bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating tumor DNA sequencing analysis of patients with metastatic renal cell carcinoma (mRCC).
Authors: Zengin Zeynep Busra , Dizman Nazli , Salgia Nicholas , Jones Jeremy , Zhang Jingbo , Liu Yunchao , Xu Bing , Li Fuwei , Wang Yan , Li Mengjian , Du Rong , Zhou Ye , Hsu Joann , Salgia Meghan , Yang Lixin , Pal Sumanta K.
Published: May 2020

e17100

Background: Despite extensive work to characterize genomic alterations (GAs) in metastatic renal cell carcinoma (mRCC), GAs are not currently used for treatment sequencing or selection. Circulating tumor DNA (ctDNA) in both blood and urine may elucidate potential mRCC biomarkers through a minimally invasive approach. We aimed to validate previous blood-based ctDNA studies (Pal et al Eur Urol 2017) and compare detection rates of clinically relevant GAs in plasma and urine. Methods: From a single institution, patients (pts) with mRCC were recruited to provide a plasma and urine specimen. ctDNA next-generation sequencing was performed using an investigational 120-gene panel, and we limited our assessment to 7 GAs with biological relevance in RCC ( VHL, MTOR, PIK3CA, TSC2, MET, AKT1, TSC1). Further, only pathogenic alterations previously recognized in RCC and cited in the Catalogue of Somatic Mutations in Cancer (COSMIC) database were considered. Clinicopathologic variables, treatment type and response to therapy were collected from an institutional mRCC patient database. Concordance analysis was performed at the gene level between blood and urine using previously published approaches (Chae et al Oncotarget 2016). Results: 50 pts (40M:10F) were enrolled with a median age of 65. 40 pts (80%) had clear cell histology, while the remainder were papillary (12%), chromophobe (4%) or other (4%). Pts received a median of 1 line of therapy (range, 0-7). GAs were identified in 45 pts (90%) in blood and in 45 pts (90%) in urine . Applying the above criteria, the most frequently observed GAs in blood specimens were TSC2 (9%), MTOR (4%), and VHL (2%). The most frequently observed GAs in urine were VHL (4%) and MTOR (2%). The rate of concordance between blood- and urine-detected GAs was 93%. Of pts bearing mTOR pathway alterations in blood or urine, 3 received everolimus-based therapy. All 3 pts remain on therapy at 10.4, 13.8 and 14.0 months, respectively. Conclusions: Biologically relevant GAs can be detected in pts with mRCC using blood and urine. Our methodology showed high concordance between both platforms. Consistent with prior reports, ctDNA assessment of pts with pretreated mRCC shows a higher frequency of TOR pathway alterations and a lower frequency of VHL mutation.
Percutaneous microwave ablation of stage T1b renal cell carcinoma: Assessment of technical feasibility, clinical outcomes, and safety.
Authors: Arellano Ronald , Guo Jianhai
Published: May 2020

e17104

Background: The use of percutaneous microwave ablation (MWA) for T1b (4.1-7.0 cm) renal cell carcinoma (RCC) has not yet been widely adopted. Methods: This single-center retrospective study investigated consecutive patients who underwent CT-guided percutaneous MWA for T1b RCC from December 2015 to May 2019. Patient baseline characteristics, tumor biological features, technical parameters, clinical outcomes, and complications were recorded and evaluated. Local progression-free and overall survival (OS) rates were estimated using the Kaplan-Meier method. Results: This study included 23 patients (18 men [mean age ± standard deviation, 74.6 y ± 10.2; range, 58–89 y] and 5 women [mean age, 71.6 y ±10.1; range, 62–86 y]; overall mean age, 74.0 y ± 10.0; range, 58-89 y) with 23 T1b tumors. Technical success was achieved in all of tumors. Local progression-free survival was 94.7%, 86.1%, and 86.1% at 1-, 2-, and 3-year respectively. OS was 95.2%, 85.7%, and 71.4% at 1-, 2-, and 3-year respectively. Of the 2 (8.7%) complications, both were classified as Clavien-Dindo grade I complication. Conclusions: CT-guided percutaneous MWA was associated with high rates of technical success, excellent local progression-free survival and OS, and a low complication rate for stage T1b RCC.
Integrated single-cell spatial multi-omics of intratumor heterogeneity in renal cell carcinoma.
Authors: Hsieh James J , Miheecheva Natalia , Ramachandran Akshaya , Lyu Yang , Galkin Ilia , Svekolkin Viktor , Postovalova Ekaterina , Bagaev Alexander , Lozinsky Yaroslav , Zyrin Vladimir , Zaitsev Aleksandr , Nuzhdina Katerina , Nomie Krystle , Ogloblina Anna , Frenkel Felix , Ataullakhanov Ravshan
Published: May 2020

e17106

Background: Clear cell renal cell carcinoma (ccRCC) exhibits conspicuous intratumor heterogeneity (ITH) - a driver of tumor evolution and metastasis. ITH in RCC has been studied extensively with bulk tumor DNA sequencing, which lacks the ability to integrate single cell resolution data, spatial architecture, and microenvironment composition. Therefore, we analyzed primary ccRCC tumors at multiple biopsy sites with CyTOF, multiplex immunofluorescence (MxIF), whole exome sequencing (WES), RNA sequencing (RNA-seq), single nuclei RNA-seq (snRNA-seq), and whole genome bisulfite sequencing (WGBS). Methods: Primary ccRCC tumors collected from 6 patients (pts) were biopsied at multiple locations and subjected to CyTOF (n = 21 sites, 6 pts), MxIF (20 markers, n = 8 sites, 3 pts), WES (n = 8 sites, 3 pts), RNA-seq (n = 8 sites, 3 pts), snRNA-seq (n = 8 sites, 3 pts), and WGBS (n = 8 sites, 3 pts), enabling integrated multi-omics analysis. MxIF, CyTOF, and genomic/transcriptomic analyses were performed by BostonGene. Results: Genomic intratumor (IT) evolution of ccRCC cells was tracked with WES, and subclonal distribution of SETD2, STAG2, TSC2 and PBRM1 mutations was observed in different IT regions. Different regions of the same tumor were similar, whereas individual patient tumors were distinct according to tumor microenvironment cellular composition measured by CyTOF or deconvoluted from RNA-seq. The cellular deconvolution of the ccRCC tumors reconstructed from RNA-seq correlated with CyTOF, snRNA-seq and WGBS, showing high concordance among the methods. The promoter CpG island methylation levels, averaged across all genes, positively correlated with ccRCC grade. MxIF revealed spatial IT heterogeneity in the distribution of immune infiltrate components. Macrophages and T cells dispersed among malignant cells; whereas, T cells formed clusters at unique tumor margins. Conclusions: The utilization of multi-omics methods produced a high-resolution portrait of the ccRCC tumor composition and identified differential ITH among regions within the primary tumors or among individual primary tumors. This study demonstrated strong concordance among the different technologies, suggesting that tumor deconvolution by bulk RNA-seq might be clinically applicable for ccRCC tumors. MxIF analysis enabled a fine elucidation of the spatial relationships among the tumor and the immune and stromal cells, missed by common omic platforms. Integrated single cell multi-omics could render specific pathobiological and therapeutic insights that impact treatment decisions.
Examining the real-world utility of immune checkpoint inhibitors in genitourinary oncology: A single-institution retrospective.
Authors: Glick Lydia , Clark Cassra , Han Timothy M. , Mark James Ryan , Gomella Leonard G. , Handley Nathan , Kelly William Kevin , Trabulsi Edouard John , Lallas Costas D. , Chandrasekar Thenappan
Published: May 2020

e17112

Background: Immune Checkpoint Inhibitors (ICI) are increasingly utilized for genitourinary (GU) malignancies. However, data is lacking on the efficacy of these drugs in “real-world” populations - patients who do not fit the strict clinical trial criteria, but may still benefit from therapy. We performed a retrospective analysis of patients receiving ICI at a single tertiary-care institution, with special attention to clinical trial enrollment, adverse events, progression and survival. Methods: Patients receiving ICI for GU malignancies at Thomas Jefferson University Hospital from January 2017 to January 2019 were identified. Descriptive statistics of treatment and pathologies were performed. Progression-free survival (PFS) was calculated from start of ICI to documentation of progression or last follow-up. PFS and overall survival were assessed using Kaplan Meier log-rank test, stratified by trial enrollment. Results: 111 patients were included: 37 on ICI clinical trial, 70 received ICI “off-trial” and 4 received ICI in both settings. 11 patients (10%) underwent multiple courses of ICI throughout treatment. The number of patients initiating ICI increased annually; by 2018, the number of patients initiated on ICI “off-trial” exceeded those initiating ICI “on-trial” (79% vs 21%). Treated pathology included Urothelial Carcinoma (UC; 42%), Renal Cell Carcinoma (RCC; 28%), and Prostate Adenocarcinoma (PCa; 20%). “Off-trial” ICI was more often administered later in the disease course, compared to a more even distribution of “on-trial” ICI administration. Mean PFS and OS for both cohorts can be seen in Table. Conclusions: As seen in our single-institution referral center, the use of immune checkpoint inhibitors has significantly increased – and is now more commonly used off-trial than on-trial. As their use becomes more common, their efficacy in “off-trial” populations must be further investigated. [Table: see text]
Effect of local therapies on survival in patients with metastatic adrenocortical carcinoma.
Authors: Shetty Impana , Venzon David J. , Mauda-Havakuk Michal , Thomas Bj , Bernstein Donna , Flowers Crystal , Anderson Victoria , Raygada Margarita , Levy Elliot B , Wood Bradford J. , Widemann Brigitte C. , Reilly Karlyne , Del Rivero Jaydira
Published: May 2020

e17114

Background: Adrenocortical carcinoma (ACC) is a rare cancer with an incidence of 0.7 – 2 cases per million persons per year, and generally has a poor prognosis with a 5-year survival rate of 20-25%. In a previous review of 330 patients with ACC, the median overall survival time of patients with Stage IV ACC was 0.9 years. Currently, complete surgical resection is the only curative treatment for ACC. Cases of recurrent or metastatic ACC are infrequently curable by surgery alone and systemic therapies have limited benefit. A previous study has suggested that local interventions to resect liver metastases improve survival. We hypothesize that local therapies increase survival of patients with metastatic ACC and here we describe the characteristics of various types of regional therapies. Methods: We conducted a retrospective chart review of 26 patients with ACC who were seen at the National Institutes of Health (NIH) between 2002 and 2019 and who are currently alive. These patients had multiple interventions that were performed including surgeries, radiofrequency ablations/embolizations/cryoablations and systemic therapies. Results: The group of patients we studied were 92% female and 8% male. The ages ranged from 23 to 77, with an average age of 57. Out of the 26 patients, 11 (42%) patients had liver metastases, 17 (65%) patients had lung metastases, 4 (15%) patients had retroperitoneal recurrence, and 5 (19%) patients had lymph node involvement. All patients with lung, retroperitoneum, liver, and lymph node metastases underwent surgical intervention. In patients with liver metastases, 73% underwent liver-directed therapies and 91% received systemic therapy. In patients with lung metastases, 59% underwent radiofrequency ablation or cryoablation and 94% had systemic therapy. Among the systemic therapies, 15% of patients received zero lines of treatment, 50% of patients received one line, 12% of patients received two lines, 19% of patients received three lines, and 4% of patients received more than three lines of treatment. Conclusions: The analysis of this cohort indicates that multiple local therapies could increase patient survival. ACC metastases are most common in the liver, followed by the lungs. Patients with recurrent/metastatic ACC should be considered for regional therapies such as metastasectomy/ablation in experienced hands which can increase long-term survival in selected patients.
Intratumoural (IT) evolutionary landscape of high-risk prostate cancer and outcome: The PROGENY (PROstate cancer GENomic heterogeneitY) study of genomic and immune parameters.
Authors: Jayaram Anuradha , Goh Gerald , Kularatne Bihani Yoshana , Waterhouse Jasmin , Shanmugabavan Yaalini , Rowan Andrew , Wong Yien Ning Sophia , Freeman Alex , Akarca Ayse , Herrero Javier , Rosenthal Rachel , McGranahan Nicholas , Hung Michelle , Emberton Mark , Attard Gerhardt , Quezada Sergio A. , Marafioti Teresa , Ahmed Hashim Uddin , Swanton Charles , Linch Mark David
Published: May 2020

e17500

Background: IT heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease and patient outcomes are uncertain. Methods: This was a prospective, single-arm, translational study using targeted multi-region prostate biopsies to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. A pre-defined exploratory objective was to evaluate the association of ITH, median inflammatory infiltrate (MII), total, clonal and neoantigens, with overall survival (OS) and time-to-next-line of therapy (TTNL). Results: 49 men with elevated prostate-specific antigen (PSA) and multiparametric-magnetic resonance imaging (MRI) detected PC underwent image-guided multiregion transperineal biopsy. 79 tumour regions from 25 patients (pts) with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification. The median follow-up was 60 months (m) with 10 death events. For %ITH, MII, total, clonal and subclonal neoantigens, patients were split by the median. Conclusions: The PROGENY study provides a diagnostic platform suitable for studying tumour ITH and has the potential to identify poor outcome subgroups in PC. Larger sample numbers in prospective trials are warranted to further investigate this hypothesis. [Table: see text]
Prostate cancer outcomes by ESRD status.
Authors: Sarabu Nagaraju , Dong Weichuan , Ray Al , Fernstrum Austin , Ponsky Lee Evan , Koroukian Siran M.
Published: May 2020

e17513

Background: Persons with end-stage renal disease (ESRD) comprise a vulnerable subgroup of the population. Yet, rarely have studies on cancer disparities accounted for ESRD status. We sought to compare prostate cancer stage at diagnosis, treatment, and outcomes among men with and without ESRD. Methods: Utilizing SEER-Medicare database between years 2000-2016, we retrieved sociodemographic variables, including age (40-54, 55-64, 65-74, and 75+), race (African American vs. all others), marital status (married/partnered vs. all others), residence in a census tract with poverty rate > 20%; cancer stage at diagnosis (local, regional, distant, and unknown); treatment (surgery and radiation therapy); and overall and cancer specific survival (OS and CSS) from the SEER, and ESRD status preceding prostate cancer diagnosis from the Medicare portion of the file. In addition to descriptive analysis, multivariable survival analysis was utilized to evaluate the association of ESRD status with OS and CSS after adjusting for patient covariates. Results: Our study population included 2,922 ESRD and 600,848 non-ESRD men diagnosed with incident prostate cancer during the study period. A disproportionately higher percentage of ESRD patients were in the 40-54 age group compared to non-ESRD (9.7 vs 3.6%). Similarly, the percentage of prostate cancer patients who were African American was 41.5% among ESRD patients, compared with 14.4% in their non-ESRD counterparts. In addition, more ESRD than non-ESRD patients lived in census tracts with poverty rates greater than 20% (31.2% vs. 18.0%). With regard to stage, 10.6% of ESRD patients but only 4.5% of non-ESRD patients were diagnosed with distant-stage disease; and while only 24.8% of ESRD patients underwent surgery, 36.9% of non-ESRD patients did so. The rate of radiation therapy was similar across the two groups. Multivariable survival models showed that, adjusting for patient covariates, ESRD status was associated with unfavorable OS and CSS (adjusted hazard ratio (AHR): 4.00 (95% confidence interval: 3.82, 4.18), and AHR: 1.54 (1.37, 1.73), respectively). Median follow up was 3.35 and 7.13 years between the ESRD and non-ESRD cohorts. Conclusions: ESRD status in prostate cancer patients is associated with marked sociodemographic and economic disparities. Compared to their non-ESRD counterparts, more ESRD patients are diagnosed with advanced-stage disease, are less likely to undergo surgery, and experience shorter overall and cancer-specific survival. Future studies should be directed to gain insight into factors contributing to unfavorable cancer-specific outcomes.
Long-term prospective health related quality of life (HRQoL) outcomes: Impact of active surveillance before treatment of low risk prostate cancer (PCa).
Authors: Jung Nathan , Frankel Jason , Conti Galen , Porter Christopher , Flores John Paul
Published: May 2020

e17518

Background: The treatment options for low risk PCa are active surveillance (AS), radiation therapy (RT), and radical prostatectomy (RP). HRQoL studies with long term follow up are lacking. We evaluated HRQoL of initial active surveillance vs initial treatment. Methods: The Center for Prostate Disease Research (CPDR) database was used. HRQoL data was collected for 5 years with the Expanded Prostate Cancer Index Composite (EPIC) and the 36-item Medical Outcomes Study Short Form (SF-36). Patients had low risk PCa, age less than 75, and follow up data of at least 1 year. AS was defined as no definitive treatment within 12 months of diagnosis and repeat biopsy or PSA within 18 months of diagnosis. Results: Patient characteristics are located in the table. Baseline HRQoL scores were comparable across treatment groups for all HRQoL domains, except for sexual function and bother, and physical health where RT were worse than RP. Of the 68 patients classified as AS, 4 had brachytherapy, 9 had hormone therapy, 38 had RP, and 17 had XRT as a first treatment after terminating their AS. In the Generalized Estimating Equations (GEE) model, the HRQoL scores were compared. Multivariate analysis was done accounting for baseline differences. Urinary function (p = 0.0017), urinary bother (p = 0.0028), hormone function (p = 0.035), bowel bother (p = 0.0122), sexual function (p < 0.01), sexual bother (p < 0.01), and physical health (p = 0.0457) were significantly different. For urinary function and bother, XRT had the best HRQoL scores at most time points, with AS getting worse over time as patients went on to receive treatment. AS had worse scores with hormone function and sexual function. RP had the best scores for bowel bother over the course of the study, but had the worst initial scores in sexual bother, which got better over time. Hormone bother (p = 0.5574), Bowel function (p = 0.098), mental health (p = 0.7231) were not statistically different between groups. Conclusions: Initially AS results in improved HRQoL. For those patients who undergo treatment after AS, HRQoL is no worse than those who got treatment initially. [Table: see text]
Clinicopathological predictors of bone metastases in prostate cancer patients.
Authors: Portilla Ingreed , Pinto Joseph , Flores Claudio J. , Araujo Jhajaira M , Villalobos Johanna A , Aguilar Alfredo
Published: May 2020

e17520

Background: To determine if there is association between the clinical-pathological characteristics and the development of bone metastases in patients with prostate cancer treated in Oncosalud during the period 2016-2018. Methods: An observational, analytical, cross-sectional and retrospective study was conducted in 386 men diagnosed with prostate cancer in a Private Clinic in Peru. We presented descriptive and analytic analysis to identify variables associated with bone metastases; in addition, odds ratios were estimated. Results: In reference to the PSA groups, those patients with PSA values higher than 20 ng / ml presented a risk 9.69 times higher to develop bone metastases (95% CI: 5.08-18.45). In regard to Gleason groups, those with a 9-10 score presented a risk of bone metastasis 2.67 times higher than patients with lower Gleason score (95% CI: 1.31-5.45). In regard to the clinical stage, those patients with a T3 stage had a 6.77 higher risk than those with lower clinical stages (95% CI: 3.79-12.09). Conclusions: Clinical-pathological characteristics associated with bone metastasis were identified in patients with prostate cancer, including age, Gleason scale, PSA value and clinical T stage.
A prospective observational study of combinatorial abiraterone (AA) and radical radiotherapy (RT) in node-positive (N+) prostate cancer (PCa).
Authors: Tan Mark Ting Le , Woo Wai Yee , Sim Yen Ling Adelene , Tuan Jeffrey , Tan Terence Wee Kiat , Li Youquan , Khor Li Yan , Yeong Joe Poh Sheng , Tan Chien sheng , Tay Kae-Jack , Lee Lui Shiong , Kanesvaran Ravindran , Chua Melvin Lee Kiang
Published: May 2020

e17555

Background: The conventional treatment backbone of N+ PCa has been hormonal therapy (HT) alone. Nonetheless, evidence from the STAMPEDE trial suggests that there could be survival benefit with the addition of local RT or AA, and there may be synergy between RT and AA in these advanced patients. We therefore conducted a prospective observational study to evaluate the efficacy of combination AA+HT+RT in patients with N+ PCa. Here, we report the preliminary biochemical response and toxicity data. Methods: Patients with N+M0/N+M1a, biopsy-proven adenocarcinoma of the prostate were enrolled. Patients were staged by 68Ga-PSMA-PET or whole body MRI. Exclusion criteria were i) ECOG ≥2; ii) cardiac event of < 6 mo interval; iii) bone and visceral metastasis. Treatment protocol entailed 18 mo of combination AA (1000 mg plus 5 mg prednisolone once daily) and HT (LHRH agonist/antagonist); RT was delivered to the prostate (78 Gy) +/- pelvis (54 Gy with simultaneous boost of 60-66 Gy to grossly involved lymph nodes in M0 patients). This was matched against a control group that received long-term HT +/- RT (N = 38). Primary endpoint of this analysis was PSA ≤0.1 ng/ml at 6 mo; secondary endpoints were PSA ≤0.1 ng/ml, testosterone ≤0.7 nmol/l at 12 mo, and toxicity outcomes. Germline genetic profiling was performed in all patients. Results: From Feb 2017 to Aug 2019, 18 men were recruited to this study, with a median fu of 15 mo (range 6.0-35.0 mo). Median age was 66.0 y (IQR 62.0-71.0y); median baseline PSA was 18.2 ng/ml (range 3.0-272); 66.7% had GS 8-10 disease; and 22.2% had M1a disease. Combination AA+HT+RT achieved PSA of ≤0.1 ng/ml in 80.0% (N = 12) and 93.3% (N = 14) of patients at 6 mo and 12 mo, respectively, in contrast to 29.4% and 25.0% of patients who were treated with HT+RT and HT alone, respectively. We observed profound castration of 87.5% (N = 14) at 6 mo, and 91.7% (N = 11) at 12 mo. Four and 6 patients experienced acute G2 genitourinary and gastrointestinal toxicities during RT, respectively; 2 patients reported late G2 GU. One patient experienced G2 fatigue and G1 liver enzyme dysfunction, resulting in dose reduction of AA. Genetic testing revealed a patient with BRCA2 frameshift mutation; interestingly, this patient failed to achieve a PSA of ≤0.1 ng/ml at 12 mo. Conclusions: We demonstrate that combinatorial AA+HT and definitive RT is well tolerated, and yield a pronounced early PSA response in N+ PCa. Long-term data will inform if this early efficacy signal leads to improved survival in these patients.
Evaluating biomarkers in metastatic castration-resistant prostate cancer patients treated with enzalutamide: PSA, circulating tumor cell counts, AR-V7 status and radiographic progression.
Authors: Gandhy Shruti U. , Karzai Fatima , Marte Jennifer L. , Bilusic Marijo , McMahon Sheri , Strauss Julius , Couvillon Anna , Williams Monique , Hankin Amy , Steinberg Seth M. , Gill Audrey , Tubbs Alisa , Schonhoft Joseph , Figg William Douglas , Arlen Philip M. , Dahut William L. , Gulley James L. , Madan Ravi Amrit
Published: May 2020

e17569

Background: Enzalutamideis ahighly effective treatment in metastatic castration resistant prostate cancer (mCRPC). Although Prostate Cancer Working Group (PCWG) guidelines recommend continuing treatment until radiographic/clinical progression (rPD/cPD), many patients discontinue therapy for rising PSA alone. Methods: We conducted an open label, randomized phase 2 trial in mCRPC patients untreated with docetaxel, abiraterone, or enzalutamide, comparing enzalutamide alone or in combination with PROSTVAC, a therapeutic cancer vaccine designed to induce an anti-tumor immune response. The study discontinued accrual after planned interim analysis indicated no difference in progression between the two arms. Patients were followed beyond 1st of 3 confirmed PSA rises until rPD. 49 patients were analyzed for Circulating Tumor Cell (CTC) count and AR-V7 status at 1st PSA rise and at rPD/cPD or last follow up. Results: 57 patients were enrolled with median follow up time of 55.4 mo. 49/57 (86%) patients had rising PSA; median time to 1st PSA rise for all patients was 6.4 mo (95% CI: 3.7-11.0 mo) after starting enzalutamide. 38/57 (67%) patients had progressive disease (majority with rPD; 1/38 (3%) with cPD); median time to progression for all patients was 23.3 mo (95% CI: 16.1-27.8 mo). 5 patients tested positive for AR-V7 within 30 days of rPD. In patients who experienced rPD/cPD, CTCs were detected in 11/24 (46%) samples taken at rPD vs. in only 3/24 (13%) samples taken at rising PSA. CTC counts were higher at rPD compared to samples taken at rising PSA (P = 0.004, Wilcoxon unpaired test). Of the 7 patients still being treated (median time on drug = 4.2 yrs), 2 experienced rising PSA; however none of the patients had detectable CTCs at a median of 30 days from last follow up. Conclusions: These data suggest that a rising PSA may not be a warning of near-term clinically significant disease progression in mCRPC patients treated with enzalutamide, given the 17-month difference between the first rise in PSA and ultimate rPD/cPD seen in this analysis. Further, CTCs and AR-V7 status associate strongly with rPD but not with rising PSA, adding biological rationale to the hypothesis that CTC counts and AR-V7 status are associated with disease progression. Collectively, these data highlight the need to continue to educate patients and providers on PCWG criteria for progression and appropriately-timed utilization of both therapies and diagnostic tests to maximize drug efficacy in mCRPC. Clinical trial information: NCT01867333 .
Outcomes of patients with metastatic castration resistant prostate cancer according to somatic sequencing of domage DNA repair genes.
Authors: Neviere Zoé , Ricou Agathe , Vaur Dominique , Muller Etienne , Krieger Sophie , Boulouard Flavie , Castera Laurent , Leconte Alexandra , Bonnet Isabelle , Moise Laura , Coquan Elodie , Meriaux Emeline , Brachet Pierre-Emmanuel , Licaj Idlir , Lequesne Justine , Joly Florence
Published: May 2020

e17595

Background: More than 20% of mCRPC present somatic DNA damage repair gene mutation (DDR). If some data are available for germline mutations, there are few studies describing the relation between somatic alterations and response to standard therapies in mCRPC. Methods: To describe outcomes of mCRPC patients treated with standard therapies according to somatic DDR status.A retrospective somatic analysis on a 69-gene panel was conducted among mCRPC patients. Progression-free survival (PFS) of first-line treatment was analyzed according to somatic DDR mutation as primary endpoint. First exposition to taxanes chemotherapy and PFS2 (time to the second event of disease progression) depending on therapeutic sequences (new-generation hormonotherapy [NGHT]/taxanes chemotherapy) were also analyzed. Results: Among 83 patients tested, 33 (40%) had a somatic DDR mutation, including 10 ATM, 5 BRCA2, 4 CHEK2, 3 CDK12, 3 FANCG, 1 BLM, 1 CHEK1, 1 FANCF, 1 FANCI, 1 FANCM, 1 MDC1, 1 MRE11A and 1 PALB2. In first-line treatment, 20 patients received taxanes and 63 NGHT. Median PFS was 9.8 months for mutated patients and 8.4 months for non-mutated patients (p = 0.9). For mutated patients, median PFS was 12.3 months in taxanes group and 9.8 months in NGHT group, (p = 0.74). One BRCA2-mutated patient treated by docetaxel was particularly long responder (PFS = 39.2 months). PFS of first exposition to taxanes was 8.2 months among mutated patients and 5.7 months among non-mutated patients (p = 0.31). Patients with BRCA1/BRCA2/ATM mutations had longer PFS compared to the others patients (10.6 months versus 5.5 months, p = 0.04). Ten patients received the chemotherapy-NGHT sequence (CHS) and 28 the NGHT-chemotherapy sequence (HCS). PFS2 were 16.5 months for mutated patients, whatever the sequence, and 11.7 months among non-mutated patients (p = 0.07). The 3 mutated patients (1 BRCA1, 1 BRCA2, 1 ATM mutation) had long PFS2 in the CHS (49.8 months). PFS2 of mutated patients in HCS was 15.6 months. Conclusions: Mutated mCRPC patients benefit from standard therapies, with long responders to taxanes among patients with BRCA1/2 and ATM mutations.
Accuracy of prostate imaging reporting and data system (PI-RADS v2) in the detection of prostate cancer (PCa).
Authors: Gill David Michael , Bishoff Jay , Lynch Steven C. , Foy Bridget , Evans Jaden D. , Haslem Derrick S. , Yeatman Timothy Joseph , McLean Logan
Published: May 2020

e17604

Background: MRI-targeted biopsy is increasingly utilized over standard 12-core transrectal ultrasound (TRUS) biopsy for men with MRI-visible prostate lesions. Some clinicians defer biopsy for PI-RADS v2 category 1 and 2 lesions per the PRECISION Study (Kasivisvanathan et. Al, NEJM, 2018). The aim of this study was to independently validate the accuracy of PI-RADS v2 in detecting prostate cancer (PCa) when applied to MRI/US fusion-guided biopsies in an independent cohort of 156 patients from a large integrated community health system. Methods: Men undergoing MRI/US fusion-guided biopsy from 2016-2020 in the Intermountain Healthcare system were consecutively analyzed in this retrospective study. MRI were interpreted from four abdominal fellowship trained radiologists all with at least 5 years of experience. Fusion biopsies were performed by two urologists. Men were stratified into groups based on their PI-RADS v2 category 1-5. Biopsies were considered positive when Gleason ≥3+3. Results: A total of 156 men had 258 lesions for which they underwent MRI/US fusion-guided biopsies in the Intermountain Healthcare system from 2016 to 2020. The PCa detection rate for PIRADSv2 category 1-2 was 29.8%, category 3 32.6%, and category 4-5 37.6%. PIRADS v2 category 1, 2, 3, 4, and 5 yielded any PCa in 25, 15.9, 23.8, 53.1, and 66.7%, respectively (Table). PIRADS v2 category 1-2, 3, and 4-5 yielded any PCa in 16.8%, 23.8%, and 57.7%, respectively. Conclusions: PI-RADS v2 categories generally correlate with PCa detection rates, however, to avoid biopsy, the test must be both sensitive and specific, with low false negative rates. In our institution, we show that PI-RADS 1, 2, and 3 do not rule out the presence of PCa, and therefore should not be used as the sole factor in determining the need for prostate lesion biopsy. [Table: see text]
Predicting prostate cancer death among 98,994 veterans: Differences by race/ethnicity.
Authors: Janet Tate , Danciu Ioana , Justice Amy , Leapman Michael , McMahon Benjamin , Wadia Roxanne
Published: May 2020

e17609

Background: Prostate cancer mortality is higher in Blacks than Whites, but existing prognostic indices fail to account for race/ethnicity. Using data from the national U.S. Veterans Affairs Healthcare System (VA), we compared prediction of prostate cancer death by race/ethnicity. Methods: Men with biopsy confirmed prostate cancer from 2002-2016 were included. We excluded those with lymph node or distant metastatic disease at diagnosis and those not classified as Non-Hispanic White (NHW), Non-Hispanic Black (NHB), or Hispanic (HSP). We set aside 20% for future validation. Cox models estimated hazard ratios (HR) for prostate cancer death, stratified by age and race/ethnicity. Each was adjusted for age, Gleason score, tumor (T) stage, PSA at diagnosis, and calendar year. Results: Among 98,994 veterans with localized disease, 64% were NHW, 30% were NHB, and 6% were HSP. At diagnosis, median age differed by race/ethnicity (NHW 66 [IQR 62-71] yrs.; NHB 63 [58-68] yrs.; HSP 66 [61-73] yrs.). During follow-up 23,316 men died, 3484 (15% overall, and by race/ethnicity) by prostate cancer. Among those < 65 yrs at diagnosis, HR for Gleason score were much stronger among NHW than NHB; associations for PSA level were stronger among NHB than NHW. HRs for HSP and NHW were similar. T stage HRs were similar by age and race/ethnicity. Conclusions: Risk associated with Gleason score and PSA varied by age and race/ethnicity. Prognostic models for prostate cancer disease progression must be evaluated in diverse populations and across age strata. [Table: see text]
Pattern of disease in recurrent cervical cancer associated with response to pembrolizumab.
Authors: Miller Kathryn , Filippova Olga T. , Hayes Sara A. , Abu-Rustum Nadeem , Aghajanian Carol , Broach Vance , Ellenson Lora H , Jewell Elizabeth Lin , Kyi Chrisann , Lakhman Yulia , Mueller Jennifer Jean , O'Cearbhaill Roisin Eilish , Park Kay J. , Sonoda Yukio , Zamarin Dmitriy , Leitao Mario M. , Friedman Claire Frances
Published: May 2020

e18006

Background: Pembrolizumab received accelerated FDA approval for treatment of metastatic or recurrent PD-L1 positive cervical cancer in 6/2018. Since then, the clinical characteristics of patients who best respond to this immunotherapy have remained undefined. We sought to describe patients with advanced cervical cancer who derived durable clinical benefit (DCB) from pembrolizumab therapy. Methods: Patients with advanced or recurrent cervical cancer who received pembrolizumab from 8/2017-12/2019 at our institution were assessed. Reviewed data included patient demographics, treatment history, baseline pattern of metastatic disease at initiation of anti-PD-1 treatment, and outcomes. Kaplan-Meier survival analysis was performed to determine progression-free survival (PFS). Treatment response was evaluated by computed tomography using RECIST 1.1 criteria. Results: 14 patients with recurrent cervical cancer received pembrolizumab. Median age was 55 years (range, 21-76); 79% (n = 11) had squamous cell carcinoma (SCC). The 3 non-SCC histologies included endocervical adenocarcinoma, high-grade endometroid adenocarcinoma, and mesonephric adenocarcinoma. 93% (n = 13) expressed PD-L1; 1 patient whose tumor was MSI-H did not undergo PD-L1 testing. 93% (n = 13) had received prior radiation, and 86% (n = 12) had received 1 or more prior lines of chemotherapy. Median duration of treatment was 4.9 months (range, 1.4-15.2), and median follow-up was 7.9 months (range, 2.1-29.9). On RECIST review, the overall response rate was 21% (n = 3), including 2 partial responses and 1 complete response. Two patients (14%) had stable disease of ≥6 months for an observed DCB of 36%. Of the 5 patients with DCB, 4 remain on pembrolizumab, with observed antitumor activity of up to 15.4 months. On univariable analysis, a lymph node and/or lung only baseline pattern of metastasis was associated with improved response to pembrolizumab (n = 7, P= 0.02). On survival analysis, patients with lymph node and/or lung pattern of disease had a 6-month PFS rate of 86%, compared to a 6-month PFS rate of 0% in patients with visceral or multi-site disease ( P< 0.001). Conclusions: Pembrolizumab showed promising activity in our patient cohort, with a DCB rate of 33%. Patients with lymph node and/or lung only patterns of metastasis at baseline had the greatest radiologic response compared to patients with visceral or multi-site disease. Our results suggest that there may be an underlying pathophysiology of metastatic patterns that confer improved response to anti-PD-1 therapy in advanced cervical cancer.
Effect of the oral CXCR4 inhibitor X4-136 on tumor control and side effects in cervical cancer treated with radiotherapy and concurrent chemotherapy.
Authors: Chaudary Naz , Hill Richard (Dick) P , Kelley Lynne , Milosevic Michael F.
Published: May 2020

e18010

Background: Cervical cancer is a global health problem. Despite scale up of prevention programs, there will be an ongoing need to improve the effectiveness of radiotherapy/cisplatin (RTCT) for women with established, locally advanced disease. We have shown that RTCT with the CXCR4 inhibitor plerixafor improves tumor control, reduces metastases and reduces RT-related side effects compared to RTCT alone. X4-136 is an oral CXCR4 inhibitor that is better suited to long-term, once daily use. In this study we examined: 1. The efficacy of RTCT and X4-136 in cervical cancer; 2. Biomarkers of response to RTCT and X4-136; and 3. Effects of RTCT and X4-136 on intestinal toxicity, an important dose-limiting RT side effect in these patients. Methods: Orthotopic cervical cancer xenografts derived from our patients were treated with RT (30 Gy; 2 Gy/day) and cisplatin (4 mg/kg/week ip) with or without concurrent X4-136 (100 mg/kg/day orally) for 3 weeks. Mice were sacrificed immediately after treatment for biomarker assessment. In separate experiments, mice had CT imaging weekly after treatment to evaluate tumor response. Acute and late intestinal toxicity was assessed histologically 3.5 and 90 days after treatment respectively. Results: RTCT alone increased CXCL12/CXCR4 signaling, intratumoral accumulation of myeloid cells and PD-L1 expression. The addition of X4-136 during RTCT abrogated these effects and improved tumor response in 2 cervical cancer models. Furthermore, the addition of X4-136 increased the proportion of surviving intestinal crypt cells in keeping with a reduction in acute RT toxicity, and reduced late histologic changes of late RT toxicity. Conclusions: The addition of X4-136 blunts RTCT-induced upregulation of the CXCL12/CXCR4 pathway, reduces intratumoral myeloid cells, improves tumor control and reduces side effects in cervical cancer. Few if any pharmacologic strategies have been identified previously that expand the therapeutic window with RT in this way. The combination of RTCT and CXCR4 inhibition warrants testing in clinical trials to validate these findings. These benefits may apply to other tumors where RTCT plays a curative role.
Ozone therapy as accompanying treatment for chemoradiotherapy in patients with locally advanced cervical cancer.
Authors: Rodionova Olga G. , Gusareva Marina A. , Voshedskiy Vitaliy I. , Vasilyeva Ekaterina O. , Sheiko Elena A. , Solntseva Anna A. , Sakun Pavel G. , Vlasov Stanislav G. , Museyko Ksenia N. , Pustovalova Alla V. , Chalabova Tatiana G. , Kit Oleg I.
Published: May 2020

e18030

Background: Chemoradiation therapy (CRT) radiomodified with platinum-based drugs is recommended for patients with inoperable cervical cancer. However, the introduction of chemotherapy medicines increases the number of hematological and non-hematological complications. Prolonged RT significantly decreases survival of patients. This requires more effective methods helping to prevent chemoradiotherapy complications. The purpose of the study was to evaluate the effectiveness of ozone therapy as an accompanying treatment for chemoradiotherapy for cervical cancer (CC). Methods: The study included 20 patients diagnosed with cT3NхM0 CC. The control group (n = 10) received standard CRT with weekly cisplatin radiomodification (40 mg/m2). The main group (n = 10) received CRT with weekly cisplatin radiomodification (40 mg/m2) and additional infusions of 250 ml ozonized solution of 0.9% sodium chloride (a total of 15 infusions). Results: In the main group, CRT did not cause a significant aggravation of gastrointestinal and general symptoms, compared with the initial state. The rate of dyspeptic disorders (nausea, diarrhea, bloating) was 10% in the main group and 100% in controls. In the control group, clinical pain decreased only by the 25th day; 100% of patients developed gastrointestinal toxicity grade 1 (80%) and 2 (20%); 100% of patients complained of weakness during treatment. 7 patients developed leukopenia. Anemia in 5 patients remained at the level of 95g/L, in 3 patients - aggravation up to 80g/L. In the main group, treatment was completed within 7 weeks. In the control group, the duration of CRT was 8 weeks due to toxicity. Conclusions: Ozone therapy in addition to the conventional conservative treatment significantly decreases the severity of CRT-induced complications which allows complete treatment planned, while maintaining optimal treatment duration.
Recurrent vulvar squamous cell carcinoma: An analysis of clinical outcomes by treatment modality including surgery, chemotherapy, and radiation.
Authors: Dinh Trish , Andrews Wright Natalie , Iyer Hari , Weberpals Johanne I
Published: May 2020

e18033

Background: Recurrent VSCC carries a poor prognosis, but real-world data on outcomes with standard treatment options are lacking. Specifically, progression free survival (PFS) in recurrent VSCC is ill-defined which is problematic for the design of clinical trials with novel therapies. We aim to address the paucity of outcome data in recurrent VSCC and to compare PFS and overall survival (OS) in patients (pts) undergoing surgery, chemotherapy, radiotherapy or a combination of these treatments. Methods: A retrospective chart review identified 246 pts from 2000-2018 diagnosed with VSCC treated at the Ottawa Hospital Cancer Center and 61 pts with recurrent disease. Data collected included patient demographics, tumour characteristics, recurrence pattern, and treatment modality (surgery only, surgery with chemotherapy, surgery with radiation, surgery with chemoradiation, chemoradiation only, chemotherapy only, or radiation only). Descriptive statistical analysis is reported. Results: Among all study pts, the stage distribution was stage I: 28%, II: 19%, III: 43% and IV: 10%. 61% of pts had one recurrence, 36% had two recurrences, and 3% had three recurrences. The 5-year survival rate was 78% for non-recurrent VSCC vs. 33% for recurrent cases. The median OS for all recurrent and non-recurrent cases was 3.7 years and 13.5 years, respectively. For primary treatment, 87% underwent surgical treatment, of which 60% also had radiation or chemoradiation. The most common treatments for first recurrence were: surgery (25%), radiation (20%), no treatment (16%) and chemotherapy (14%), and for second recurrence: no treatment (50%), radiation (25%), surgery (17%) and chemotherapy (8%). The median PFS after primary treatment and after first and second recurrences were 8.7, 5.3 and 1.4 months (mo), respectively, with no significant difference between treatment regimens. However, when grouped (surgery with or without chemotherapy, radiation or chemoradiation vs. non-surgical management), there was a significant PFS benefit for surgical (15.6 mo) over non-surgical management (0.7 mo) in the treatment of a second recurrence (p = 0.05). Conclusions: At our centre, surgery and radiation have been the mainstay of treatment for recurrent VSCC with particular advantage of surgery in the treatment of a second recurrence. Our study establishes a baseline for VSCC outcomes following standard treatment. Accurate PFS data is an important outcome for the design of future studies in recurrent VSCC with new drug therapies.
A CD3 x FRα T-cell engaging bispecific antibody for efficient killing of ovarian cancer cells with minimal cytokine release.
Authors: Buelow Ben , Avanzino Brian , Balasubramani Aarti , Boudreau Andrew , Davison Laura , Ganesan Priya , Harris Katherine , Hartstein Sharon , Malik-Chaudhry Harbani , Pham Duy , Prabhakar Kirthana , Rangaswamy Udaya , Saiganesh Sowmya , Schellenberger Ute , Ugamraj Harshad , Kehm Hannes , Trinklein Nathan , Iyer Suhasini
Published: May 2020

e18050

Background: Ovarian Cancer (OvCa) is the leading cause of gynecologic cancer mortality in women. Since the introduction of platinum-based chemotherapy there has been little change in the prognosis of OvCa patients, with < 30% overall survival in advanced disease, creating an urgent medical need for novel therapies. Few ovarian epithelium-specific surface proteins are suited for Ab targeting. However, studies have shown folate receptor α (FRα) to be highly over-expressed in OvCa; expression level and stage correlate, and FRα is absent or minimally expressed in normal tissues. However, naked Ab therapy has shown limited efficacy while CAR-T therapy has been plagued by toxicity and limited efficacy. ADCs have demonstrated some activity but present the risk of toxin-mediated side effects. Using Teneobio’s unique antibody discovery platform, we have developed a CD3 x FRα T-BsAb that retains the potent cytotoxicity of other T-cell redirecting therapies but with significantly reduced cytokine release. Methods: Antibodies targeting CD3 and FRα were generated via immunization of our proprietary transgenic animals. Candidate antibodies were selected by repertoire deep sequencing of B-cells from draining lymph nodes, high-throughput gene assembly, recombinant expression, and functional screening. Bispecific antibodies targeting CD3 and FRα were assembled and evaluated for their ability to selectively activate primary human T-cells and mediate killing of FRα+ tumor cells in vitro and in vivo. T-cell activation surface markers, cytokine production and tumor cell cytotoxicity were measured. Results: Primary human T-cells were activated only in the presence of both the CD3 x FRα T-BsAb and FRα (either recombinant or cell-surface protein). Potent and selective cytotoxicity against FRα+ tumor cells was observed in co-cultures of primary human T-cells and OvCa tumor cell lines. Strikingly, our T-BsAb mediated comparable tumor cell cytotoxicity to CD3 x FRα T-BsAbs containing a high affinity anti-CD3 domain but with significantly reduced cytokine production. Our Ab showed preliminary evidence of tumor growth inhibition in xenograft models of OvCa in vivo. Conclusions: We have created a novel CD3 x FRα T-BsAb that mediates T-cell killing of FRα+ tumor cells with minimal production of cytokines. This molecule may improve safety, efficacy, and offer opportunities for combination therapy to treat OvCa.
FSCN1 as prognostic marker in borderline tumors of the ovary.
Authors: El-Balat Ahmed , Holtrich Uwe , Karn Thomas , Becker Sven
Published: May 2020

e18061

Background: Risk factors for invasive recurrence of borderline tumours (BOT) of the ovary are needed. The actin-bundling protein Fascin-1 (FSCN1) is involved in alteration of adhesion and cell motility and has been associated with invasion and metastasis in different cancers. Methods: We studied a retrospective cohort of 124 bordeline tumors of the ovary (BOT) with validated diagnosis by an independent pathologist for expression of FSCN1 as potential prognostic biomarker. Results: We found strong expression of the actin-bundling protein FSCN1 in 62 of these tumors. FSCN1 positive patients were slightly younger (46.9±2.2 vs. 53.3±2.3 years, P = 0.049). Expression of FSCN1 was more frequently detected in BOT with serous compared to mucinous histotype (58/78 [74.4%] vs. 3/41 [7.3%], p < 0.001), and in cases with micropapillary pattern (25/28 [89.3%] vs. 38/98 [38.8%], P < 0.001). In addition, a non significant trend was observed for more frequent expression of FSCN1 among cases with implants (8/10 [80.0%] vs. 55/116 [47.4%], P = 0.095). When we compared progression free survival of the patients we found numerical lower but not statistically significant PFS rates of 90.5±6.4% vs. 94.4±5.4% for 10 years, and 81.4±10.3% vs. 94.4±5.4% for 15 years, in BOT with FSCN1 expression compared to those tumors negative for FSCN1, respectively. Conclusions: Our analysis suggests an association of FSCN1 expression in BOT with micropapillary pattern and implants, which have been linked to inferior prognosis. Cases with FSCN1 expression in our cohort displayed numerical lower PFS rates prompting further studies of this marker.