Florida Health Proton Therapy Institute, Jacksonville, FL, 2 Mayo Clinic Arizona, Phoenix, AZ Purpose/Objective(s): The ProtecT trial underscores the importance of definitive treatment in men with prostate cancer who have life expectancies >10 years and the validity of radiation therapy (RT) as a treatment option. RT can be given with photons or protons. To shed light on the controversy of which is better, clinical outcomes of proton therapy (PT) and photonbased intensity-modulated RT (IMRT) cohorts from two institutions were directly compared.
2608 Molecular Profiling of Small Cell Bladder Cancer Reveals Gene Expression Determinants of an Aggressive Phenotype P. Grivas,1 V.S. Koshkin,1 J. Pettiford,1 L. Atkins,1 P. Elson,1 J. Reynolds,2 C. Magi-Galluzzi,2 J. McKenney,2 K. Isse,3 L.R. Saunders,3 M. Hu,1 A.F. Fergany,4 G.P. Haber,4 J.A. Garcia,1 B. Rini,1 A.J. Stephenson,4 R.D. Tendulkar,5 M. Abazeed,5 and O.Y. Mian5; 1Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, 2Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, 3AbbVie Stemcentrx, San Francisco, CA, 4Cleveland Clinic Glickman Urology and Kidney Institute, Cleveland, OH, 5Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH Purpose/Objective(s): SCBC is a rare variant of bladder cancer with relatively poor outcomes. Treatment options are often extrapolated from other anatomic sites. We performed molecular profiling to better characterize unique features in SCBC with the goal of identifying novel therapeutic targets and biomarkers for risk stratification. Materials/Methods: A retrospective analysis of 63 patients with biopsyconfirmed SCBC treated with radiotherapy, chemotherapy, and surgery at a single high volume academic center between 1994-2015. Small cell histology (SC%) was quantitatively determined by independent pathologic review. DLL3 and PD-L1 protein expression were measured by IHC in 53 patients. Formalin fixed and paraffin embedded tumor tissue was available
Volume 99 Number 2S Supplement 2017 for gene expression analysis in 39/63 primary tumors (median SC% Z100%), 1 metastatic sample, and 6 adjacent normal samples (nZ46 total) using the HTG EdgeSeq OBP assay with probes for 2568 genes. An average of 1.1x107mRNA probes were sequenced per sample and analyzed using the RNAseq workflow in the Partek Genomics Suite. Results: Median age was 71 (nZ63, range 39-90), 83% were men, SC% range was 5-100%, estimated median OS was 22.8 months. Unsupervised hierarchical clustering of gene expression patterns from 46 samples produced 4 distinct clusters; independent consensus clustering confirmed 4 stable and well-demarcated gene clusters. Patients with tumors in cluster 1 (where 5 of 6 normal samples were located) did not have metastases at diagnosis and did not develop distant recurrence, both of which were over-represented in the other 3 clusters. Kaplan-Meier analysis revealed a trend towards longer overall survival in cluster 1 patients (log rank p Z 0.065). Higher gene expression of PRC1, NCAM1 (CD56) and DLL3 correlated with higher SC%, as did lower gene expression of ERBB2, PD-L1 and HPGD (p < 0.01). PD-L1 protein expression determined by IHC (1% cells) was noted in 30% of patients but did not correlate with outcome, SC%, DLL3 protein expression (IHC), or PDL1 gene expression. DLL3 protein expression (1% cells) was noted in 68% of patients and DLL3 > 10% correlated with decreased OS (p Z 0.03). Higher DLL3 protein expression correlated with DLL3 gene expression (Spearman r Z 0.70, p < .01) and with SC% (r Z 0.33, p Z 0.01). Conclusion: This is the first study to reveal distinct gene expression patterns that define aggressive behavior, metastatic potential and outcomes in SCBC. The prognostic value of differential gene expression networks and the presence of underlying genetic and epigenetic alterations is the subject of ongoing prospective validation in a larger cohort. Author Disclosure: P. Grivas: Consultant; Genentech, Dendreon, Bayer, Clovis, Bristol-Myers Squibb, AstraZeneca. V.S. Koshkin: None. J. Pettiford: None. L. Atkins: None. P. Elson: None. J. Reynolds: None. C. Magi-Galluzzi: None. J. McKenney: None. K. Isse: None. L.R. Saunders: None. M. Hu: None. A.F. Fergany: None. G. Haber: None. J.A. Garcia: None. B. Rini: Research Grant; Pfizer. Consultant; Pfizer, Merck, BMS, Roche. A.J. Stephenson: None. R.D. Tendulkar: None. M. Abazeed: None. O.Y. Mian: None.
2609 Long-Term PSA Outcomes in a Single Institution, Prospective Randomized 131Cs / 125I Permanent Prostate Brachytherapy Trial B.J. Moran Jr and M.H. Braccioforte; Prostate Cancer Foundation of Chicago, Westmont, IL Purpose/Objective(s): To evaluate biochemical (PSA) outcomes in a prospectively enrolled group of patients diagnosed with low to intermediate risk, localized prostate cancer randomized to undergo permanent iodine-125 (I-125) or cesium-131 (Cs-131) brachytherapy. Materials/Methods: Between 4/5/2007 and 6/16/2008, 140 patients were randomized by random number assignment to I-125 (nZ70) or Cs-131 (nZ70) monotherapy at a single institution. Patients were treated to a minimum prostatic dose of 144 Gy for I-125 and 115 Gy for Cesium-131. Sources were delivered via a pre-planned, template-based, pre-loaded needle technique. Biochemical relapse-free survival (BRFS) was estimated using the Kaplan-Meier method and the Phoenix definition (“nadir plus 2 ng/ml”) was used to identify failures. PSA failure times were assigned “at call”. Results: Low risk patients made up 81.4% of the overall group, while 18.6% were intermediate risk. Average age was 61 years. There was no difference in either risk composition or age between the isotopes used. A total of 1,474 serum PSA measurements were obtained on the 140 patients (average 10.5 per patient). Median follow-up was 95 months. There were a total of 10 failures (7%): 6 (8.6%) in the I-125 group and 4 (5.7%) in the Cs-131 group. At nine years, with 19 patients (14%) at risk, BRFS was 89% for the I-125 group and 86% for the Cs-131 group, log rank pZ0.45. Conclusion: Permanent, low dose rate brachytherapy provides excellent PSAbased outcomes for low to intermediate risk patients. No significant difference in BRFS between these two isotopes has been detected at this point in follow-up. Author Disclosure: B.J. Moran: None. M.H. Braccioforte: None.
Poster Viewing E255
2610 A Phase 1/2 Trial of Stereotactic Body Radiation Therapy for Prostate Cancer With a Simultaneous Integrated Boost to MRI-Identified Regions of High Tumor Volume (NCT02470897) B.A. Morris,1,2 R.A.B. Bayliss,1 N. Anger,1 Z.S. Morris,1 and M.A. Ritter1; 1Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI, 2University of Wisconsin School of Medicine and Public Health, Madison, WI Purpose/Objective(s): Stereotactic body radiation therapy (SBRT) is a promising treatment option for low- and intermediate- risk prostate carcinoma. Dose escalation beyond currently standard SBRT regimens may further improve outcomes, particularly for bulkier tumors, but could be limited by adjacent organ dose constraints. However, selective dose escalation to identified regions of high tumor burden may offer a safer approach than uniform dose escalation. Therefore, this ongoing prospective study seeks to test the planning and delivery feasibilities and the tolerability of treating patients with a modest dose escalation to the entire prostate and a simultaneous integrated boost (SIB) to MRI-identified lesions. Materials/Methods: Low- or intermediate- risk prostate cancer patients (Gleason score 7, PSA 20, T stage 2b) are eligible and treated based on ability to undergo pre-treatment pelvic MRI. Patients enrolled to date undergoing MRI (nZ10) received LINAC-based prostate SBRT (5 x 8.0 Gy delivered every other day) with urethral, anterior rectal wall and bladder base doses constrained to 7.25 Gy/fraction. MRI-identified PI-RADS 4 or 5 lesions received a SIB to 8.5 - 9.0 Gy/fraction. Patients not undergoing MRI imaging (nZ6) received a uniform SBRT dose (5 x 7.5 Gy) with the same normal tissue constraints. Intra-fractional shifts were monitored with a repeat alignment scan after half of the fractional dose was delivered. Acute bowel and bladder toxicity was assessed using RTOG toxicity scales and the IPSS. Urinary, bowel and sexual quality of life will be assessed at regular intervals using the expanded prostate cancer index composite (EPIC-26) questionnaire. Results: Median follow up was 8 months with a range of 2-16 months. Dosimetric evaluation of planned and delivered dose indicates that prostate SBRT including both a dose constraint applied to the urethra, anterior rectum and bladder base as well as a SIB to MRI-identified tumor subvolumes can be reproducibly planned and delivered. There were no grade 3 or 4 acute or late GI or GU toxicities and only two patients reported acute grade 2 urinary symptoms (2/16 or 12.5%). Average IPSS scores increased only modestly from pretreatment baseline scores of 8.2 to 6 week scores of 10.4 (pZ0.02). Conclusion: This ongoing trial employs a simultaneous integrated boost to MRI-detected lesions during SBRT while constraining doses to immediately bordering normal organ subvolumes. Results to date indicate that this approach is dosimetrically feasible and deliverable, while preliminary outcomes find it to be well tolerated acutely. Additional accrual and follow up for this ongoing trial will be required to assess longer term conventional and patient reported toxicity outcomes as well as tumor control. Author Disclosure: B.A. Morris: Employee; Epic. R.B. Bayliss: None. N. Anger: None. Z.S. Morris: None. M.A. Ritter: None.
2611 The Analysis of Radioactive Implant Migration in Patients Treated With Iodine-125 Seeds for Permanent Prostate Brachytherapy with Median Lobe Hyperplasia K. Muraki,1 E. Ogo,1 H. Suefuji,2 H. Eto,1 C. Hattori,1 C. Tsuji,1 Y. Miyata,1 H. Himuro,1 S. Hayashi,1 K. Chikui,1 M. Nakiri,1 T. Igawa,1 and T. Abe1; 1Kurume University, Kurume, Japan, 2Ion Beam Therapy Center, SAGA HIMAT Foundation, Tosu, Japan Purpose/Objective(s): Prostate cancer with MLH is a relative contraindication of PPB, because of the increased risk of post-implant dysuria and the technical difficulties of stability while implanting intravesical tissue. We examined that the treatment outcome, seed migration, and urination disorders after treatment in MLH patients who received PPB. The purpose of our research concerns is to what degree MLH implants could be stabilized.