bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular underpinnings of RB status as a biomarker of poor outcome in advanced prostate cancer.
Authors: Mandigo Amy C. , McNair Christopher , Ku Kexin , Pang Angel , Guan Yi Fang , Holst Jeff , Brown Myles , Kelly William Kevin , Knudsen Karen E. 
Published: February 2020

189 Background: There is emergent and compelling evidence to support RB status as a biomarker in advanced prostate cancer. RB loss is strongly associated with poor progression-free, disease-specific, and overall survival in prostate cancer (PCa). Preclinical studies in PCa have revealed RB positive tumors are more responsive to CDK4/6 inhibitors. An ongoing randomized Phase IB/II study of enzalutamide with and without ribociclib in patients with metastatic castration-resistant, chemotherapy naïve PCa has become a pioneer trial to include a positive RB status as inclusion criteria in a PCa study (NCT02555189). Beyond CDK4/6 inhibitors, therapeutic agents that target tumor metabolism have been introduced in the clinic. Current data suggests that RB status may be crucial to understand and predict therapeutic response to these agents within tumors. Methods: The biological significance of RB loss was studied utilizing isogenic model systems and human tumor xenografts of castration resistant prostate cancer (CRPC) with and without RB deletion. The mechanism that drives aggressive tumor phenotypes was identified through comprehensive transcriptomic, cistromic, and metabolomic analysis. Novel functions of RB were identified and the response to clinically-relevant therapeutics was examined. Results: Exclusively in CRPC, RB loss results in significant rewiring of cancer cell metabolism. Functional investigation revealed a causative link between RB loss and antioxidant production sufficient to alter responsiveness to genomic insult and selected chemotherapeutics. Observed changes in response to therapeutic intervention were attributed to RB-dependent modulation of intracellular reactive oxygen species. Conclusions: RB loss is strongly associated with poor outcome in advanced PCa. Molecular investigation identified RB-dependent rewiring of cancer cell metabolism as a significant consequence of RB loss, sufficient to alter response in model systems to therapeutic strategies of clinical relevance. These studies significantly advance understanding of the means by which RB loss enhances lethal tumor phenotypes, and are of relevance for development of RB status as a clinically actionable biomarker.
Impact of 18F-fluciclovine PET on salvage radiotherapy plans for men with post-radical prostatectomy recurrence of prostate cancer.
Authors: Payne Heather Ann ,   FALCON Study Group
Published: February 2020

19 Background: Imaging options to localize lesions in men with biochemical recurrence (BCR) of prostate cancer after radical prostatectomy (RP) are limited, especially at low PSA levels. Consequently, radiation oncologists typically target the prostate bed (PB) with or without pelvic lymph nodes (LN) based on clinical or pathologic features. The FALCON study (NCT02578940) evaluated the clinical benefit of 18F-fluciclovine PET through its impact on management plans for men with BCR. Here, we report the impact on salvage radiotherapy (RT) decisions in men post-RP. Methods: Men with a first BCR episode following curative-intent therapy who were being considered for salvage therapy underwent 18F-fluciclovine PET at one of 6 UK sites. Physicians documented patients’ treatment plans pre- and post-scan. Imaging results and management plans were stratified by prior treatment as determined from patient records. Results: Sixty-five (63%) of the 104 FALCON patients had undergone RP. Of these, 62 (median PSA, 0.32 ng/mL) had a pre-scan plan for salvage RT. Lesions were found in 21 (34%) patients (median PSA, 0.32 ng/mL), of whom 10 (16%; median PSA, 0.54 ng/mL) had extraprostatic findings (Table). Post-scan, 25 (40%) men had a management change, 17 (68%) due to a positive scan. Of the 25 post-scan revisions, 17 (68%) were changes to the treatment modality: 8 to systemic therapy, 8 to watchful waiting, 1 other. A further 8 (32%) men had RT fields modified: PB alone modified to include a boost to a 18F-fluciclovine-avid lesion (n = 7) or whole pelvis field refocused on a smaller area (n = 1). Conclusions: Two fifths of men scheduled to undergo salvage RT after RP had their management plan revised following 18F-fluciclovine PET. The majority of changes involved a completely new treatment modality. Future studies to evaluate the clinical outcomes of such changes are warranted. Clinical trial information: NCT02578940. [Table: see text]
Circulating tumor (ct) DNA-based comprehensive genomic profiling to identify microsatellite instability (MSI) and defective DNA damage repair (DDR) in prostate cancer (PCa) patients.
Authors: Drusbosky Leylah M. , Kiedrowski Lesli Ann , Johnson Kelsey , Nagy Rebecca , Saam Jennifer , Bilen Mehmet Asim , Gupta Niraj K. , Lilly Michael B. 
Published: February 2020

190 Background: Recent trials in PCa have shown efficacy of PARP inhibitors (PARPi) in patients (pts) with mutations in DDR genes such as BRCA1/2 (TOPARP-B, GALAHAD), as well as efficacy of immunotherapy (IO) in PCa pts with MSI. The combination of PARPi + IO is currently being evaluated in the KEYNOTE-365 trial. This analysis explored the utility of ctDNA in identifying PCa pts who may benefit from PARPi, IO, or a combination. Methods: ctDNA-based comprehensive genomic profiling (Guardant360) of 2,165 PCa pts was performed between 10/2018-08/2019. Frequency of pathogenic somatic BRCA1/ 2 mutations and MSI are reported. Results: Out of 2,165 PCa pts tested, Guardant360 identified 24 (1.1%) and 59 (2.7%) pts harboring pathogenic somatic BRCA1 or BRCA2 variants, respectively; MSI was detected in 40 (1.8%) PCa pts. Of the 40 MSI samples, 9 (22.5%) pts also had a somatic pathogenic BRCA1 and/or BRCA2 mutation . One pt harbored pathogenic somatic mutations in both BRCA1 and BRCA2. The variant allele frequency (VAF) for somatic pathogenic BRCA1 (N=2) ranged from 0.2-0.88%, and BRCA2 (N=8) ranged from 0.05-12.4%. There were no BRCA1/2 mutations at VAFs suspicious for germline in MSI PCa pts. A median of 19 genomic alterations (range 8-28) was identified among the 9 pts with pathogenic BRCA1/2 variants. The most frequent co-occurring aberrations were found in TP53, APC, AR, BRCA2, ARID1A, PTEN, RB1, and PIK3CA. An 82yo male with recurrent metastatic PCa underwent Guardant360 testing which identified BRCA2 T3085fs at 7.9% VAF and MSI. He was treated with pembrolizumab for 3 cycles and remains in remission. Another 51yo with MSI was treated with pembrolizumab for 4 cycles. He also remains in remission. Subsequent analysis shows clearance of ctDNA and MSI. Conclusions: ctDNA-based comprehensive genomic profiling can be used to detect PCa pts eligible to receive PARPi, IO, or a combination, improving clinical treatment decision making and pt outcomes, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling. PSA and objective responses to IO have been observed in PCa pts with MSI detected by ctDNA.
Androgen receptor cfDNA longitudinal mutational analysis in metastatic castrate-resistant prostate cancer.
Authors: Ledet Elisa Marie , Cotogno Patrick , Hatton Whitley , Jaeger Ellen , Moses Marcus W. , Manogue Charlotte , Lewis Brian E. , Barata Pedro C. , Sartor A. Oliver , Layton Jodi Lyn 
Published: February 2020

197 Background: Androgen receptor (AR) mutations commonly occur in metastatic castrate resistant prostate cancer (mCRPC). Methods: Circulating tumor DNA (ctDNA) data were obtained from Guardant 360 assays throughout the clinical course of mCRPC patients (pts). Retrospective analysis for any pt with ≥ 3 Guardant assays at least 4 weeks apart were reviewed. Patients must have at least 1 AR mutation or amplification to qualify for inclusion. Statistical analyses, including chi-sq and longitudinal analyses, were conducted. Results: Of the 259 patients with Guardant testing, a total of 88 patients had at least 3 Guardant tests; of these, 59 (67%) had at least one AR alteration. Patients had a median of 4 Guardant assays (range 3-10). Patients with AR amplification, AR mutation or both were identified (23, 20, 16 respectively). The most common and clinically relevant AR mutations found alone or in combination with amplification were T878A (22%), L702H(19%), W742C (19%), and H875Y (10%). These particular functional AR mutations occurred alone in 16 patients. Only 3 patients had neither amplification nor common AR mutation. 17/59 patients were found to have at least one common AR mutation and amplification at some point (on same or different Guardant). One patient had seven different AR mutations with no amplification and two other patients had 3 AR mutations. Remainder of patients had either AR amplification or ≤ 2 alternative mutations. Patients with an AR amplification were 0.1138x (95% Cl 0.0289 - 0.4491) significantly less likely of having a common known functional mutation (p <0.002) at any point. Conclusions: Patients with the most frequently identified known functional AR mutations are less likely to have AR amplification in pts with mCRPC; these common AR mutations have been shown to be associated with resistance to 2nd generation androgen deprivation. Further clinical correlation between treatment regimen and %cfDNA of these and other non-AR driver mutations is planned.
Biomarkers of prolonged time to treatment failure in metastatic castration-resistant prostate cancer patients treated with abiraterone or enzalutamide: A real life patients-based nomogram and web app.
Authors: Silveira Vilbert Maysa Tamara , Pandolfi Natasha Carvalho , Cesca Marcelle Goldner , Calsavara Vinicius Fernando , Corassa Marcelo , Rinck José Augusto , Dettino Aldo A. , Coelho Ricardo Lima , Xerfan Mariana , Oliveira Thiago Bueno 
Published: February 2020

202 Background: Survival outcomes for metastatic castration resistant prostate cancer (mCRPC) patients (pts) have greatly improved following the approval of Docetaxel and abiraterone(Abi)/enzalutamide(Ez). However, it is not clear who is likely to benefit more from these therapies in real life clinical practice. Methods: A retrospective cohort study was performed with mCRPC pts treated with Abi/Ez in pre-Docetaxel setting. Primary endpoint: to identify predictive biomarkers of long time to treatment failure (TTF), develop a nomogram and convert it into a web app. Secondary endpoint: to correlate biomarkers with overall survival (OS). Kaplan Meier survival estimates and Cox Regression models were used for time-to-event analyses. Statistical analysis was made with R software. All statistical tests were two-sided and statistical significance was fixed at 0.05. Results: From May2012 to October2017, 117 pts were assessed, 81 received Abi and 36 Ez. Median follow-up of 21 months (mo), estimated median TTF was 12.8mo (95%CI 9.98-15.7) for the total population. Predictive biomarkers for TTF included in the first nomogram model were time from start of androgen deprivation therapy (tADT) to start of Abi/Ez, pain at baseline, Gleason score, baseline testosterone and lower PSA nadir in castration sensitive prostate cancer (CSPC). The second nomogram model included pain and Gleason plus neutrophil counts, tADT to CRPC and baseline PSA at CRPC. C-index: 0.726 and 0.731 respectively, providing a reliable prediction of long-term benefit with Abi/Ez in this setting. All these characteristics were significantly associated with OS. Conclusions: The two nomogram achieved a good internal validation and can work as a tool to the decision-making process of the best strategy to first-line therapy in mCRPC pts.[Table: see text]
Characterization of Wnt signaling pathway (WSP) aberrations in advanced prostate cancer.
Authors: Ghali Fady , Patel Devin , Jamieson Christina , Parsons J Kellogg , McKay Rana R. 
Published: February 2020

203 Background: Aberrations in Wnt signaling pathway (WSP) are implicated in disease progression and resistance of multiple malignancies including prostate cancer (PCa). We sought to characterize the clinical phenotype and molecular genotype of PCa patients with WSP alterations. Methods: Eligible patients included those with PCa having undergone clinical-grade next generation DNA sequencing of tumor derived from prostate or metastasis tissue. We identified patients with somatic activating mutations in CTNNB1 and RSPO2, or inactivating mutations in APC, RNF43, or ZNRF3. Patient and disease characteristics were collected. Clinical and outcome parameters were associated with WSP mutation status using STATA(V. 13.1, College Station, Texas). Results: A total of 169 patients were identified of whom 29 (18.1%) had a WSP activating mutation. Median age of the overall cohort was 64.85 (IQR 56.77, 70.36). 115 (68.0%) patients had Gleason 8-10 disease, 34 (20.1%) presented with de novo metastatic disease, 85 (50.3%) developed CRPC and 23 (13.6%) developed visceral metastases. Clinical characteristics were similar between biomarker groups. There was no association with the presence of a Wnt activating mutation and RB1, p53, pTEN, or BRCA1/2 alteration. Median time to CRPC was 39.42 (IQR 14.50 – 87.52) and 24.39 (IQR 14.99 – 46.03) months for no-WSP and WSP-aberrant respectively. Median 5-year OS was 83.7% (95% CI 73.0-90.4%) and 79.6% (95% CI 52.9 – 92.2%) months for no-WSP and WSP-aberrant respectively. Table evaluates biomarker status with time to CRPC development and overall survival (OS). Conclusions: We observe that somatic WSP activating mutations are present in 18.1% of patients with mPCa, consist with prior reports. Understanding the clinical significance of WSP alterations is critical to inform treatment strategies in patients with advanced disease.[Table: see text]
The psychological impact of early prostate cancer: A prospective evaluation.
Authors: Dresler Hadas , Keizman Daniel , Sarid David , Oren Debi 
Published: February 2020

210 Background: Early prostate cancer is often considered as being associated with a good prognosis and quality of life. However, early prostate cancer research mainly focus on its medical aspects, rarely considering its psychological impact. We aimed to prospectively analyze the correlation between illness perception, quality of life (QOL) and psychological distress among prostate cancer patients, in comparison to healthy controls. Methods: Early prostate cancer patients and healthy controls were prospectively recruited through convenience sampling. Participants filled questionnaires of demographic, illness perception (IPQ-R), QOL (MOS SF-36) and anxiety and depression (HADS). We compared the illness perception, QOL and psychological distress between patients and healthy controls. Results: 51 early prostate cancer patients and 65 healthy men controls were included. Median age was 69. Patients and healthy participants differed in illness perception ['consequences' (p<.001), 'emotional representations' (p<.001)] and psychological distress (p<.01). There was a correlation between the patient illness perception and QOL (p<.05) and psychological distress (p<.05). Among patients, the correlation between psychological distress and QOL was mediated by illness perception (p<.05), while it was not among controls. Conclusions: Diagnosis of early prostate cancer may have a psychological impact. Among early prostate cancer patients, a correlation may exist between illness perception, and quality of life (QOL) and psychological distress. Our results emphasize the need to identify patient distress and to implement therapeutic interventions also in a disease which usually is associated with a good prognosis.
Cost-effectiveness of upfront therapeutic options in low-volume de novo metastatic hormone-sensitive prostate cancer.
Authors: Parikh Neil Rohit , Chang Eric M. , Nickols Nicholas George , Rettig Matthew , Raldow Ann C. , Steinberg Michael L. , Koontz Bridget F. , Vapiwala Neha , Deville Curtiland , Feng Felix Y , Spratt Daniel Eidelberg , Reiter Robert Evan , Phillips Ryan , Tran Phuoc T. , Kishan Amar Upadhyaya 
Published: February 2020

211 Background: Low-volume de novo metastatic hormone-sensitive prostate cancer (mHSPC) has historically been treated with lifelong androgen deprivation therapy (ADT). Recently, however, the addition of several advanced therapeutic options – radiation therapy (RT) to the primary, advanced hormonal therapy agents such as abiraterone acetate/prednisone (AAP), and chemotherapy – to ADT have been shown to improve survival in low-volume mHSPC. The objective of this study was to compare the cost-effectiveness of treating low-volume mHSPC patients upfront with RT+ADT, AAP+ADT, or docetaxel+ADT. Methods: A Markov-based cost-effectiveness analysis was constructed comparing three treatment strategies for low-volume mHSPC patients: (1) upfront RT+ADT --> salvage AAP+ADT --> salvage docetaxel+ADT; (2) upfront AAP+ADT --> salvage docetaxel+ADT, and (3) upfront docetaxel+ADT --> salvage AAP+ADT. Transition probabilities were calculated using data from STAMPEDE arms C/G/H, COU-AA-301, COU-AA-302, and TAX-327. RT was delivered via five-fraction stereotactic body radiation therapy. The analysis utilized a 10-year time horizon, and a $100,000/quality adjusted life year (QALY) willingness-to-pay threshold. Utilities were extracted from the literature; costs were taken from Medicare fee schedules and VA oral drug contracts. Results: At 10 years, total cost was $140K, $259K, and $189K, with total QALYs of 4.66, 5.03, and 3.72 for strategies (1) upfront RT+ADT, (2) upfront AAP+ADT, and (3) upfront docetaxel+ADT, respectively. Compared to upfront RT+ADT, upfront AAP+ADT was not cost-effective (ICER: $321K/QALY). This result remained unchanged even after modification of various model inputs in 1-way sensitivity analysis. Upfront docetaxel+ADT was both more costly and less effective than upfront RT+ADT (ICER: -$53K/QALY). Conclusions: At 10 years, RT+ADT is cost-effective compared to other advanced systemic therapy options alone, and should be considered as a viable treatment strategy in all patients with a low-burden of metastatic disease. Additional studies are needed to determine whether any benefit exists in combining RT to the primary with upfront advanced systemic therapy.
The effect of androgen deprivation therapy on 68GA-PSMA-tracer uptake in nonmetastatic prostate cancer patients.
Authors: Cem Onal , Guler Ozan Cem , Torun Nese , Reyhan Mehmet , Yapar Ali Fuat 
Published: February 2020

22 Background: To evaluate the effect of neoadjuvant androgen deprivation treatment (ADT) on prostate specific membrane antigen (PSMA) tracer uptake demonstrated in 68Ga-PSMA-positron emission tomography (PET/CT) in non-metastatic hormone-naïve prostate cancer patients. Methods: The clinical data of 108 prostate cancer patients who received neoadjuvant ADT were retrospectively analyzed. All patients had a baseline 68Ga-PSMA-PET/CT scan and a second scan was delivered median of 2.9 months after initiation of ADT. Patients with clinical and radiological evidence of distant metastasis were excluded from the study. The maximum standardized uptake value (SUVmax) of primary tumor (SUVp) and metastatic lymph nodes (SUVln) as well as PSA response were assessed between pre- and post-ADT 68Ga-PSMA-PET/CT scans. Results: The median SUVp and SUVln were 14.0 (range, 4.9 – 78.4) and 13.2 (range, 3.6 – 64.5), respectively. There was a significant moderate correlation between baseline serum PSA and SUVp (Spearman = 0.513, p<0.001). There were significant decreases in post-treatment serum PSA, SUVp, and SUVp. A decrease in SUVp was seen in 91 patients (84%) with a median value of 66% (range, 5% – 100%), while 17 patients (16%) had no change in or an increase in PSMA tracer uptake with a median value of 24% (range, 0% – 198%). Patients with Gleason score (GS) of 7 had significantly higher metabolic response rates compared to other patients. The disease progression was significantly higher only in patients with GS > 7 disease compared to GS 7 disease. The PSA response to ADT was lowest in patients with ISUP high-grade tumors. A total of 16 patients (15%) had progressive disease, and in 9 patients (8%), radiotherapy decisions were modified according to post-treatment 68Ga-PSMA-PET/CT scans. Conclusions: The current study includes the largest number of patients analyzed to date and demonstrates that ADT causes a significant decrease in serum PSA values and SUVp and SUVln. The authors demonstrate that 68Ga-PSMA-PET/CT may be used as a quantitative imaging modality after neoadjuvant ADT in hormone-naïve non-metastatic PC patients.
Comparative efficacy of local versus systemic salvage therapies for recurrent prostate cancer after primary radiotherapy.
Authors: Bauman Glenn , Ding Keyue , Chin Joseph , Iaboni Alessandra , Klotz Laurence , Dearnaley David P. , Horwitz Eric M. , Crook Juanita M. , O'Callaghan Christopher J. 
Published: February 2020

221 Background: We sought to compare two common salvage strategies for radio-recurrent prostate cancer: androgen deprivation therapy (ADT: PR7 RCT NCT00003653) or local salvage ablation using cryotherapy (CRYO: single institution study Williams, Eur Urol. 2011;60(3):405). Methods: Pre-salvage therapy prognostic variables common to the two datasets (Gleason score at initial treatment, time from original RT, use of ADT at time of original RT, PSA at time of salvage, patient age) were used for propensity matching between patients from previously published ADT (1) and CRYO (2) datasets. Progression free survival (PFS, defined as time from initial treatment to development of castrate resistance or death); Disease Specific Survival (DSS, defined as time from salvage to prostate cancer related death) and Overall Survival (OS, defined as time from salvage to death from any cause) were compared between the propensity matched cohorts using Log-Rank and Cox PH regression statistics. Raw linear propensity scores included in the PH model to account for residual variability. A planned subset analysis examined the effect of neoadjuvant ADT among the CRYO cohort (no CRYO patients had adjuvant ADT). Results: Overall, 1119/1386 (ADT) and 172/187 (CRYO) patients were included in the propensity matched analysis. Median follow up was 6.7 yrs (ADT) and 18.7 yrs (CRYO). Median PFS (95% CI) was 10.7 yrs (9.5, 12.3) for CRYO vs. 7.0 yrs (6.1, 10.0) for ADT (HR 0.63 (0.44, 0.89), p = 0.009). Median OS was also longer for CRYO vs. ADT: 12.3 (11.0, 13.8) vs. 10.2 (9.4, not reached) yrs (HR 0.69; p = 0.02). 10 year DSS event rate was 16.5% CRYO vs. 18.5% ADT but was not statistically different. Neoadjuvant ADT did not affect outcomes in CRYO. Conclusions: A 3-year PFS and 2-year OS benefit was noted for the CRYO vs. ADT cohorts while no difference was noted in DSS. Potential explanations include residual bias not corrected for in the propensity scoring, variable follow-up duration, adverse effects from differing cumulative exposure to ADT or a combination of these factors. Prospective comparisons are required to control for these potential biases and compare other important outcomes such as side effects and quality of life.