bluuebunny/crossref_metadata_2025_split huggingface dataset:
SPOP mutation as a predictive marker for treatment of metastatic castration-resistant prostate cancer.
Authors: Stangl Andrew , Willner Christopher , Maahs Lucas , Burmeister Charlotte , Hwang Clara , Pilling Amanda 
Published: March 2021

160 Background: Predictive markers linking molecular background to treatment response and clinical outcomes are currently lacking in prostate cancer. Missense mutations in SPOP (speckle-type POZ protein) define a distinct molecular subtype, occurring in about 12% of both clinically localized and metastatic disease. SPOP mutations occur early in prostate tumorigenesis and facilitate dysregulation of the androgen-receptor (AR) signaling network, suggesting mutant SPOP can impact response to AR-directed therapies. We hypothesized that SPOP mutation will be associated with superior response to next-generation AR inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Methods: This is a retrospective study to evaluate patients who progressed to mCRPC and were treated with AR-targeted therapy (i.e. enzalutamide, abiraterone acetate). Eligibility criteria inlcuded androgen deprivation therapy, metastatic disease documented by bone lesion or soft tissue identified on imaging, castrate testosterone level ( < 50g/dL), and evaluable tissue for DNA analysis. SPOP status was determined by next-generation sequencing. Time to PSA progression (PSA TTP) was defined per PCWG2 as PSA increase of 25% from nadir and a minimum of 2 ng/ml calculated from date of primary treatment initiation to the date of PSA progression. Overall survival (OS) was calculated from start of treatment to date of death. Statisitcal comparision of the SPOP mutant or wild-type was determined using Kaplan-Meier and independent t-test analysis. Results: The analysis included 69 men with mCRPC with previous or ongoing ADT and receipt of AR-directed therapy (aberaterone acetate, enzalutamide). SPOP status was determined for all patients: 7 patients SPOP mutant, 62 patients SPOP wild-type. Mutant SPOP was associated with significantly longer PSA TTP (22.5 vs. 9.7 months, p = 0.031) and improved OS (21 vs. 29 months, p = 0.12) with enzalutamide or abiraterone as compared to SPOP wild-type patients. Conclusions: Our data demonstrate that SPOP mutations predict for better outcomes with next-generation AR inhibitors in men with mCRPC. SPOP mutations are a prominent molecular sub-type with potential to impact clinical management in men with metastatic, therapy resistant prostate cancer.
Clinically advanced penile (pSCC) and male urethral (uSCC) squamous cell carcinoma: A comparative genomic profiling (CGP) study.
Authors: Spiess Philippe E. , Mata Douglas A , Bratslavsky Gennady , Jacob Joseph M , Necchi Andrea , Gjoerup Ole , Danziger Natalie , Lin Douglas I. , Decker Brennan James , Sokol Ethan , Huang Richard , Ross Jeffrey S. 
Published: March 2021

2 Background: Although SCC of the penile skin (pSCC) and the male urethral surface epithelium (uSCC) arise in nearby locations and can feature similar histology, their clinical manifestations, disease course, and surgical and medical treatment options are distinct. We performed CGP on pSCC and uSCC to examine genomic profiles differences. Methods: Tissues obtained from men with clinically advanced pSCC (n = 230) and uSCC (n = 17) underwent hybrid capture-based CGP to evaluate all classes of genomic alterations (GAs). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: The median ages were similar in both groups. pSCC exhibited a slightly higher frequency of HPV-16/18 infection (29% vs. 12%, P = .16), although the TP53 mutation frequencies were nearly identical (55% vs. 59%, NS). CDKN2A inactivation (P = .08), CCND1 amplification trending higher and TERT promoter mutations (P = .01) were more frequent in pSCC, potentially indicating prior HPV infection. GAs in NOTCH1 were exclusively identified in pSCC. Potentially actionable GAs identified in both groups included PIK3CA activating mutations (TKIs) as well as pathogenic alterations in FBXW7 and PTEN (MTOR inhibitors). Rare BRCA1 and BRCA2 inactivation (PARP inhibitors) was seen in pSCC only. High-positive PD-L1 staining was elevated in pSCC (34 vs. 14%, P = .06). Although average TMB was similar in both groups, pSCC exhibited an elevated frequency of cases with CD274 ( PD-L1) amplification as well as TMB >10 mut/Mb which are on label for immune checkpoint inhibitor (ICPI) treatment. Conclusions: CGP of pSCC and uSCC identifies opportunities for both targeted and ICPI therapies. Compared to uSCC, pSCC had genomic features more similar to head and neck SCC including slightly increased cell-cycle perturbation, HPV infection, and NOTCH pathway signaling alterations. Further use of CGP in the treatment planning for pSCC and uSCC may be warranted. [Table: see text]
The impact of telemedicine on patient-reported outcomes in urologic oncology.
Authors: Gadzinski Adam John , Abarro Isabelle O. , Stewart Blair , Gore John L. 
Published: March 2021

200 Background: Nearly 20% of Americans live in rural communities. These individuals face barriers to accessing cancer care, including prevalent poverty and substantial travel burden to seeing cancer providers. We aimed to assess the impact of a rurally focused telemedicine program on patient outcomes in our urologic oncology outpatient clinic. Methods: We prospectively identified patients from rural Washington State, or who lived outside Washington, with a known or suspected urological malignancy being evaluated at the University of Washington Urology Clinic via an in person clinic or a telemedicine appointment. Patients were invited to complete a post-visit survey that assessed satisfaction, travel time, costs, and work absenteeism. We compared patient-reported outcomes between those seen as in-person versus telemedicine visits. Results: We invited 1453 eligible patients from August 2019–July 2020 to participate; 615 patients (42%) completed the survey. 198 patients had in person visits and 417 had telemedicine visits. Median age was 68, 89% were male, and 73% were white. 525 patients (85%) were from Washington; the remainder resided out-of-state. Patients were being evaluated for prostate cancer (62%), kidney cancer (14%), urothelial cancer (22%), and testis cancer (2%). Patient-reported outcomes are displayed in Table. Twenty-two patients coming for in-person visits (11%) paid ≥ $1000 in total travel costs. No differences were noted in patient satisfaction between in-person and telemedicine visit types. Conclusions: Patients traveling to our clinic from out-of-state and rural Washington incur significant travel time, costs, and time away from work to receive outpatient urologic cancer care. Telemedicine provides a medium for cancer care delivery that eliminates the significant travel burden associated with in-person clinic appointments. [Table: see text]
Effect of healthcare system on prostate cancer-specific mortality in African American and non-Hispanic white men.
Authors: Klebaner Daniella , Courtney Patrick Travis , Rose Brent S. 
Published: March 2021

23 Background: Disparities in prostate cancer-specific mortality (PCSM) between African American and non-Hispanic White (White) patients have been attributed to biological differences; however, recent data suggest poorer outcomes may be related to barriers to medical care from the healthcare system in which patients receive care. We sought to evaluate potential drivers of disparities by comparing outcomes between African American and White men in the Surveillance, Epidemiology and End Results (SEER) national cancer registry and a relatively equal-access healthcare system, the Veterans Health Administration (VHA). Methods: We identified African American and White patients diagnosed with prostate cancer between 2004-2015 in the SEER and VHA databases. We analyzed metastatic disease at diagnosis with multivariable logistic regression, and PCSM with cumulative incidence analysis and sequential competing-risks regression adjusting for disease and sociodemographic factors. Results: The SEER cohort included 306,609 men (57,994 [18.9%] African American and 248,615 [81.1%] White) with a median follow-up of 5.3 years (interquartile range [IQR] 2.6-8.1 years), and the VHA cohort included 90,749 men (27,412 [30.2%] African American and 63,337 [69.8%] White) with a median follow-up of 4.7 years (IQR 2.4-7.6 years). In SEER, African American men were significantly more likely to present with metastatic disease (African American 4.3% versus White 3.0%, p< 0.001; multivariable odds ratio [OR] 1.25, 95% confidence interval [CI] 1.19-1.32, p< 0.001), whereas in the VHA, African American men were not significantly more likely to present with metastatic disease (African-American 3.2% versus White 3.3%, p= 0.26; multivariable OR 1.07, 95% CI 0.98-1.17, p= 0.12). In SEER, the 8-year cumulative incidence of PCSM was significantly higher for African American compared with White men (6.9% versus 5.1%, p< 0.001), whereas in the VHA, African American compared with White men did not have a significantly higher 8-year cumulative incidence of PCSM (5.5% versus 5.4%, p= 0.93). African American race was significantly associated with an increased risk of PCSM in SEER (univariable subdistribution hazard ratio [SHR] 1.39, 95% CI 1.33-1.45, p< 0.001), but was not significantly associated with PCSM on uni- and multivariable regression in the VHA. When adjusted for disease characteristics at diagnosis in SEER, disease extent, PSA, and Gleason score contributed to 85% of the risk of PCSM for African American men (adjusted SHR 1.06, 95% CI 1.02-1.12, p= 0.008). Conclusions: Racial disparities in PCSM were present in a national cohort, SEER, but not as pronounced in a relatively equal-access healthcare system, the VHA, potentially due to differences in metastatic disease at diagnosis among African American and White men between cohorts. These findings may be attributable to reduced barriers to care in the VHA.
Cell cycle progression score and PTEN as prognostic factors for metastasis in intermediate- and high-risk prostate cancer overall, and in those who also received salvage radiotherapy.
Authors: Trock Bruce J. , Rajamani Saradha , Vidal Igor , Glavaris Stephanie , Jones Tracy , Han Misop , Partin Alan W. , Cohen Todd , Stone Steven , De Marzo Angelo M 
Published: March 2021

247 Background: The cell cycle progression (CCP) score and PTEN have never been evaluated together as prognostic markers for risk of metastasis in a radical prostatectomy (RP) cohort of men with National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa), nor in such patients who also received salvage radiation (SRT) alone or with androgen deprivation (SRT+ADT). This study evaluated CCP score and PTEN in both settings. Methods: Participants were treated with RP at Johns Hopkins from 2007-2015. Paraffin-embedded RP tissue was analyzed blind to clinical outcome at Myriad Genetics, for CCP score using qRT-PCR, and PTEN by immunohistochemistry. For overall evaluation of CCP and PTEN in intermediate- and high-risk men a case-cohort sample was selected. Intermediate- and high-risk men with biochemical recurrence who received SRT or SRT+ADT were also sampled to provide a population at particularly high risk. Metastasis-free survival (MFS) was analyzed with the proportional hazards model, weighted for case-cohort design for the overall analysis, and adjusted for CAPRA-S. The clinical cell-cycle risk (CCR) score, a fixed algorithm combining CCP and CAPRA-S was also analyzed in both contexts. Data were analyzed independently by Johns Hopkins and Myriad Genetics. Results: The case-cohort consisted of 209 men, including 47% with Gleason score >4+3, 48% extra-prostatic extension, and 18% with seminal vesicle or lymph node involvement; 42 (20%) developed metastasis. In univariate analyses CCP, CAPRA-S, and PTEN were all highly significant. In multivariable analysis, only CCP and CAPRA-S retained significance (Table section A). CCR was also strongly prognostic, HR=7.9 (95% CI 4.4, 14.5) per unit change, p<0.00001. SRT (56%) or SRT+ADT (44%) were received by 172 men, of whom 78% had Gleason >4+3, 48% extra-prostatic extension, and 34% seminal vesicle or lymph node involvement; 19 (11%) developed metastases. Again, CCP and CAPRA-S, but not PTEN, were statistically significant (Table section B). CCR was also statistically significant, HR=1.7 (95% CI 1.2, 2.4), p=0.002. Conclusions: This is the first comparison, in a recent cohort of intermediate- and high-risk men, of CCP score and PTEN as risk factors for metastasis, and first evaluation in such men receiving SRT. In both multivariable settings, CCP score, but not PTEN, was significantly associated with MFS, adjusted for CAPRA-S. CCR, a fixed algorithm that combines CCP and CAPRA-S was also significant in both settings. [Table: see text]
Barriers and facilitators of germline genetic evaluation for prostate cancer.
Authors: Loeb Stacy , Li Randall , Sanchez Nolasco Tatiana , Byrne Nataliya , Cheng Heather H. , Leader Amy , Giri Veda N. 
Published: March 2021

28 Background: Genetic counseling and germline testing have an increasingly important role for patients with prostate cancer, with the recent approval of precision therapeutic options and implications for cancer screening in families. Although current guidelines recommend germline genetic evaluation for all men with metastatic prostate cancer and some with localized disease, recent data suggests it is underutilized. Our objective was to perform a qualitative study of barriers and facilitators of genetic counseling and germline genetic testing among physicians who manage prostate cancer. Methods: We conducted semi-structured interviews with medical oncologists, radiation oncologists, and urologists from different U.S. practice settings until thematic saturation was achieved at n = 14. The interview guide was based on the Tailored Implementation in Chronic Diseases Framework to identify key determinants of practice. Interview transcripts were independently coded by ≥2 investigators using a constant comparative method. Disagreements were resolved by team discussion. NVivo12 was used for data organization and analysis. Results: The decision to perform or refer for germline genetic evaluation is affected by factors at multiple levels (Table). Although patient factors play a role in some cases (e.g., refusal of testing for specific reasons), the dominant themes in the decision to conduct germline genetic evaluation were primarily at the physician and organizational level. Physician knowledge of prostate cancer genetics, coordination of care between providers, perceptions of the guidelines for genetic testing, and concerns about cost were most frequently discussed as the main factors affecting utilization of germline genetic evaluation. Conclusions: There are currently numerous barriers to the performance of germline genetic evaluation for prostate cancer. Efforts to expand physician education and to facilitate coordination of care surrounding genetic evaluation are important to promote guideline-concordant care. [Table: see text]
Cabozantinib versus other TKIs after CPI treatment in the real-world management of patients with metastatic renal cell carcinoma (mRCC).
Authors: Marteau Florence , Harrow Brooke , McCarthy Christine , Wallace Joel , Monnette Alisha , Wang Yunfei , Doshi Gurjyot K. 
Published: March 2021

293 Background: Checkpoint inhibitors (CPIs) are a treatment option for patients with metastatic renal cell carcinoma (mRCC), but there is limited clinical data on the efficacy of targeted therapies following CPI treatment. Cabozantinib is a tyrosine kinase inhibitor (TKI) that targets multiple receptor kinases implicated in tumorigenesis. In the US, cabozantinib is approved for use in patients with advanced RCC including after CPI treatment. Methods: This retrospective observational cohort study (NCT04353765) evaluated outcomes associated with cabozantinib or other TKIs (axitinib, lenvatinib, pazopanib, sorafenib, sunitinib) in patients with mRCC following CPI treatment. Eligible patients initiated TKI therapy between May 1, 2016 and Sep 31, 2019 and had received a CPI as their last systemic treatment prior to TKI therapy. Patients were identified from the US Oncology Network iKnowMed electronic health record database through structured queries and a targeted chart review. The following real-world outcomes were assessed: 6-month response rate (RR6months; primary); overall response rate (ORR); overall survival (OS); time to treatment discontinuation (TTD); rates of dose reductions, and discontinuation due to adverse events (AEs). The p value for RR6months was used to test for non-inferiority. Results: Eligible patients ( n = 247) had a mean (SD) age of 65.9 (10.5) years and 74.1% were male; 75.7% ( n = 187) received cabozantinib and 24.3% ( n = 60) received other TKIs. All patients had intermediate or poor MSKCC score; more poor-risk patients received cabozantinib than other TKIs (28.9% vs 20%). Outcomes data are shown in the Table. Compared with other TKIs, cabozantinib was associated with a significantly higher RR6months and ORR, and TTD was twice as long with cabozantinib. Discontinuation due to AEs was more frequent with other TKIs than with cabozantinib, although this was not statistically significant; 21.7% of discontinuations occurred during the first 3 months of treatment. AEs leading to discontinuation were consistent with the known safety profile of the products. Conclusions: In this mRCC population receiving routine care in the US, cabozantinib was used more frequently than other TKIs after CPI treatment. Cabozantinib was an effective and well tolerated option post-CPI, with a high response rate in the real-world setting.abozantinib was associated with a significantly higher response rate and a lower discontinuation rate due to AEs; TTD was double that of other TKIs. [Table: see text]
Axitinib and avelumab (AA) as first-line treatment of metastatic renal cell carcinoma (mRCC): A real-world outcome review in the Northwest of England, United Kingdom.
Authors: Allison Jennifer , Charnley Natalie , Stevenson Robert , Waddell Tom , Pillai Manon Rhys 
Published: March 2021

294 Background: The combination of the immune checkpoint inhibitor avelumab and VEGF-targeted, antiangiogenic tyrosine kinase inhibitor axitinib (AA) has demonstrated superior PFS and ORR compared to sunitinib in patients with mRCC and is an option for first line treatment across all IMDC risk scores. In this retrospective review we report our real world experience of this combination in three cancer centres in the Northwest of England. Methods: Treatment naïve mRCC patients receiving AA through the Early Access to Medicine Scheme at 3 cancer sites in the UK between May 2019 and July 2020 were identified. Primary outcomes of interest include overall response rate (ORR), adverse events (AEs) and preliminary survival observations. Results: A total of 44 patients were identified with a median follow up of 6.9 months (0.8-13.5 mo). Median age was 68 (48-81); 68% were male. The patients’ adult comorbidity evaluation score (ACE-27) was calculated: 0 = 43%, 1 = 30%, 2 = 7% and 3 = 20% . 45%, 48% and 7% of patients had favourable (F), intermediate (I) and poor (P) IMDC risk scores respectively. All had clear cell histology with 16% demonstrating sarcomatoid change. Most patients had undergone a nephrectomy (70%) and 36% had a single organ site of metastatic disease. ORR in the whole cohort was 60% (CR 5%, PR 55%, SD 25%, PD 2%, NE 13 %). Median time to first response was 2.6 months (0.6- 8.2mo). At time of data cut-off, 64% of patients remain on treatment (80% F, 48% I and 67% P). 14% of patients discontinued treatment due to disease progression while 22% stopped due to toxicity. The majority of patients (68%) continued axitinib at the starting dose of 5mg BD. Dose escalation of axitinib was possible in 9% patients while 23% needed a dose reduction due to toxicities. AEs were observed in 36 (82%) patients (G3 36%); the commonest being mucositis 30%; hypertension 23% (G3 11%); fatigue 25%; thyroid dysfunction 18%; diarrhoea 20% (G3 5%); hepatitis 20% (G3 11%). 9% of patients experienced an infusion reaction to avelumab. Overall, 9 (20%) patients received steroids for suspected immune related adverse events (irAEs); 6 (14%) were managed as G3≤ irAEs. 9 (20%) patients required inpatient admission due to AEs; 5 (11%) were associated with irAEs. Of the patients who discontinued AA treatment, 50% received subsequent therapy (12.5%, 75% and 12.5% receiving combination checkpoint inhibitor therapy, other VEFG TKi and TKi/MTOR combination respectively). 4 patients remain on active surveillance with no evidence of progression. Conclusions: Our early experience of AA in this real world setting reports comparable clinical responses to the published data. Treatment is well tolerated, with lower than expected levels of G3 or above AEs which is reassuring in a non-trial selected population. Follow-up is ongoing and updated efficacy and safety outcomes will be presented.
Feasibility study of gallium-68 citrate PET as a bone-tropic imaging biomarker in mCRPC.
Authors: de Kouchkovsky Ivan , Behr Spencer , Zhang Li , Foye Adam , Vanbrocklin Henry , Small Eric Jay , Feng Felix Y , Friedlander Terence W. , Li Patricia , Frey Natalie , Chung Andy , Lui Austin , Subramanian Aishwarya , Rodvelt Tammy J. , Barlesi Brigid , Evans Michael , Aggarwal Rahul Raj 
Published: March 2021

31 Background: Transferrin receptor (TFRC) expression is controlled by the PI3K and MYC signaling pathways, which are frequently dysregulated in prostate cancer (PC). Gallium-68 citrate (68Ga-citrate) is an iron biomimetic, which can be used to image PC in a TFRC dependent fashion. We performed a single-center pilot imaging study to investigate the use of 68Ga-citrate PET in patients with metastatic castration-resistant PC (mCRPC). Methods: Following written informed consent, mCRPC patients were prospectively enrolled and underwent 68Ga-citrate PET imaging. Optional metastatic tumor biopsies were undertaken at the time of imaging. Results: 34 mCRPC patients underwent 68Ga-citrate PET imaging. The median age was 67.5 years old. Median duration of castration resistance was 17.5 months; 14.7% of patients were post-docetaxel. Median serum PSA was 35.2 ng/dL. A total of 483 lesions were detected on conventional imaging (CT, 99mTc-HDP) or 68Ga-citrate PET, including 420 osseous and 63 soft tissue (nodal and visceral) lesions (Table). 67.3% of all lesions were detected on 68Ga-citrate PET, including 74.5% of all osseous lesions but only 19.0% of all soft tissue lesions (p<0.0001). Eight (1.7%) lesions were detected on 68Ga-citrate PET imaging only. Per-lesion average SUVmax (SUVmax,avg) was 6.7. Metastatic biopsies of PET avid lesions were performed in 20 patients (59%); adenocarcinoma histology was confirmed in 14 (70%) cases, treatment-emergent small cell neuroendocrine cancer (t-SCNC) in 6 (30%). There was no significant difference in SUVmax,avg between patients with adenocarcinoma or t-SCNC (SUVmax,avg 7.3 vs 7.6, respectively; Table). Serial 68Ga-citrate PET perfomed in a patient with biopsy-confirmed t-SCNC after 2 cycles of carboplatin/cabazitaxel demonstrated an early metabolic response (28.5% decrease in average SUVmax) confirmed on subsequent conventional imaging. Conclusions: 68Ga-citrate PET detects mCRPC bone metastases in patients with biopsy-proven prostatic adenocarcinoma or t-SCNC, distinguishing it from lineage dependent agents such as PSMA tracers. Detection of an early metabolic response in the bone of a treated t-SCNC patient was observed. Further prospective studies are ongoing coupling serial Ga-citrate PET with investigational agents targeting the MYC signaling pathway. Clinical trial information: NCT02391025. [Table: see text]