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2647 Prognostic significance of PD-L1 expression on tumor-infiltrating mononuclear cells in patients with urothelial carcinoma
Abstracts become a cornerstone in the treatment of kidney cancer, and presents with a high risk of DDI. Active communication with the GP is mandatory in order to request re-evaluation of the medications used for the treatment of cormorbidities, in order to minimize the risk of DDI, which consequences on sunitinib efficacy remain unknown. Prescriptions should be amended and modified, as part of a multidisciplinary care of these patients, which require tools and an organisation to favor collaboration between oncologists/ urologists and GPs. No conflict of interest. 2646 POSTER Relationship and predictive role of the dual expression of FGFR and IL8 in metastatic renal cell carcinoma (mRCC) R. Iacovelli1 , M. De Tursi2 , A. Ciardi3 , C. Mosillo3 , C. Carella2 , C. Natoli2 , G. Naso3 , C. Enrico3 . 1 European Institute of Oncology, Medical Oncology Unit of Urogenital and Head & Neck Tumors, Milan, Italy; 2 Universita` G. D’Annunzio, Dipartimento di Scienze Orali e Mediche, Sezione di Oncologia, Chieti, Italy; 3 Sapienza Universita` di Roma, Dipartimento di Scienze Radiologiche, Oncologiche ed Anatomo-Patologiche, Rome, Italy Background: The expression of interleukin-8 (IL8) has been related with worse prognosis and primary resistance to targeted agents in mRCC. Despite these data, no agents are specifically available for these patients. GOLD trial (Lancet Oncol 2014), reported such as dovitinib, a tyrosine kinas inhibitors (TKI) targeting the fibroblast growth factor receptor (FGFR), is effective as well as sorafenib in third-line treatment of mRCC. We aim to investigate the relationship between IL8 and FGFR in mRCC. Material and Methods: Patients affected by mRCC and treated with targeted agents in two University centers in Italy were reviewed for availability of histological samples of primary tumor. Clinical information were collected from patient’s files. The expression of IL8, FGFR1 and FGFR2 was evaluated by immunohistochemistry (IHC). Only cased with IHC expression >5% were considered positive. Spearman’s and Chi’s square tests were used to define the correlation and the difference in expression of tumor markers, respectively. Median survivals were estimated by Kaplan–Meier method and compared with log-rank test. Study was approved by IRB. Results: A total of 36 patients have been analyzed. 94% received nephrectomy, 92% had clear cell histology, 42% were metastatic at diagnosis, 89% received TKI and the other had bevacizumab or temsirolimus. The FGFR1, FGFR2 and IL8 were found expressed in 8.3%, 30.6% and 36.1% of cases, respectively; all cases positive for FGFR1 were also positive for FGFR2. Significant correlations was found between FGFR1/2 and IL8 (rs=0.51; p = 0.002). FGFR1/2 was found expressed in 72.7% and 27.3% of cases with or without expression of IL8 (p = 0.002). When patients with dual expression of FGFR and IL8 were compared to others, a significant difference was found in terms of PFS (5.1 vs. 12.0 months; p = 0.04), and a clinically but not statistically significant difference was found in terms of OS (14.2 vs. 41.2 months), probably due to the low number of cases. Conclusions: This analysis first investigated and found a relationship between the expression of the IL8 and FGFR in patients affected by RCC and treated with targeted agents for the metastatic disease. Further studies are awaited to assess the role of FGFR inhibitors in mRCC patients who express the IL8. No conflict of interest. 2647 POSTER Prognostic significance of PD-L1 expression on tumor-infiltrating mononuclear cells in patients with urothelial carcinoma S. Lim1 , J.W. Seo2 , S.Y. Rha3 . 1 Kunyang University Hospital, Internal medicine, Daejeon, Korea; 2 Hallym University Sacred Heart Hospital, Department of pathology, Anyang, Korea; 3 Yonsei Medical College of Medicine, Internal medicine, Seoul, Korea Background: Programmed cell death ligand-1 (PD-L1) expression was shown to be associated with clinicopathological features and clinical outcomes in various tumor types. However, there has been only limited data on whether PD-L1 expression is a prognostic factor among patients with urothelial carcinoma (UC). Methods: Using formalin-fixed paraffin-embedded tumor samples from 89 patients who were treated with UC at Yonsei University College of Medicine, we assessed the prognostic value of PD-L1 expression. Expression of PD-L1 in tumor cell membrane or tumor infiltrating mononuclear cells (TIMCs) was measured by immunohistochemistry, and PD-L1-positivity was defined as staining in 1% of cells. Kaplan–Meier methods, log-rank test and Cox-regression test were used for survival analysis.
S529 Results: Median age was 69 years (range, 41−88 years), and 73% of pts were male. All patients underwent radical cystectomy for invasive UCs, and most patients (79.7%) were in pathological stage III or IV. Out of 89 samples, 37.1% and 64.0% were PD-L1 positive in tumor cell membrane and TIMCs, respectively. No correlation was found between PD-L1-positivity and gender, age, or stage. PD-L1 positivity in tumor cell was not associated with recurrence free survival (RFS) (p = 0.83) or overall survival (OS) (p = 0.63). In contrast, PD-L1 positivity in TIMCs showed a tendency for longer RFS (p = 0.10) and had a statistically longer OS (p = 0.04). After adjustment by age, gender and stage, PD-L1 positivity was associated with prolonged OS (p = 0.04). Conclusion: PD-L1 is widely expressed in tumor cell membrane and TIMCs in UC. PD-L1 in tumor cells was not associated with OS, whereas positive PD-L1 expression in TIMCs was significantly predictive of longer survival. No conflict of interest. 2648 POSTER Novel DNA methylation therapeutic targets in urothelial carcinoma (UC) from patients with paired metachronous primary and metastatic tumors N. Hahn1 , H. Cramer2 , S. Badve2 , L. Cheng2 , Y. Gokmen-Polar2 , D. Miller3 , A. Buechlein3 , D. Rusch3 , F. Fang3 , D. Frankhouser4 , R. Bundschu5 , J.O. Ganbat6 , R. Foster7 , R. Bihrle7 , T. Masterson7 , T. Gardner7 , M. Koch7 , L. Marchionni8 , Y. Pearlly9 , K. Nephew3 . 1 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Oncology and Urology, Baltimore, MD, USA; 2 Indiana University Melvin and Bren Simon Cancer Center, Pathology, Indianapolis, USA; 3 Indiana University, Biochemistry, Bloomington, USA; 4 Ohio State University, Biomedical Sciences, Columbus, USA; 5 Ohio State University, Physics, Columbus, USA; 6 Ohio State University, Computer Science and Engineering, Columbus, USA; 7 Indiana University Melvin and Bren Simon Cancer Center, Urology, Indianapolis, USA; 8 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Oncology, Baltimore, MD, USA; 9 Ohio State University, Hematology, Columbus, USA Background: The critical processes driving the biology of UC metastases remain incompletely understood. The current study was performed to provide initial identification of differentially methylated targets distinct within tumor metastases compared to primary muscle-invasive UC (MIUC) specimens from patients with paired samples. We tested the primary hypothesis that uniquely methylated regions with potential therapeutic impact can be identified in UC metastases compared to primary tumors. Materials and Methods: Formalin fixed paraffin embedded (FFPE) tumor samples were identified from subjects with a histologic diagnosis of UC who had both their primary surgical resection and a core biopsy or fine needle aspiration (FNA) of a metastatic tumor recurrence at a metachronous time point performed at the Indiana University Simon Cancer Center. Unamplified DNA was extracted from tissue sections with over 75% tumor present. Samples passing 260/280 nm quality control checks with at least 40 ng DNA available were analyzed using double-enzyme reduced representation bisulfite sequencing (dRRBS) on the Illumina HiSeq platform. A false discovery rate correction with a q-value cutoff of 0.05 was utilized to determine genes with at least 2-fold significantly different methylation between the primary and metastatic tumor cohorts. Results: Initially, 46 potential primary-metastatic tumor pairs were identified, with archived FFPE tissues still available from 28 patients. DNA >40 ng and passing QC testing was available from 15 primary/ metachronous metastases pairs. dRRBS analysis identified 2,110 significantly differentially methylated genes in promoter, distal promoter, and 1st exon regions in metastases compared to primary tumors. Genes with the highest degree of significantly increased methylation in metastases compared to primary tumors included those involved in tumor suppressor function (URI1), DNA replication/repair (INTS9, PDS5B, RTEL1, FBXO42, FBXO33, TP53BP1, RAD51, ZNF217), and immune modulation (CREM, CSMD1, TTLL5, PRKCD) all q < 0.05. Full pathway and clustering analyses will be presented. Conclusions: We demonstrate that global DNA methylation analysis of archived metastatic UC tumor samples is feasible. Differentially methylated genes with potential therapeutic impact between primary and metastatic UC tumor samples were identified. Furthermore, a number of genes not previously described in MIUC samples in The Cancer Genome Atlas (TCGA) project were identified using dRRBS, a more comprehensive epigenetic approach. Analysis of the methylome is strongly encouraged in future clinical trials and archived independent biorepositories to further assess the significance of DNA methylation in clonal evolution during the transition from primary to metastatic UC. No conflict of interest.
S529 Results: Median age was 69 years (range, 41−88 years), and 73% of pts were male. All patients underwent radical cystectomy for invasive UCs, and most patients (79.7%) were in pathological stage III or IV. Out of 89 samples, 37.1% and 64.0% were PD-L1 positive in tumor cell membrane and TIMCs, respectively. No correlation was found between PD-L1-positivity and gender, age, or stage. PD-L1 positivity in tumor cell was not associated with recurrence free survival (RFS) (p = 0.83) or overall survival (OS) (p = 0.63). In contrast, PD-L1 positivity in TIMCs showed a tendency for longer RFS (p = 0.10) and had a statistically longer OS (p = 0.04). After adjustment by age, gender and stage, PD-L1 positivity was associated with prolonged OS (p = 0.04). Conclusion: PD-L1 is widely expressed in tumor cell membrane and TIMCs in UC. PD-L1 in tumor cells was not associated with OS, whereas positive PD-L1 expression in TIMCs was significantly predictive of longer survival. No conflict of interest. 2648 POSTER Novel DNA methylation therapeutic targets in urothelial carcinoma (UC) from patients with paired metachronous primary and metastatic tumors N. Hahn1 , H. Cramer2 , S. Badve2 , L. Cheng2 , Y. Gokmen-Polar2 , D. Miller3 , A. Buechlein3 , D. Rusch3 , F. Fang3 , D. Frankhouser4 , R. Bundschu5 , J.O. Ganbat6 , R. Foster7 , R. Bihrle7 , T. Masterson7 , T. Gardner7 , M. Koch7 , L. Marchionni8 , Y. Pearlly9 , K. Nephew3 . 1 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Oncology and Urology, Baltimore, MD, USA; 2 Indiana University Melvin and Bren Simon Cancer Center, Pathology, Indianapolis, USA; 3 Indiana University, Biochemistry, Bloomington, USA; 4 Ohio State University, Biomedical Sciences, Columbus, USA; 5 Ohio State University, Physics, Columbus, USA; 6 Ohio State University, Computer Science and Engineering, Columbus, USA; 7 Indiana University Melvin and Bren Simon Cancer Center, Urology, Indianapolis, USA; 8 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Oncology, Baltimore, MD, USA; 9 Ohio State University, Hematology, Columbus, USA Background: The critical processes driving the biology of UC metastases remain incompletely understood. The current study was performed to provide initial identification of differentially methylated targets distinct within tumor metastases compared to primary muscle-invasive UC (MIUC) specimens from patients with paired samples. We tested the primary hypothesis that uniquely methylated regions with potential therapeutic impact can be identified in UC metastases compared to primary tumors. Materials and Methods: Formalin fixed paraffin embedded (FFPE) tumor samples were identified from subjects with a histologic diagnosis of UC who had both their primary surgical resection and a core biopsy or fine needle aspiration (FNA) of a metastatic tumor recurrence at a metachronous time point performed at the Indiana University Simon Cancer Center. Unamplified DNA was extracted from tissue sections with over 75% tumor present. Samples passing 260/280 nm quality control checks with at least 40 ng DNA available were analyzed using double-enzyme reduced representation bisulfite sequencing (dRRBS) on the Illumina HiSeq platform. A false discovery rate correction with a q-value cutoff of 0.05 was utilized to determine genes with at least 2-fold significantly different methylation between the primary and metastatic tumor cohorts. Results: Initially, 46 potential primary-metastatic tumor pairs were identified, with archived FFPE tissues still available from 28 patients. DNA >40 ng and passing QC testing was available from 15 primary/ metachronous metastases pairs. dRRBS analysis identified 2,110 significantly differentially methylated genes in promoter, distal promoter, and 1st exon regions in metastases compared to primary tumors. Genes with the highest degree of significantly increased methylation in metastases compared to primary tumors included those involved in tumor suppressor function (URI1), DNA replication/repair (INTS9, PDS5B, RTEL1, FBXO42, FBXO33, TP53BP1, RAD51, ZNF217), and immune modulation (CREM, CSMD1, TTLL5, PRKCD) all q < 0.05. Full pathway and clustering analyses will be presented. Conclusions: We demonstrate that global DNA methylation analysis of archived metastatic UC tumor samples is feasible. Differentially methylated genes with potential therapeutic impact between primary and metastatic UC tumor samples were identified. Furthermore, a number of genes not previously described in MIUC samples in The Cancer Genome Atlas (TCGA) project were identified using dRRBS, a more comprehensive epigenetic approach. Analysis of the methylome is strongly encouraged in future clinical trials and archived independent biorepositories to further assess the significance of DNA methylation in clonal evolution during the transition from primary to metastatic UC. No conflict of interest.