bluuebunny/crossref_metadata_2025 huggingface dataset:
Late toxicity and quality of life from GETUG-AFU 22 study.
Authors: Latorzeff Igor , Guerif Stephane , Pelissier Sandra , Meyer Emmanuel , Fraisse Julien , Supiot Stephane , Crehange Gilles , Lagneau Edouard , Ronchin Philippe , Benyoucef Ahmed , Hasbini Ali , Pommier Pascal , De Laroche Guy , Salomon Laurent , Sargos Paul
Published: February 2020

331

Background: Radical prostatectomy (RP) is recommended as a standard treatment for localized prostate cancer. However no recommendations exist for pts with immediate detectable PSA after RP. Methods: Pts with localized prostate cancer, treated by RP (R0 or R1), with a PSA level post-RP ≥0.2 ng/mL and ≤2 ng/mL at randomization and N0 M0 on imaging were included. Pts were randomized (1:1) to radiotherapy (RT) alone (RT arm) or 6 months degarelix hormone therapy (HT) with RT (RT+HT arm). RT consisted of pelvic irradiation (46 Gy in 23 Fr) with a boost on the prostate bed (66 Gy in 33 Fr). The primary endpoint was event-free survival (EFS). Acute and late toxicities were evaluated as secondary endpoints and scored using CTCAE V4.0 scale. Quality of life (QOL) was assessed with QLQ-C30 and QLQ-PR25 questionnaires at 12 and 24 months. Late toxicity was reported at 24 months. Results: From Jan-2013 to Sept-2015, 125 pts were included (RT arm: 64 pts; RT+HT arm: 61). Median follow up is 38 months (31.4; 44). The baseline characteristics are well-balanced between two arms: median age was 66 yrs (50-77), all men having an ECOG ≤1 (ECOG 0 in 92%), a median Gleason score of 7 (3-9), a median PSA of 0.3 ng/mL (0.09-1.82) post-RP and 0.6 ng/mL (0.12-3.65) at randomization. All pts received 33 Fr of RT. In the RT+HT arm 98.4% of pts received the 6 months of HT planned. All pts were eligible for safety analysis. At 24 months, no difference in late genitourinary (GU) or gastrointestinal (GI)toxicity was observed between the two arms (p=0.145) Grade 3 late toxicities were reported for 15/125 pts (12%): 8/64 pts (6.5%) in the RT arm and 7/61 pts (5.5%) in RT+HT arm (NS) and no toxicity grade >3 was observed. Evaluation of QOL was assessable at 12 and 24 months of FU for 80%/89% pts and 59%/77% pts in RT/RT-HT arms respectively. At 12 months QLQ-PR25 HT related symptoms was significantly more important in the RT-HT arm (p=0.04). At 24 months no significant difference in QLQC-30 or QLQ-PR25 analysis was reported. Conclusions:, At 24 months in this phase II trial no significant difference in GI/GU toxicity and.QOL was observed between the two arms. GETUG-AFU 22 efficacy analysis is still pending. Clinical trial information: NCT01994239.
Predicting radiation-induced immune trafficking and activation in localized prostate cancer.
Authors: Williams Scott , Keam Simon P. , Halse Heloise , Nguyen Thu , Mitchell Catherine , Caramia Franco , Byrne David , Haupt Sue , Ryland Georgina , Darcy Phillip K. , Sandhu Shahneen Kaur , Blombery Piers , Haupt Ygal , Neeson Paul J.
Published: February 2020

340

Background: Prostate cancer is frequently cured with high-dose rate brachytherapy as a front-line treatment. However, a significant number unfortunately develop intrinsic resistance. Although considered to be an immune-excluded tissue, immune responses are implicated in driving tumour-eradication in prostate cancer. This has not been proven, and yet is used as the rationale for numerous clinical trials combining radiation and immunotherapies. We hypothesise that there is a predictable but differential relationship between radiation and the immune responses in prostate cancer that could be used to fulfil a clinical need - identifying patients that would benefit from immune intervention in conjunction with radiation. Methods: We present here the results of comprehensive immunological profiling of a cohort of world-unique pre- and post-radiation tissues from 24 patients (RadBank cohort). These were assessed using pathological classification, tissue segmentation (cancer/surrounding stroma), multiplex IHC, gene expression profiling, T-cell receptor sequencing, and spatial computational analysis. Results: Our data resolved three classes of prostate cancer tissue based on immune infiltrate level, immune-activation and -checkpoint gene signatures, spatial clustering and T cell clone sequencing: We have begun to resolve clear patient and clinical classifiers based on immune responses to radiation, and identified patients groups likely to benefit from immune therapy alongside radiation. Conclusions: Importantly, these classifications are associated with baseline gene expression profiles that may be used for pre-clinical stratification and more sophisticated treatment paradigms.
Periprostatic venous androgen levels in a subset of patients with prostate cancer: An investigation into a novel role of testosterone in localized prostate cancer.
Authors: Thomas Lewis , Alyamani Mohammad , Li Jianbo , Purysko Andrei , Klein Eric A. , Sharifi Nima
Published: February 2020

341

Background: While androgens drive prostate cancer (PCa), studies of systemic levels in eugonadal patients have not shown a relationship with development or progression of PCa. This study characterizes the relationship between systemic, local venous, and tissue androgen levels to understand the regulation and influence of androgens on localized PCa. Methods: Peripheral & periprostatic venous blood & prostate tissue were collected from patients undergoing radical prostatectomy (RP). Androgen levels (testosterone (T) and dihydrotestosterone (DHT)) were assessed by mass spectrometry. PCa grade and stage, PSA, prostate volume, and periprostatic vein diameter (PPVD) on MRI were recorded. A second cohort of patients undergoing just prostate MRI (non-surgical) was assessed to investigate the relationship between PPVD and disease severity. Results: Samples were collected from 176 patients. Analysis identified a subset of patients with elevated periprostatic T (ppT) relative to systemic T (sT) including 25% with ppT/sT > 2, 14% with ppT/sT > 4, and 7% with ppT/sT > 10. Patients with ppT/sT > 4 had supraphysiologic T levels in the periprostatic venous blood (mean 4223ng/mL). These patients also had higher than predicted levels of tissue T and DHT (tT/sT of 0.48 vs 0.24 (p = 0.004) and tDHT/sT of 7.31 vs 4.72 (p = 0.011)). In the surgical cohort, PPVD was increased in patients with elevated ppT/sT levels (5.8mm vs 3.7mm, p = 0.013). In the biopsy cohort (n = 200), increased PPVD was associated with an increased risk of diagnosis of PCa (4.39mm vs 3.43mm p = 0.006) and clinically significant PCa (4.35mm vs 3.43mm p = 0.01). Conclusions: In a subset of patients with PCa, periprostatic venous T levels were highly elevated compared to peripheral levels. Tissue T and DHT were also increased, and MRI demonstrated increased PPVD. We hypothesize that collateralization of venous drainage from the gonadal vein leads to both high local T and dilated veins. In a biopsy cohort, increased PPVD was associated with an increased risk of diagnosis of any and clinically significant PCa, suggesting that high periprostatic androgen levels may play a role in development of PCa.
Multiple primary prostate tumors with differential drug sensitivity.
Authors: Wilkinson Scott C. , Ye Huihui , Terrigino Nicholas , Carrabba Nicole , Atway Rayann , Trostel Shana Y. , Bright John , Hennigan S. Thomas , Lis Rosina , Lake Ross , Harmon Stephanie , Turkbey Baris , Pinto Peter A. , Choyke Peter L. , Karzai Fatima , VanderWeele David James , Kelly Kathleen , Dahut William L. , Sowalsky Adam G.
Published: February 2020

342

Background: The differential aggressiveness of potentially independent prostate cancer clones remains largely unknown. Appropriate prostate cancer staging using mpMRI and biopsy tissue can be confounded by sampling error. To date, there has been no understanding of whether clonal variability influences management decisions for localized prostate tumors. We sought to identify the sensitivity and genomic profile of distinct localized tumors from a patient following systemic intense neoadjuvant androgen deprivation therapy (ADT). Methods: A 66-year-old man with high risk prostate cancer enrolled in a Phase 2 study of intense neoadjuvant ADT (goserelin + enzalutamide; inADT). Baseline mpMRI showed a single semi-contiguous lesion encompassing the right apical-mid PZ extending into the left distal apical PZ. MR/US-fusion targeted biopsy was performed before 6 months of inADT. A second mpMRI was performed before radical prostatectomy. Whole exome sequencing on microdissected tumor foci identified somatic mutations and copy number alterations, which were further used with immunohistochemistry to assess tumor clonal architecture and genomic/phenotypic evolution of treatment resistant tumor. Results: We found two clonally independent tumors exhibited intrinsic heterogeneity at baseline which correlated with response or resistance. Biopsies of distinct left- and right-sided tumors showed differing histologies. mpMRI and pathology showed near complete response of the left-sided tumor and substantial resistance of the right-sided tumor, which exhibited a large intraductal component. Histology and whole exome data highlighted a divergence in the status of PTEN and TP53, tumor suppressor genes implicated in prostate cancer progression. Conclusions: These data highlight that even nascent prostate cancer is heterogenous and neoadjuvant therapeutic strategies will need to consider this for clinical optimization. Evolutionary trajectories that resulted in tumor heterogeneity in this case likely contributed to our observation that two independent prostate tumor nodules with distinct genetic alterations responded differently to neoadjuvant intense ADT. Clinical trial information: NCT02430480.
Immunosuppressive milieu of high-risk localized prostate cancer.
Authors: Adorno Febles Victor Ricardo , Adeegbe Dennis , Ahsan Aarif , Wu Jiansheng , Khodadad-Jamayran Alireza , Lepor Herbert , Wysock James , Taneja Samir , Huang William C. , Balar Arjun Vasant , Melamed Jonathan , Deng Fang-Ming , Ren Qinghu , Tsirigos Aristotelis , Kufe Donald W. , Heguy Adriana , Wong Kwok-Kin , Wise David R.
Published: February 2020

344

Background: The immune factors that modulate the aggressiveness of localized treatment-naïve prostate cancer remain poorly understood. Methods: Fresh tumor and peripheral blood were collected at the time of radical prostatectomy in patients with localized prostate cancer. We evaluated the immune cell composition of 22 patient samples employing multi-parametric flow cytometry. Samples were grouped by histological grade into intermediate (INTPCA) and high-grade (HIGHPCA) prostate cancers based on standard NCCN criteria and immune cell abundances were quantified by mean +/- SEM. Statistical significance was assessed using the Mann-Whitney test. Results: INTPCA and HIGHPCA tumors harbored a similar increase in CD8+ T cells ( p < 0.0005 and p < 0.05, respectively) and CD11b+CD68-CD16+ myeloid-derived cells (p < 0.05) relative to the peripheral blood. Other cell types were similarly decreased in both INTPCA and HIGHPCA, including CD11b+CD68+CD14+ ( p < 0.005 and p < 0.05, respectively). By contrast, regulatory T cells were the only cell type in our analysis to be uniquely enriched in HIGHPCA rather than INTPCA ( p < 0.05). The most unique feature found in phenotypic profiling of the immune repertoire of HIGHPCA relative to INTPCA was an increase in the immune inhibitory receptor ligand, PD-L1, in the tumor associated macrophages (CD11b+CD68+CD14+) compared to the periphery (p < 0.05). Conclusions: Collectively, our findings reveal that HIGHPCA harbors a distinct immunological landscape. Although effector CD8+ T cells are preferentially expressed in the tumor, these are met with an increased proportion of regulatory T cells as well as PD-L1 expressing macrophages that contribute to the inert tumor microenvironment. These are key features of aggressive prostate cancer that may serve as potential biomarkers and therapeutic targets.
Racial/ethnicity differences when endorsing influential factors for prostate cancer treatment choice: An analysis of data from the personal patient profile-prostate (P3P) I and II trials.
Authors: Berry Donna Lynn , Hong Fangxin , Halpenny Barbara , Epstein Matthew , Trinh Quoc-Dien
Published: February 2020

351

Background: Race and ethnicity impact the type of treatment received for localized prostate cancer in American men. We hypothesized that there may be differences in men’s influential values and preferences related to treatment decisions. Methods: We analyzed samples from two multicenter, randomized trials of the Patient Profile-Prostate (P3P) decision aid, first comparing the trial groups on demographic and decisional variables using Chi-square tests. Stratified (P3P I vs II) logistic regression was then used to assess the univariate association between race/ethnicity and endorsement of moderate-or-strong influence of 14 lifestyle factors, current or future symptoms, or important others on the decision. A multivariable stratified logistic regression with backward variable selection was used to further estimate the association between influential factors and race/ethnicity. Results: Data from 494 and 392 participants in P3PI and P3PII, respectively, were analyzed for 40 Hispanic, 168 non-Hispanic black, 637 non-Hispanic white, 19 others and 6 missing. Age (p=.0001), education (p<.0001), marital status (p<.0001), income (p<.0001), Internet use for information (p<.0001) and decisional control preference were significantly different across racial/ethnic groups. In adjusted analyses, racial/ethnic differences existed for influence of age (Non Hispanic Black (NHB) vs. Non Hispanic White (NHW) OR: 0.56 95%CI 0.38-0.85p=.002), religion/spirituality (NHB vs. NHW OR: 3.2095%CI1.95-5.26, p<.0001), future bladder function (NHB vs. NHW OR: 0.5795%CI0.35-0.90, p=.04), future ability to engage in recreation (NHB vs. NHW OR: 0.5495%CI 0.34-0.86, p=0.02), and a story of a famous person with prostate cancer (NHB vs. NHW OR: 2,11 95%CI1.30-3.43, p=.007). Conclusions: Our results suggest racial/ethnic differences for influences underlying treatment choice. Better understanding these influences may help us present salient information about treatment options to patients and address disparities.
Edmonton Prostate Interdisciplinary Cancer Clinic (EPICC): Real-world efficacy outcomes of a multidisciplinary clinic for metastatic castration-resistant prostate cancer.
Authors: Follett Graeme , Tilley Derek , Basappa Naveen S. , Danielson Brita Lavender , Chetner Michael , Kolinsky Michael Paul , North Scott A. , Rayner-Myers Sarah , Todd Gerry , Fairey Adrian S.
Published: February 2020

36

Background: Multidisciplinary management improves complex treatment decision making in cancer care but its impact for metastatic castration resistant prostate cancer (M1 CRPC) has not been documented. The Edmonton Prostate Interdisciplinary Cancer Clinic (EPICC) is a multidisciplinary specialized clinic focused on the delivery of novel therapeutics (Androgen Receptor Axis Therapy; ARAT) to men with chemotherapy-naïve M1 CRPC. The objective of the current study was to assess the efficacy of ARAT in the EPICC. Methods: The study was a retrospective quality assurance analysis. Eligible patients had a new diagnosis of chemotherapy-naïve M1 CRPC with minimal symptoms. EPICC patients were assessed and treated by a multidisciplinary cancer control team that included nursing oncology, pharmacy oncology and physician oncology (urologic, medical and radiation). Patients were treated in first line with an ARAT (abiraterone (AA) or enzalutamide (EZ)) from October 2017 to March 2018. The main efficacy outcome was overall survival (OS). The Kaplan-Meier method and Cox regression model were used to analyze survival data. Statistical tests were two-sided (p≤0.05). Results: From October 2017 to March 2018, 160 chemotherapy-naïve M1 CRPC patients were assessed in the EPICC. Median age at EPICC admission was 77 years (range, 54-92 years). Median PSA level at EPICC admission was 26.6 ng/mL (range, 0.1-5000 ng/mL). 84 out of 160 (53%) patients had received prior radical local therapy (RLT) with curative intent. 83 (57%) patients were treated with EZ and 64 (43%) patients were treated AA. Median OS for the entire cohort was 23 months. In multivariable analysis, absence of prior RLT (HR 3.6, 95% CI 1.9 to 6.6, p < 0.001), PSA > 20 ng/mL (HR 3.2, 95% CI 1.4 to 7.2, p = 0.004), and higher ECOG performance status (1 vs 0: HR 2.4, 95% CI 1.3 to 4.4, p = 0.005; 2 versus 0: HR 3.5, 95% CI 1.5 to 8.0, p = 0.003; and 3 versus 0: HR 12.7, 95% CI 2.5 to 63.8, p = 0.002) were independently associated with poorer OS. Conclusions: Multidisciplinary management of chemotherapy-naïve M1 CRPC with ARAT is feasible. Real world efficacy of ARAT in EPICC are similar to data reported in phase 3 trials.
5-alpha reductase inhibitors (5-ARI) and prostate cancer mortality among men with regular access to screening and health care.
Authors: Mucci Lorelei A. , Pernar Claire Hampton , Rencsok Emily , Stopsack Konrad H. , Grob Sydney , Giovannucci Edward L. , Olumi Aria F , Kibel Adam S. , Preston Mark A. , Wilson Kathryn M.
Published: February 2020

39

Background: The excess risk of high-grade prostate cancer in the Prostate Cancer Prevention Trial (PCPT) among men randomized to finasteride raised concerns that a chemoprevention benefit would be offset by increased mortality. Two 2019 publications had contrasting results whether 5-ARIs increased prostate cancer mortality. In PCPT, there was no excess prostate cancer mortality. In a VA study, 5-ARI use was associated with later stage at diagnosis and 39% higher prostate cancer mortality risk. We studied men with regular access to health care and screening to address this conflicting evidence. Methods: We performed two parallel analyses in the Health Professionals Follow-up Study. 5-ARI use was reported on biennial questionnaires starting in 1996. In line with PCPT, we studied 38,047 men for cancer incidence and mortality through 2016. In line with the VA study, we undertook a case-only study of 4,225 patients with localized/locally advanced cancers followed similarly. We estimated hazard ratios (HR) and 95% confidence intervals accounting for screening patterns, lifestyle factors, and concomitant medications. Results: 5-ARI ever-users (n = 4,101; 10.7%) were more likely to have had regular PSA screening (74% vs. 57% nonusers) and a negative prostate biopsy before diagnosis. Neither ever 5-ARI use (HR 1.08, 0.73-1.60, 445 events) nor long-term use ( > 4 years, HR 1.03, 1.03-2.02) were associated with lethal prostate cancer. There was no difference in stage. Diagnostic PSA levels were lower in 5-ARIs users (10.0 vs. 16.0 ng/ml in never-users). Among nonmetastatic cases, 278 men died of prostate cancer; there was no association between 5-ARIs and prostate cancer survival (HR 0.85, 0.51-1.43). Conclusions: Our results align with PCPT and show no excess risk of lethal prostate cancer, no higher stage at diagnosis, and no excess mortality after diagnosis associated with 5-ARI. Men on 5-ARIs had more interactions with health care, which may have led to higher quality care. This contrasts with the VA study where men on 5-ARIs were diagnosed later due to suppressed PSA and had worse survival. These results show the importance of real-world data in framing the benefits and risks associated with 5-ARIs.
Comprehensive genomic profiling (CGP) of histologic subtypes of urethral carcinomas (UrthCa).
Authors: Jacob Joseph , Shapiro Oleg , Necchi Andrea , Grivas Petros , Sokol Ethan , Vergilio Jo-Anne , Killian Keith , Lin Douglas I. , Williams Erik , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Chung Jon , Alexander Brian Michael , McGregor Kimberly , Elvin Julia Andrea , Schrock Alexa Betzig , Danziger Natalie , Ross Jeffrey S. , Bratslavsky Gennady
Published: February 2020

426

Background: UrthCa is an uncommon GU malignancy that can progress to advanced metastatic disease. Methods: 126 metastatic UrthCa underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 49 (39%) urothelial (UrthUC), 31 (24%) squamous (UrthSCC), 34 (27%) adenocarcinomas (UrthAC) and 12 (9%) clear cell (UrthCC) were evaluated. UrthUC and UrthSCC were more common in men; UrthAC and UrthCC more common in women. Ages were similar in all groups. GA in PIK3CA were the most frequent potentially targetable GA; mTOR pathway GA in PTEN also identified. GA in other potentially targetable genes were also identified including ERBB2 (6% in UrthUC, 3% in UrthSCC and 12% in UrthAC), FGFR1-3 (3% in UrthSCC), BRAF (3% in UrthAC), PTCH1 (8% in UrthCC) and MET (8% in UrthCC). Possibly reflecting their higher GA/tumor status, potential for immunotherapy benefit associated with higher TMB and PD-L1 staining levels were seen in UrthUC and UrthSCC compared to UrthAC and UrthCC. MSI high status was absent throughout. Conclusions: CGP reveals GA that may be predictive of both targeted and immunotherapy benefit in patients with advanced UrthCa and that could potentially be used in future adjuvant, neoadjuvant and metastatic disease trials.[Table: see text]
The emerging target KRAS G12C in genitourinary malignancies.
Authors: Grivas Petros , Necchi Andrea , Bratslavsky Gennady , Shapiro Oleg , Jacob Joseph , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Keith , Williams Erik , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Schrock Alexa Betzig , Chung Jon , McGregor Kimberly , Reddy Prasanth , Alexander Brian Michael , Sokol Ethan , Danziger Natalie , Ross Jeffrey S.
Published: February 2020

434

Background: KRAS has recently emerged as a druggable driver with novel agents targeting G12C genomic alteration (GA). Methods: FFPE tissue from 1453 renal clear cell carcinomas (RCCC), 3879 urothelial bladder carcinomas (UBC) and 8322 prostate acinar adenocarcinomas (PAAC) underwent comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on 0.8 to 1.2 Mbp of sequenced DNA and MSI was determined on 114 loci. PD-L1 expression (Dako 22C3) was measured by IHC. Results: KRAS GA were identified in 7 RCCC (<1%), 202 UBC (5.2%), and 158 PAAC (1.9%). KRAS G12C mutations were observed in 0 RCCC, 24 (2%) of UBC, and 1 (<1%) PAAC. Age/gender distributions were similar. VHL, SETD2, and PBRM1 mutations were the most frequent concurrent GA in the 7 RCCC with KRAS G12C GA. In KRAS G12C mutated UBC, co-mutations in TERT were significantly reduced and in KDM6A were significantly increased (both p<0.05) in cases with KRAS G12C GA versus KRAS G12C negative tumors. Conclusions: KRAS G12C mutations are extremely rare in the major genitourinary malignancies. However, given the emerging interest in identifying KRAS G12C for potential basket-type clinical trials using novel anti-KRAS G12C targeted therapies, further study of these alterations in genitourinary malignancies, especially bladder and prostatic carcinomas, appears warranted.[Table: see text]
Randomized phase III trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC) as perioperative chemotherapy for muscle invasive urothelial bladder cancer (MIUBC): Preliminary results of the GETUG/AFU V05 VESPER trial on toxicity and pathological responses.
Authors: Culine Stephane , Gravis Gwenaelle , Flechon Aude , Soulie Michel , Guy Laurent , Laguerre Brigitte , Mottet Nicolas , Joly Florence , Allory Yves , Harter Valentin , Pfister Christian
Published: February 2020

437

Background: The optimal perioperative chemotherapy regimen for patients (pts) with MIUBC is not defined. Methods: Between February 2013 and February 2018, 494 pts were randomized in 28 French centres and received either 4 cycles of GC every 3 weeks or 6 cycles of dd-MVAC every 2 weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). The primary endpoint was the progression-free survival at 3 years. Secondary endpoints included toxicity, pathological responses and overall survival. Results: In the neoadjuvant group, 218 pts received dd-MVAC and 219 pts GC. The median number of cycles was 6 (0-6) and 4 (1-4), respectively. 60% of pts received 6 cycles in the dd-MVAC arm, 84% received 4 cycles in the GC arm. 199 pts (91%) and 198 (90%) pts underwent surgery, respectively. Complete pathologic responses (ypT0pN0) were observed in 84 (42%) and 71 (36%) pts, respectively (p=0.02). An organ-confined status (<ypT3pN0) was obtained in 154 (77%) and 124 (63%) pts, respectively (p=0.002). In the adjuvant group (57 pts), the median number of cycles was 5 (1-6) and 4 (1-4), respectively. 40% of pts received 6 cycles in the dd-MVAC arm, 60% received 4 cycles in the GC arm. Most of CTCAE grade ≥ 3 toxicities concerned hematological toxicities. At least one of these where reported for 125 (50%) pts in the dd-MVAC group and 134 (54%) pts in the GC group (p=NS). Gastrointestinal (GI) grade ≥ 3 disorders were more frequently observed in the dd-MVAC arm (p<0.0001) as well as grade ≥ 3 asthenia (p<0.00001). Four deaths (3 in the dd-MVAC) occurred during chemotherapy. Conclusions: Complete pathological responses and organ-confined status were more frequently observed in the dd-MVAC arm. Toxicity was manageable with more severe asthenia and GI side effects in the dd-MVAC arm. Clinical trial information: 2012-000563-25.
Trends in management and outcomes in patients with upper tract urothelial carcinoma following radical nephrouretectomy at Memorial Sloan Kettering Cancer Center.
Authors: Wong Nathan Colin , Assel Melissa , Tracey Andrew , Alvim Ricardo , Almassi Nima , Singla Nirmish , Clinton Timothy Nguyen , Chesnut Gregory Thomas , Sjoberg Daniel D. , Bajorin Dean F. , Coleman Jonathan
Published: February 2020

469

Background: Although there have been changes in the treatment paradigm of patients with upper tract urothelial carcinoma (UTUC) over the past 2 decades, there is limited data on the particular management strategies and associated outcomes. We evaluated surgical trends, perioperative management, and oncologic outcomes of patients who underwent radical nephroureterectomy (RNU) for UTUC at Memorial Sloan Kettering Cancer Center over a 24-year period. Methods: Between 1995 and 2018, we identified 760 patients with UTUC who underwent RNU. 15 had multiple RNU and we kept only the first procedure for analysis. Generalized additive models were fitted to examine the association between date of surgery and continuous while generalized additive models with a logit link were used to estimate categorical variables. As surgical approach was defined using three different categories (open, laparoscopic and robotic) a generalized additive multinomial model was used. Generalized additive cox proportional hazards models were used to estimate the association between surgery date and estimate 2-year cancer-specific survival. Results: The use of pre-operative diagnostic endoscopic biopsies also increased from 12% to 72% which coincides with an increased proportion high grade disease on final pathology from 55% to 91%. The rate of open RNU declined from 100% to 54% with a coinciding rise in the utilization of minimally invasive approaches. Laparoscopy peaked in 2008 and then was subsequently replaced by the robotic approach. Mean lymph node yield increased over the study interval with more retroperitoneal lymph node dissections performed. Utilization of neoadjuvant chemotherapy also increased over time with a current rate of 31%, coinciding with an increase in pT0 rate from only 2% to 9%.The 2-year cancer specific survival probability has improved from 76% to 87% over the study period. Conclusions: Several changes in treatment patterns for patients with UTUC over the past 2 decades appear to correspond with an improvement of oncologic outcomes. How these changes directly relate to each other requires further investigation.
Association of radical cystectomy and increased risk of skeletal-related events in bone-metastatic urothelial carcinoma.
Authors: Almassi Nima , Easthausen Imaani J. , Ghafoor Soleen , Christos Paul J. , Donahue Timothy F. , Rosenberg Jonathan E. , Farooki Azeez
Published: February 2020

477

Background: Bone metastases are common in patients with advanced cancer of the bladder or upper urinary tract; however, few studies have assessed the morbidity of bone metastases in these patients. We sought to characterize bone-associated morbidity by measuring the frequency of skeletal-related events (SREs) and identify predictors of SREs in this population. Methods: We retrospectively identified 328 patients with bone-metastatic bladder or upper urinary tract cancer managed at Memorial Sloan Kettering between 2000 and 2018. SREs were defined as presence of spinal cord compression from bone metastasis, pathologic fracture, treatment of bone metastasis with radiotherapy or surgery, or hypercalcemia of malignancy. SRE-free survival was estimated using Kaplan-Meier analysis; competing-risks regression analysis was used to identify predictors of SREs. Results: In total, 198 patients (60%) developed ≥1 SRE, including 84 (26%) with multiple SREs. The most common SREs were bone radiotherapy (n=165 [83%]), pathologic fracture (n=73 [37%]), and orthopedic surgery (n=39 [20%]). Median SRE-free survival was 7.4 months. On competing-risks regression analysis, history of radical cystectomy (hazard ratio [HR], 1.40; 95% CI, 1.05-1.86; P=0.02) and hip involvement at the time of bone metastasis diagnosis (HR, 1.65; 95% CI, 1.12-2.42; P=0.01) were independently associated with risk of SRE. Conclusions: SREs are common among patients with bone-metastatic cancer of the bladder or upper urinary tract and typically occur soon after the development of bone metastasis. Patients with a history of radical cystectomy or with hip involvement at the time of bone metastasis diagnosis have a higher risk of SRE.
Predictive value of fibroblast growth factor receptor (FGFR) alterations on anti-PD-(L)1 treatment outcomes in patients (Pts) with advanced urothelial cancer (UC): Pooled analysis of real-world data.
Authors: Kim William Y. , Rose Tracy L. , Roghmann Florian , Eckstein Markus , Jarczyk Jonas , Zengerling Friedemann , Sikic Danijel , Breyer Johannes , Bolenz Christian , Hartmann Arndt , Mayhew Gregory , Shibata Yoichiro , Uronis Joshua M. , Galluzzi Aaron , Sundaram Ramesh , Xia Qi , Wu Kathy , Santiago-Walker Ademi E. , Erben Philipp , Wirtz Ralph
Published: February 2020

493

Background: The tumor microenvironment in UC harboring FGFR gene alterations is characterized by decreased T-cell infiltration and low immune marker expression, potentially implicating suboptimal response to immune checkpoint inhibitors. The association between FGFR gene mutations/fusions and anti-PD-(L)1 treatment outcomes in advanced UC was assessed using real-world pt data. Methods: A pooled dataset of matched clinical and genomic data for advanced UC pts treated with anti-PD-(L)1 in any line from the Bladder Cancer Research Initiative for Drug Targets in Germany (BRIDGE) Consortium and UNC-CH was assessed. FGFR status was defined by a prespecified panel of FGFR2/3 mutations and fusions. Overall survival (OS) was analyzed using Kaplan-Meier estimates and Cox proportional hazards models. Multivariate analyses were performed using potential prognostic covariates (sex, age, baseline tumor stage, urothelial histology, smoking history, primary tumor location, and ECOG) in a Cox regression model for OS to assess their impact on the effect of FGFR alterations. Results: Median OS for FGFR+ pts (n=28) who received any line of anti-PD-(L)1 therapy was 9.5 mo vs 7.5 mo for FGFR− pts (n=139) (HR: 1.03, 95% CI: 0.60-1.76, p=0.93). Median OS for pts treated with first-line anti-PD-(L)1 was 5.42 mo in FGFR+ pts (n=10) and was not reached for FGFR− pts (n=31) (HR: 2.06, 95% CI: 0.68-6.24, p=0.19); median OS in second-line anti-PD-(L)1 was 6.5 mo (FGFR+; n=14) vs 5.7 mo (FGFR−; n=86) (HR: 0.89, 95% CI: 0.44-1.81, p=0.74). The multivariate analyses showed a significant trend of poorer OS in FGFR+ pts with first-line anti-PD-(L)1 (HR: 10.42, 95% CI: 1.45-74.97, p=0.02); wide CI may be attributed to small sample size for some categories in several covariates. Conclusions: Treatment with first-line anti-PD-(L)1 in FGFR+ pts may be associated with poorer OS outcomes in FGFR+ pts; however, this trend was not observed in FGFR+ pts treated with any line and second-line anti-PD-(L)1. Investigation of the predictive value of FGFR alterations to immunotherapy outcomes in larger real-world pt datasets is warranted.
Histologic subtype and response to immune checkpoint inhibitor (ICI) therapy in advanced urothelial cancer (aUC).
Authors: Miller Natalie J. , Khaki Ali Raza , Diamantopoulos Leonidas Nikolaos , Bilen Mehmet Asim , Sacristan Santos Victor , Morales-Barrera Rafael , Devitt Michael Edward , Nelson Ariel Ann , Shreck Evan , Assi Hussein , Rodriguez-Vida Alejo , Lythgoe Mark , Drakaki Alexandra , Joshi Monika , Isaacsson Velho Pedro , Moses Marcus W. , Galsky Matt D. , Sonpavde Guru , Yu Evan Y. , Grivas Petros
Published: February 2020

495

Background: Urinary tract cancer can be pure urothelial carcinoma (PUC) or variant UC (VUC, defined here as pure non-UC or mixed UC + non-UC); VUC often has a worse prognosis. Little is known about outcomes for patients (pts) with VUC receiving ICI. We hypothesized that VUC does not compromise ICI efficacy in pts with aUC. Methods: We performed a retrospective cohort study across 18 institutions. Demographic, clinicopathologic, treatment and outcomes data was collected for pts with aUC who received ICI. Pts were stratified to PUC vs VUC; VUC was further divided by histologic subtype, i.e. squamous, neuroendocrine (NE), etc. We compared overall response rate (ORR) using logistic regression, progression free survival (PFS) and overall survival (OS) using Kaplan-Meier and Cox proportional hazards; p<0.05 was significant. Results: 519 consecutive pts were identified; 405, 414 and 411 included in ORR, OS and PFS analyses, respectively. Demographics included mean age 69, 27% female, 66% ever smokers, 15% upper tract disease, 54% with extirpative surgery. ORR to ICI between pts with PUC and VUC was comparable (both 28%, p=0.86) without significant differences for individual subtypes vs PUC. Median OS for pts with PUC was 11.0 vs 9.9 mo for VUC (p=0.45), but only 3.7 mo for those with NE features (HR=3.01 [95% CI 1.63-5.57] vs PUC, p<0.001). Median PFS was 4.1 vs 5.2 mo for PUC vs VUC (p=0.46) and 2.8 mo for NE (HR=1.85 [95% CI 0.94-3.61] vs PUC, p=0.07). Conclusions: ORR to ICI and OS were comparable across histologic types; however, OS was shorter for tumors with NE features. VUC should not exclude pts from receiving ICI in routine practice and clinical trials.[Table: see text]
p16INK4a expression and survival outcomes in patients with penile squamous cell carcinoma: The M.D. Anderson Cancer Center Experience.
Authors: Chahoud Jad , Pham Rachel , Guo Ming , Pickering Curtis R. , Qiao Wei , Khanna Abha , Netto Frederico , Pettaway Curtis Alvin , Rao Priya
Published: February 2020

5

Background: Penile Squamous Cell Carcinoma (PSCC) is associated with high risk human papillomavirus (HR-HPV) in about 50% of cases. The immunohistochemical test for p16INK4a (p16) is highly correlated with HR-HPV expression and used as prognostic marker for squamous cell carcinomas in various sites. The prognostic role of this marker in PSCC remains unclear. We studied whether the expression of HPV or p16INK4a is associated with survival in a large PSCC cohort. Methods: We conducted a single institution analysis of PSCC patients who received treatment between 1991-2017.Patients with a confirmed diagnosis of PSCC and available tissue were tested for HR-HPV status using the Cobas PCR assay. Histological subtype, tumor grade, LVI and p16 staining patterns were confirmed by an experienced pathologist. Patient characteristics were summarized using descriptive statistics of clinico-pathologic variables. Kaplan-Meier was used to estimate median overall survival (OS) and cancer specific survival (CSS). Log rank test, univariate and multivariate Cox models were applied to identify the prognostic factors for survival. Results: We identified 147 patients with PSCC, with available tissue for testing. The median follow-up was 5.2 years (95% CI; 4.48, 6.68y). Patients with p16(+) tumors showed a significantly longer median OS and CSS in comparison to the p16(–) group (p=0.038 and p=0.012), with respective 5 year OS probability of 73% (95% CI; 0.74, 0.98) in comparison to 56% (95% CI; 0.46, 0.67) and 5 year CSS probability of 89% (95% CI; 0.7, 1) in comparison to 64% (95% CI; 0.54, 0.75). In contrast, HPV status by PCR did not predict survival outcomes, with 5 year CSS probability for HPV(+) of 75% (95% CI; 0.61, 0.91) compared to 65% (95% CI; 0.55, 0.78) for HPV(–) patients. Multivariable analysis to evaluate the association with CSS, showed that p16(+) along with lymph node status was associated with lower risk of death (HR=0.28, 95%CI; 0.09-0.8, p=0.002), and OS (HR=0.49, 95%CI; 0.19-1.24, p=0.13) after adjusting for the covariates. Conclusions: Tumor p16 status was an independent prognostic factor for CSS in our PSCC cohort providing unique information above that of lymph node status alone.
Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer: NEODURVARIB Trial.
Authors: Rodriguez-Moreno Juan Francisco , de Velasco Guillermo , Bravo Fernandez Inmaculada , Alvarez-Fernandez Carlos , Fernandez Ricardo , Vazquez-Estevez Sergio , Virizuela Juan Antonio , Gajate Pablo , Font Albert , Lainez Nuria , Barquín García Arantzazu Martínez , Ruiz-Llorente Sergio , Beltran Luis , Rodríguez-Antona Cristina , Berraondo Pedro , García-Donas Jesús
Published: February 2020

542

Background: Cisplatin-based chemotherapy remains the perioperative treatment in muscle-invasive bladder carcinoma (MIBC). Recent evidence suggests that immune checkpoint inhibitors could be incorporated in this setting. Olaparib is a PARP inhibitor with well-established activity in HRD tumor. Results from trials assessing the combination of durvalumab and olaparib suggest a synergistic effect. However, a molecular characterization is crucial to warrant a rational development. Methods: A phase II clinical trial was designed to assess the impact of neoadjuvant treatment with the combination of durvalumab plus olaparib in the molecular profile of MIBC (NCT03534492; SOGUG-2017-A-IEC(VEJ)-2). Efficacy and safety were secondary objectives. Subjects with cT2-T4a MIBC aimed for cystectomy were treated during 6 to 8 weeks pre-cystectomy. Diagnostic and surgical samples, pre and postreatment blood samples have been collected for the molecular analysis. We present results regarding efficacy and safety. Results: From November 2018 to October 2019 28 patients have been enrolled. 52%/48% of patients had PS 0/1. Median age was 70. TNM stage was: pT2 in 73,6% patients, pT3 in 10.6%, pT4 in 15.8% and 10.6% presented nodal spread. 13 patients have completed neoadjuvant treatment so far and 12 have undergone cystectomy. A wound dehiscence and one death related to surgical procedures were postoperative complications. Pathological complete response rate is 44,5%. Radiological evaluation is ongoing. 10 serious adverse events non-treatment related have been communicated. Any grade of toxicity has been reported in 91% of patients but adverse events grade 3-4 was detected in only 8.3% of cases. Grade 1 pruritus was the unique IR adverse event described in one patient. PARP inhibitors-related adverse events were grade 1 nausea and vomiting (25%), and grade 1 anemia (25%). Conclusions: Preliminary clinical data suggest that Durvalumab in combination with Olaparib could be active and well-tolerated neoadjuvant treatment of MIBC. Molecular characterization and biomarker discovery will be presented separately. Clinical trial information: NCT03534492.
Association of KRT20 and KRT5 with response to neoadjuvant chemotherapy in patients diagnosed with muscle invasive bladder cancer.
Authors: Roghmann Florian , Reike Moritz , Wirtz Ralph , Kriegmair Maximilian , Erben Philipp , Tully Karl , Weyerer Veronika , Eckstein Markus , Hartmann Arndt , Wezel Felix , Bolenz Christian , Tannapfel Andrea , Noldus Joachim , Juette Hendrik
Published: February 2020

562

Background: Patients with muscle-invasive bladder cancer (MIBC) that underwent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) show improved overall survival. Those with a pathological complete response (pCR) usually have the best prognosis. In the literature, improved response to NAC has been associated with basal tumor characteristics in MIBC so far. The aim of the present study was to examine the association of luminal (KRT20) and basal (KRT5) mRNA expression patterns at transurethral resection (TUR) with pCR at RC after NAC in a contemporary cohort of consecutive MIBC patients. Methods: Clinical Data and formalin fixed paraffin embedded tumor tissue samples from TUR and RC of 49 patients with MIBC were retrospectively analyzed. Using RT-PCR KRT20 and KRT5 mRNA expression were measured in 40-∆Ct values and normalized against the control gene CALM2. Statistical analyses comprised nonparametric and chi2 testing, partition models and spearman correlation analyses. Results: The study cohort had a median age of 63 years and consisted of 38/49 (78%) males. After NAC, 17/49 (35%) patients had cPR. Using partition models, we found that patients with high-KRT20 (≥39.5 ∆Ct) had a higher chance of pCR (57% vs. 26%, p=0.04). Using a cutoff for KRT5 at <38.1 ∆Ct within the subgroup of patients with low-KRT20 (<39.5 ∆Ct, n=35), we found poorest response among low-KRT20/low-KRT5 compared to low-KRT20/high-KRT5 and high-KRT20 (13% vs. 37% vs. 57%, p=0.29), respectively. For low-KRT20/low-KRT5, low-KRT20/high-KRT5 and high-KRT20 median KRT5 was 34.8 vs. 39.5 vs. 34.1 ∆Ct ( p=0.001) and median KRT20 was 37.9 vs. 32.9 vs. 40.1 ∆Ct,( p=0.001), respectively. Conclusions: Patients with MIBC showing high expression of KRT20 were more likely to show pCR at RC after NAC. Moreover, we were able to identify a high risk group of patients with lowKRT20/lowKRT5 that was less likely to achieve pCR at RC after NAC. Our findings are contradicting previous studies and need further verification in larger cohorts. However, our results might be useful for treatment stratification in MIBC patients.
Cost-effectiveness of radical cystectomy versus trimodality therapy for muscle invasive bladder cancer.
Authors: Suskovic Nathan , Raldow Ann C. , Royce Trevor Joseph , Smith Angela
Published: February 2020

575

Background: Muscle invasive bladder cancer (MIBC) comprises 25% of all bladder cancers at the time of diagnosis. Radical Cystectomy (RC) has traditionally been the gold standard curative treatment for MIBC. Trimodality therapy (TMT) with maximal transurethral resection of bladder tumor, chemotherapy, and radiation is a treatment alternative and Category 1 recommendation by the NCCN. TMT has shown equivalent survival for carefully selected patients. However, the comparative cost effectiveness between RC and TMT is unknown. Therefore, the purpose of this study was to compare the cost-effectiveness of RC versus TMT for MIBC. Methods: We developed a Markov model using TreeAge software to simulate a 5-year outcome for one million 65-year old hypothetical patients with MIBC undergoing either RC or TMT. Hypothetical patients in the RC treatment pathway would have an adverse event, no adverse event, or immediate death after surgery. After RC, patients either would have no evidence of disease or transition to locoregional recurrence, metastatic recurrence, or death. Hypothetical patients in the TMT treatment pathway would either have an adverse event or no adverse from treatment. After TMT, patients either would have disease-free bladder intact survival or transition to locoregional failure, metastatic recurrence, or death. Patients with locoregional failure from TMT transition into non-salvageable disease or salvageable disease. Patients with salvageable disease prompted a salvage cystectomy. Model probabilities and utilities were extracted from the literature. Costs were derived from 2019 National Medicare Fee Schedule. Results: RC and TMT were associated with quality adjusted life years (QALY) of 2.88 and 3.38 respectively (incremental QALYs of 0.5 favoring TMT). The mean costs of RC and TMT were $37,107 and $23,916 respectively. TMT was less expensive with an incremental cost of $13,191. Conclusions: In patients aged 65 and older with MIBC, TMT was the dominant strategy as compared to RC, as it was both cheaper and associated with increased QALYs based upon model assumptions. The results of this study are the first to evaluate the cost effectiveness of RC and TMT.
A phase I/II trial of sitravatinib (sitra) combined with nivolumab (nivo) in patients (pts) with advanced clear cell renal cell cancer (aCCRCC) that progressed on prior VEGF-targeted therapy.
Authors: Msaouel Pavlos , Thall Peter F. , Yuan Ying , Wang Xuemei , Jonasch Eric , Gao Jianjun , Campbell Matthew T. , Shah Amishi Yogesh , Corn Paul Gettys , Tam Alda , Ahrar Kamran , Rao Priya , Sircar Kanishka , Der-Torossian Hirak , Tannir Nizar M.
Published: February 2020

612

Background: Sitra is a receptor tyrosine kinase (RTK) inhibitor targeting TAM receptors (Tyro3, Axl, MerTK), split family receptors (VEGFR2 and c-Kit) and c-Met. Inhibition of these RTKs has direct biological activity against aCCRCC and can also enhance immunotherapy with nivo by reducing immunosuppressive regulatory T-cells, myeloid derived suppressor cells, and type 2 tumor-associated macrophages. We therefore hypothesized that the addition of sitra to nivo will produce higher clinical activity than nivo alone. Methods: The objective of this phase I/II trial is to evaluate the safety and efficacy of sitra + nivo in pts with aCCRCC that progressed on up to two prior VEGF-targeted therapies. Eligibility criteria were similar to those used for CheckMate 025. The late-onset Bayesian EffTox design is used to account for potential late-onset immune-related toxicities, and allow optimal dose-finding of sitra from four dose levels (60, 80, 120, 150 mg/day) continuously based on both efficacy and toxicity. Additional objectives include estimation of survival times and correlative biomarkers. Results: A total of 38 pts have enrolled as of 22 October 2019 with 34 pts evaluable for response at ≥12 weeks. Tumor reductions have been noted in 28/34 pts (82.3%) with objective responses demonstrated in 13/34 pts (ORR = 38.2%), median progression-free survival of 10.5 months (95% CI 7.6 – 13.5), and 23/34 pts (67.6%) achieving disease control ≥ 6 months. Toxicities requiring dose-reduction of sitra within 12 weeks from treatment initiation have been noted in 14/34 pts (41.2%). The most common treatment-related adverse events include fatigue, diarrhea, palmar-plantar erythrodysesthesia, hypertension, and elevated lipase. There was one nivo-related Grade 5 event (myasthenia gravis). Updated dose-finding, safety and efficacy data will be presented. Conclusions: The combination of sitra + nivo has not demonstrated unexpected safety signals and produces higher objective responses and longer disease control compared with what is historically expected with nivo alone in pts with aCCRCC that progressed on prior VEGF-targeted therapy. Clinical trial information: NCT03015740.