bluuebunny/crossref_metadata_2025_split huggingface dataset:
EMBARK post hoc analysis of impact of treatment suspension (TxS) on health-related quality of life (HRQoL).
Authors: Freedland Stephen J. , Gleave Martin , De Giorgi Ugo , Rannikko Antti , Saad Fred , Ramirez-Backhaus Miguel , Nasr Anchen F. , Ivanova Jasmina I. , Ganguli Arijit , Kral Pavol , Reisman Arlene , Shore Neal D. 
Published: June 2024

5005 Background: EMBARK (NCT02319837) showed enzalutamide (ENZ) + leuprolide (L) and ENZ mono delayed metastasis-free survival vs placebo (P) + L while maintaining high global HRQoL in high-risk biochemically recurrent nonmetastatic hormone-sensitive prostate cancer. Treatment was suspended (TxS) at week 37 if PSA <0.2 ng/mL; reinstated if PSA rose to ≥2.0 ng/mL with radical prostatectomy (RP) or ≥5.0 ng/mL without RP. This analysis examined HRQoL after TxS. Methods: Longitudinal change in HRQoL from new baseline, week 37 (time of TxS), to subsequent assessments until week 205 were assessed via mixed model repeated measures using separate models for each instrument. Intention to treat analysis was used. Results: Treatment was suspended in 90.9% (321/353), 85.9% (304/354), and 67.8% (240/354) of patients treated with ENZ + L, ENZ mono, and P + L, respectively. A numerical trend inHRQoL improvement after week 37 TxS was seen in all 3 arms, which often reached clinically meaningful threshold at week 205 (Table). Post TxS, all arms reached clinically meaningful improvement in hormonal treatment side effects at the subsequent assessments of week 49 to week 97; however, patients slowly deteriorated, with clinically meaningful deterioration at week 205 relative to week 37 with ENZ + L and P + L. No statistically significant differences were observed between arms in change from week 37 to week 205. Conclusions: This post hoc analysis confirmed that TxS, as expected, leads to clinically meaningful improvements in HRQoL. Clinical trial information: NCT02319837 . [Table: see text]
Health-related quality of life (HRQOL) results from PRESTO (AFT-19), a phase 3 randomized trial of intensification of androgen blockade in patients with high-risk biochemically relapsed castration sensitive prostate cancer.
Authors: Chen Ronald C. , Mazza Gina L. , Fruth Briant , Xiao Han , Picus Joel , Taplin Mary Ellen , Dorff Tanya B. , Appleman Leonard Joseph , Weckstein Douglas Jay , Patnaik Akash , Bryce Alan Haruo , Shevrin Daniel , Mohler James L. , Anderson Daniel M. , Rao Arpit , Tan Alan , Ryan Charles J. , Eggener Scott , Morris Michael J. , Aggarwal Rahul Raj 
Published: June 2024

5006 Background: The PRESTO trial (NCT03009981) showed that in patients with biochemically relapsed prostate cancer following radical prostatectomy with a PSA doubling time of ≤ 9 months and without evidence of metastatic disease by conventional imaging, intensified androgen receptor blockade for 52 weeks (androgen deprivation therapy [ADT] plus apalutamide [Apa], or ADT plus Apa and abiraterone acetate [Abi] plus prednisone) prolonged PSA progression-free survival compared to ADT alone (Aggarwal et al, JCO 2024). Here we report the HRQOL results. Methods: HRQOL measures included the Hot Flash Related Daily Interference Scale (HFRDIS), Expanded Prostate Cancer Index Composite (EPIC)-26 Sexual domain, PROMIS Fatigue Short Form and EQ-5D-5L, which assesses overall HRQOL in the 504 randomized patients. Published minimally important difference thresholds for these HRQOL measures are: HFRDIS 1.66 points, EPIC Sexual 10-12, PROMIS Fatigue 3-5, and EQ-5D-5L 0.06. General linear mixed modeling was used to estimate between-arm mean differences in HRQOL according to an intent-to-treat approach. Results: Mean changes from baseline to end of treatment (EOT) for each arm and for each HRQOL measure are summarized in Table. No statistically significant mean difference was reported between intensified androgen receptor blockade (Arm B, Arm C) vs ADT alone (Arm A) in any HRQOL measure. Further, numerical differences across arms for all HRQOL measures are below published minimally clinically important difference thresholds. Conclusions: Intensified androgen receptor blockade with Apa or Apa/Abi added to 52 weeks of ADT improves PSA progression-free survival without negatively affecting HRQOL. These HRQOL results add further support to intensification of androgen blockade in patients with high-risk biochemically recurrent prostate cancer. Clinical trial information: NCT03009981 . [Table: see text]
Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore.
Authors: De Bono Johann S. , Morris Michael J. , Sartor Oliver , Wei Xiao X. , Fizazi Karim , Herrmann Ken , Piulats Josep M. , Mahammedi Hakim , Logothetis Christopher , George Daniel J. , Eldjerou Lamis K. , Wong Connie , Barys Louise , Rajagopal Nisha , Rodosthenous Theodoulos , Chi Kim N. 
Published: June 2024

5008 Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). In this exploratory analysis, associations between baseline circulating tumor DNA (ctDNA) and outcomes were assessed. Methods: Patients were randomized 1:1 to 177Lu-PSMA-617 (7.4 GBq Q6W; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients known to have actionable mutations (e.g. BRCA) were excluded. The primary endpoint was rPFS. Baseline plasma ctDNA was analyzed using a customized 585-gene sequencing assay. ctDNA fraction was assessed in all samples passing quality control. Alterations in key prostate cancer drivers (prevalent in >10% participants) were assessed in samples with ctDNA fraction >1%. Univariate Cox regression (reference: ARPI change) was used to assess association of ctDNA fraction or alterations with rPFS, prostate-specific antigen response (≥50% decline; PSA50) and RECIST response (RR) at the June 21, 2023 data cutoff. Results: Of 360 samples from 468 patients, 255 passed quality control and 156 had ctDNA fraction >1% (median 5.85%; range 0–85). Detection of ctDNA alterations was comparable between arms and with published data. Median rPFS was shorter for patients with ctDNA fraction > versus ≤1% (HR 2.753; 95% CI 1.957–3.872; p<0.0001) (Table); ctDNA fraction >1% was also associated with worse RR and PSA50 response. Median rPFS was shorter for patients with detected versus undetected AR(HR 1.954; 95% CI 1.333–2.865; p<0.001), TP53(1.655; 1.13–2.426; p<0.01) and PTEN(1.62; 1.018–2.578; p<0.05) alterations. Median rPFS was longer with 177Lu-PSMA-617 versus ARPI change in patients with detected AR, TP53, PTEN(Table) , PI3K pathway and DNA repair pathway alterations. There was no significant association between ctDNA alterations and PSA50 or RR. Conclusions: ctDNA fraction >1% and AR, TP53and PTENalterations were associated with worse outcomes in PSMAfore regardless of treatment. Nonetheless, patients with these negative prognostic biomarkers did better with 177Lu-PSMA-617 than with ARPI change. Clinical trial information: NCT04689828 . [Table: see text]
Prognostic PSMA-PET PROMISE nomograms for patients with prostate cancer.
Authors: Fendler Wolfgang Peter , Karpinski Madeleine J. , Hüsing Johannes , Claassen Kevin , Möller Lennart , Kajüter Hiltraud , Oesterling Florian , Grünwald Viktor , Umutlu Lale , Lanzafame Helena , Telli Tugce , Merkel-Jens Anja , Hüsing Anika , Kesch Claudia , Herrmann Ken , Stang Andreas , Hadaschik Boris A. 
Published: June 2024

5016 Background: Prostate Specific Membrane Antigen Positron-Emission-Tomography (PSMA-PET) was introduced for prostate cancer staging in 2012. PSMA-PET reported by standardized PROMISE criteria delivers accurate staging with potential prognostic value. Here we assess the prognostic value of PSMA-PET including tumor volume in a large prostate cancer dataset with overall survival follow-up and compare it head-to-head to clinical risk scores. Methods: Prostate cancer patients, who underwent PSMA-PET between October 2014 and December 2019 at the Essen University Hospital, were analyzed retrospectively. We collected PSMA-PET stage using the molecular imaging TNM system (miTNM), tumor volume, SUVmean and overall survival follow-up. The dataset was split into development and validation cohorts (2:1). We created a visual and quantitative nomogram based on Cox regression models with LASSO penalty using the development cohort. Performance of nomograms in the validation cohort were measured using C-index and calibration plots. Head-to-head comparison to clinical risk scores for each staging group was examined using ROC-curves and C-index. Results: The cohort includes 1612 prostate cancer patients across all disease stages with 567 (35.2%) recorded deaths. PSMA-PET based predictors included into the quantitative PSMA-PET nomogram were locoregional lymph node metastases (miN2), distant metastases (miM1a, miM1b pattern, miM1c), tumor volume and tumor SUVmean (Table). The visual nomogram includes distant metastases and total tumor lesion count. Overall C-indices were 0.81 or 0.78 for the quantitative or visual nomogram, respectively. The quantitative PSMA-PET nomogram was superior to STARCAP at initial staging (AUC: 0.72 vs. 0.53; p=0.02), to EAU risk score at BCR (AUC: 0.69 vs. 0.52; p<0.001), and to NCCN groups at any timepoint (AUC: 0.81 vs. 0.73; p<0.001). The visual PSMA-PET nomogram was superior to EAU risk score (AUC: 0.64 vs. 0.52; p<0.001) and NCCN groups (AUC: 0.79 vs. 0.73 p<0.001). Conclusions: Our prognostic PSMA-PET nomograms based on PROMISE criteria were accurate in early and late stages of prostate cancer. Prediction of overall survival was superior when compared to clinical risk tools. Multi-center validation in the PROMISE registry is ongoing. Development cohort (n=1110 patients) univariate regression findings for PROMISE variables included in the quantitative PSMA-PET nomogram for prediction of overall survival.[Table: see text]
68Ga-PSMA PET/CT response and clinical outcomes in patients treated with enzalutamide as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC): Results of a prospective study.
Authors: Giunta Emilio Francesco , Caroli Paola , Scarpi Emanuela , Altavilla Amelia , Marini Irene , Celli Monica , Casadei Chiara , Lolli Cristian , Schepisi Giuseppe , Bleve Sara , Brighi Nicole , Cursano Maria Concetta , Martinelli Giovanni , Matteucci Federica , De Giorgi Ugo 
Published: June 2024

5018 Background: 68Ga prostate specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT) is a highly sensitive diagnostic tool whose adoption is constantly increasing in prostate cancer patients, also for monitoring response to therapies. We evaluated the impact of 68Ga-PSMA PET/CT response, as compared to prostate-specific antigen (PSA) response, in patients treated with enzalutamide as first-line therapy (1L) for mCRPC. Methods: From Oct 2017 to May 2022, in an observational prospective study, 70 consecutive mCRPC patients were treated with 1L enzalutamide 160 mg QD and underwent 68Ga-PSMA PET/CT within 3 weeks before (baseline) and 12 weeks (SD: ±4 weeks) after treatment initiation. We measured at both the timepoints the sum of metabolic total volume (sMTV), mean and maximum standardized uptake volume (sSUVmean and sSUVmax, respectively) and total lesion activity (sTLA), which is the product of MTV and SUVmean, for a maximum of 20 lesions. On the basis of EAU/EANM criteria, patients were categorized as PSMA responders (PET-R, in case of complete/partial response or stable disease) or PSMA non-responders (PET-NR, in case of progressive disease). Based on prostate-specific antigen (PSA), patients were classified as biochemical responders (PSA-R, in case of PSA decrease ≥ 50%) or non-responders (PSA-NR in all other cases). Survival analysis was performed using the Cox regression hazard model and the Kaplan-Meier method. Results: At the data cut-off (31st Dec 2023), 69 mCRPC patients were considered fully evaluable. The median age was 75 years (range: 47-91), GS was <8 in 24 (35%) and ≥8 in 37 (53%), the median baseline PSA was 2.57 µg/L (range: 0.09-197). We observed a median sSUVmax of 41.6, median SSUVmean of 28.2 and median sTLA of 44.8. The median follow-up was 57 months. In the Table, we reported survival results according to PSA and PET response. Differences between the discordant groups were not statistically significant for both median progression-free survival (mPFS) and median overall survival (mOS) (p=0.09 and 0.41, respectively), even if a positive trend for PET was shown. At multivariate analysis, only sTLA at 12 weeks was significantly associated with both mPFS (p=0.0004) and mOS (p=0.0006). Conclusions: 68Ga-PSMA PET/CT response appeared more accurate than PSA monitoring to predict survival to enzalutamide initiation in mCRPC. Some PET parameters may better predict survival benefit and need future validation. [Table: see text]
Dissecting the significance of ACP1 gene alterations in prostate cancer (PCa).
Authors: Abdallah Nour , Elliott Andrew , Nabhan Chadi , Stanford Stephanie M , Agarwal Neeraj , Bagrodia Aditya , Garje Rohan , Bottini Nunzio Bottini , McKay Rana R. 
Published: June 2024

5025 Background: The acid phosphatase 1 ( ACP1) gene encodes low molecular weight protein tyrosine phosphatase (LMPTP), which is overexpressed in PCa. Previous studies demonstrate that LMPTP plays a critical role in PCa growth and metastasis and is evolving as a potential therapeutic target. Thus, we analyzed ACP1 expression in primary and metastatic PCa samples and the association of ACP1 with molecular profiles and clinical outcomes. Methods: NextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed for PCa specimens (n=5028) submitted to Caris Life Sciences. ACP1-High/Low expression was defined as quartile 4 (Q4) and 1 (Q1) of RNA transcripts per million (TPM). DNA mutational profiles were analyzed for samples stratified by ACP1 expression quartiles. Gene set enrichment analysis was used to assess the Hallmark collection of cancer pathways. Tumor cell PD-L1+ status (≥2+, ≥5%; SP142) was tested by immunohistochemistry. Immune cell fractions in the tumor microenvironment (TME) were estimated by RNA deconvolution using QuanTIseq. Overall survival (OS) was assessed from the time of specimen collection to death or last follow-up, with hazard ratio (HR) calculated using the Cox proportional hazards model, and P values calculated using the log-rank test. Results: Samples included 3058 (60.8%) derived from the prostate, 634 (12.6%) from lymph node metastases (LNM), and 1307 (26.0%) from distant metastases (DM). ACP1 expression was higher in LNM and DM than in the prostate (49.8 and 47.9, respectively, vs 44.1 TPM, p<0.0001 each). TP53 mutations were enriched in the highest ACP1 quartile (37.9% Q4 vs 27.0% Q1, p<0.001) among prostate samples but not LNM or DM. Pathways associated with cell cycle regulation, oxidative phosphorylation, and androgen response were enriched in Q4, while epithelial-mesenchymal transition and TNF-α signaling via NFKB pathways were enriched in Q1. Both neuroendocrine and androgen receptor signaling increased in Q4. M2 macrophages and NK cell fractions were increased, while T cells and M1 macrophages were decreased in Q4. PD-L1 expression did not differ by ACP1 expression. High ACP1 was associated with worse OS among prostate tumors (63.4 vs 86.3 months (mos) in ACP1-high vs low tumors, HR 1.5, 95% CI 1.3-1.7, p<0.0001) and DM (22.0 vs 27.7 mos in ACP1-high vs low tumors, HR 1.2, 95% CI 1.0-1.4, p<0.05) but not LNM (31.9 vs 30.9 mos in ACP1-high vs low tumors, HR 1.0, 95% CI 0.8-1.3, p=0.88). OS from the start of ARSI and taxane chemotherapy was similar in ACP1 high/low groups across prostate, LNM, and DM. Conclusions: In the largest study investigating the significance of ACP1 expression in PCa, we demonstrate that ACP1-high tumors exhibit a distinct molecular profile enriched for TP53 alterations and associated with a ‘cold’ TME. Our findings may provide a rationale for novel therapeutic targeting of ACP1-high tumors.
Metastatic pure seminomas with early relapse: Prognostic roles of high dose chemotherapy and surgery of residual disease.
Authors: Duval Lucile , Allignet Benoît , Chevreau Christine , Gravis Gwenaelle , Mazza Camille , Gross-Goupil Marine , Laguerre Brigitte , Peyrat Patrice , Izarn Floriane , Patrikidou Anna , Flechon Aude 
Published: June 2024

5031 Background: Metastatic seminomatous germ cell tumors (mSGCT) are a rare form of cancer. Few studies focused on early relapse (< 12 months) after first-line chemotherapy (ChT). We aimed to evaluate the impact of salvage retroperitoneal lymph node dissection (RPLND), and high-dose ChT with hematopoietic stem cell transplantation (HDCT-HSCT) in mSGCT patients in a situation of early relapse. Methods: Ninety-one mSGCT patients treated between 2005 and 2022 in 7 French expert centers for an early recurrence after an initial favorable response to 1st-line ChT were retrospectively included. Patient clinical characteristics, progression-free survival after first relapse (PFS) and overall survival (OS) were evaluated. We also assessed the role of HDCT-HSCT as first salvage treatment, and the impact of complementary RPLND after salvage ChT. Results: After a median follow-up of 56 months, 3-year PFS and OS rates were 77.6% (95%CI, 68.3-88.1) and 88.4% (95%CI, 81.0-96.4), respectively. HDCT-HSCT was not associated with longer PFS or OS compared to standard-dose 2nd-line ChT. In contrast, patients who underwent RPLND after salvage ChT demonstrated significantly longer PFS (at 3-years: 97.1% vs 63%; HR 0.15; 95%CI 0.03-0.65; p=0.012) and a notable trend towards improved OS (at 3-years: 97.0% vs 81.8%; HR 0.15; 95%CI 0.02-1.23; p=0.078). Conclusions: In mSGCT patients with first-year relapse, RPLND after salvage treatment is correlated with longer PFS and tends to be associated with longer OS. Identification of a subpopulation that might benefit from HDCT-HSCT ought to be performed since it did not confer survival benefits in the overall population.
Prognostic reclassification and survival outcomes in intermediate- and poor-risk nonseminomatous germ cell tumors (NSGCT).
Authors: Jobanputra Kunal Naishadh , Prakash Gagan , Arora Amandeep , Jadhav Bhagyashri , Pal Mahendra , Pawar Akash , Dey Sayak , Bakshi Ganesh , Murthy Vedang , Maitre Priyamvada , Menon Nandini Sharrel , Shah Minit Jalan , Menon Santosh , Popat Palak , Ringe-Katdare Aparna , Sable Nilesh , Agrawal Archi , Noronha Vanita , Prabhash Kumar , Joshi Amit 
Published: June 2024

5033 Background: Intermediate and poor-risk nonseminomatous germ cell tumors (NSGCT) form a large group of patients with varying prognosis. There is a need to revisit the existing International Germ Cell Cancer Collaborative Group (IGCCCG) classification to identify the ‘poorest subset’ of patients. Methods: We retrospectively analysed the outcomes of consecutive patients with intermediate and poor-risk NSGCT who were diagnosed between 2015 to 2021 at our centre and had received first-line chemotherapy. Overall survival (OS) and relapse-free survival (RFS) were calculated by Kaplan-Meier analysis. A multivariate risk factor model was constructed out of the prognostic factors for OS and RFS. Concordance statistic (c-statistic) was computed and compared between the proposed model and IGCCCG classification and boot-strap sampling was used to evaluate this comparison. Results: A total of 360 patients were included, having a median age of 29 (IQR: 24-34) years, with 149 in the intermediate-risk and 211 in the poor-risk according to the IGCCCG classification. Most of the patients had testis as the primary site of the tumor (336 patients, 93.3%). Median follow-up was 58.0 months (95%CI 50.7-65.3). The 5-year OS was 84.4% (95%CI 78.5-90.8) in the intermediate-risk versus 55.3% (95%CI 48.4-63.1) in the poor-risk (p < 0.001). RFS at 5 years was 76.8% (95%CI 70.0-84.3) in the intermediate-risk and 46.2% (95%CI 39.7-53.9) in the poor-risk (p < 0.001). Age above 35 years, baseline alpha-fetoprotein (AFP) >10,000 ng/mL, presence of liver and brain metastasis were identified to be poor prognostic risk factors for OS, while lung metastasis in addition to the above factors was prognostic for RFS by multivariate analysis. The multivariate model using the above four risk factors for OS had a higher c-statistic (0.668) than the existing IGCCCG classification (0.632) with an improvement of 0.036 (Table). This model also showed a similar improvement in c-statistic over IGCCCG classification for RFS (0.659 vs 0.625). Conclusions: The proposed model showed better discriminatory ability than the existing IGCCCG classification. This emphasizes the need to revise the risk stratification to identify the ‘very-high risk’ subset of patients for potential treatment intensification.[Table: see text]
Association of tumor genetics with outcomes in patients (pts) with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA-617.
Authors: Panian Justine , Henderson Nicholas , Barata Pedro C. , Bilen Mehmet Asim , Graham Laura , Heath Elisabeth I. , Herchenhorn Daniel , Hwang Clara , Kilari Deepak , Koshkin Vadim S , Nauseef Jones T. , Sokolova Alexandra , Zakharia Yousef , Schweizer Michael Thomas , Dorff Tanya B. , Armstrong Andrew J. , Alva Ajjai Shivaram , McKay Rana R. 
Published: June 2024

5050 Background: 177Lu-PSMA-617 is approved for the treatment (tx) of mCRPC. Though tx is associated with improved survival, not all pts experience a benefit. Acquired resistance is common and some pts have intrinsic resistance. There is a lack of data on genomic markers that could aid in selecting pts for tx. In this study, we aim to characterize molecular predictors of benefit to 177Lu-PSMA-617. Methods: We used the retrospective Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database (n=2100). The primary endpoint was to investigate the association of genomic alterations with a ≥50% PSA decline (PSA50) from baseline following 177Lu-PSMA-617. Associations were assessed using Wald-chi square test and Cox regression in multivariable analysis. Secondary endpoints included clinical progression-free survival (PFS) and overall survival (OS). Results: We identified 115 pts with PSMA PET+ mCRPC treated with 177Lu-PSMA-617 who had commercial genetic sequencing prior to tx (median age 72 yrs, 25% non-white). Median number of prior lines for mCRPC was 3 with 71 pts (62%) receiving >1 androgen receptor signaling inhibitor (ARSI) and 55 pts (48%) receiving >1 taxane; 11 pts (9%) received ARSI with 177Lu-PSMA-617. Overall, the PSA50 was 49% with median OS and PFS of 14.0 and 7.6 months (mos), respectively. In pts with a PSA50, median OS and PFS were 22.6 and 11.6 mos, respectively, vs 11.2 and 5.6 mos for those without a PSA50. Genetic alterations associated with PSA50 are in the table. PSA50 was 48% in pts with (n=32) vs 49% in pts without DDR alterations (n=83). PSA50 was 44% in pts with tumor suppressor gene alterations (TSGa) ( PTEN, p53, RB1) (n=68) vs 56% in pts without (n=47). Median PFS was 7.6 vs 7.3 mos for pts with and without any TSGa (p=0.90), and median OS was 12.2 mos vs 22.6 mos for pts with and without TSGa (p=0.004). Of the 43 pts with AR alterations, 8/15 (53%) with LBD mutations, 10/27 (37%) with AR amplification, and 0/1 with AR-V7 had a PSA50. FGFR, CDK12 and MYC alterations were enriched in individuals without a PSA50 (75-83%). Conclusions: We demonstrate that CDK12, MYC and FGFR alterations were associated with a lower PSA50 with 177Lu-PSMA-617. Larger cohorts should be investigated for confirmation, as biomarkers to inform relative benefit of tx could be useful in prioritizing options for mCRPC. [Table: see text]