bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of TP53 gene Pro72Arg (rs1042522) single nucleotide polymorphism among Egyptian breast cancer patients
Authors: Ahmed Shaza , Safwat Gehan , Moneer Mohamed M. , El Ghareeb AbdelWahab , El Sherif Ahmed A. , Loutfy Samah A. 
Published: March 2023

AbstractBackgroundThe P53 protein has an essential role in several cellular processes, including DNA repair, apoptosis, and cell cycle arrest. The pathophysiology of many cancer types has frequently been linked to polymorphisms in theTP53locus. Over 200 single nucleotide polymorphisms (SNPs) have been identified in TP53. However, Pro72Arg (rs1042522) at codon 72, shows contradictory results in terms of cancer risk. In this study, we aimed to determine if the Pro72Arg (rs1042522) SNP in theTP53gene would be linked to breast cancer (BC) risk among Egyptian patients.Materials and MethodsGenomic DNA was extracted from blood samples of 100 healthy volunteers and 100 breast cancer patients (50 familial and 50 non-familial).TP53Genotyping was performed using tetra-primer amplification refractory mutation (Tetra-ARMS) PCR. Data were analyzed using SNPstat software.ResultsThe prevalence ofTP53(Pro72Arg) rs1042522 genotypes carrying the high-risk allele [Pro/Arg (CG) and Arg/Arg (GG)] were significantly higher in BC patients compared to healthy volunteers and were associated with BC susceptibility (OR 0.2; [95% CI 0.11–0.38];P = 0.0001). However, there was no statistical significant difference in the prevalence ofTP53(Pro72Arg) rs1042522 genotypes carrying the high-risk allele between familial and non-familial BC patients. In addition, there was no association between the prevalence ofTP53(Pro72Arg) rs1042522 genotypes carrying the high-risk allele and BC patients’ clinical and pathological characteristics including tumor size, tumor grade, lymph node status, presence of lymphovascular invasion, expression of ER, PR and Her-2 in both of familial and non-familial BC patients.ConclusionsTP53(Pro72Arg) rs1042522 is more prevalent among BC patients but not associated with disease progression.
Underutilization of best systemic therapy in patients with metastatic prostate cancer.
Authors: Roadman Daniel , Cao David , Vourganti Srinivas 
Published: March 2023

111 Background: Advancement of treatment pathways in the management of metastatic prostate cancer (mPC) has identified newer systemic agents associated with survival advantage over androgen deprivation therapy (ADT) alone. Despite FDA approvals and guideline recommendations outlining standard of care (SOC) intensification of (ADT) with such additional systemic therapies such as docetaxel or novel hormonal therapies (NHT), these treatments are not being utilized uniformly by all practitioners. Our objective is to assess the utilization of such advanced therapies in patients with mPC and study differences in prescribing patterns. Methods: Between 2017 to present, we retrospectively identified all consecutive men with prostate cancer in a single health system. Electronic health record ICD code inquiries were used to identify patients. The population was further restricted utilizing diagnosis codes to include only those with metastatic prostate cancer and to exclude patients with second primary cancers. All treatment modalities and demographic information were analyzed to assess for prescribing patterns. Results: In total, 5,761 men had a diagnosis of prostate cancer. Exclusion criteria applied stepwise removed those with age <18 years (2 patients) and secondary malignancies (1046 patients), resulting in 4,713 men for analysis. Of these, 665 men were found to have mPC and included in the final cohort. Mean patient age was 70.3 ± 9.6 years. We found no statistically significant difference in SOC prescribing pattern based on race, ethnicity, insurance type, zip code, 2020 United States census household median income, nor year of treatment. There was, however, overall low utilization of intensification of ADT with docetaxel or NHT at 42%, with 58% of patients still being treated with only first generation antiandrogens or luteinizing hormone releasing hormone agonists. Conclusions: In a large health system, we found that next generation care can be provided independent of insurance payor profile, race, ethnicity, and socioeconomic status. However, despite guidelines to support newer systemic agents for patients with mPC, we continue to observe that it is underused in clinical practice. Additional studies are needed to identify potential clinician and patient barriers, as well as prescribing pattern failures that are limiting the implementation of evidence-based treatment beneficial to overall survival.
Leukocyte subtypes and myeloid derived suppressor cells as prognostic markers in metastatic castration resistant prostate cancer treated with cabazitaxel: A satellite study of the CABASTY phase III trial.
Authors: Heisbourg Jean-David , Oudard Stephane , Beuzeboc Philippe , Bennamoun Mostefa , Saldana Carolina , Voog Eric , Barthelemy Philippe , Thiery-Vuillemin Antoine , Hasbini Ali , Houede Nadine , Belhouari Houda , Helissey Carole , Parfait Beatrice , Thibaudin Marion , Phan Letuan , Kotti Salma , Yaovi Eric 
Published: March 2023

126 Background: CABASTY trial investigated the benefit of an adapted schedule of cabazitaxel (16 mg/m2 bi-weekly versus 25 mg/m2 tri-weekly) in mCRPC patients previously treated with docetaxel and alternative androgen-targeted therapy. The study met its endpoints with a significantly decreased incidence of grade ≥ 3 neutropenia without a decrease in overall survival. This preplanned analysis evaluated the prognostic impact of neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-platelets ratio (NPR) myeloid derived suppressor cells (MDSC) and leukocyte subtypes counts in this setting. Methods: 44 patients treated with cabazitaxel were included. Peripheral blood mononuclear cells were isolated and myeloid compartment analysis were performed at baseline, week 6 (S6) and week 12 (S12) of treatment using a multi-parametric flow cytometry panel. We investigated at each timepoints the association of NPR, NLR, MDSC and leukocytes subtypes with PSA response rate (PSArr), Progression Free Survival, and Overall Survival with a preplanned uni- and multivariate analysis. Results: The NLR, NPR, MDSC subtypes and lymphocytes count at baseline were prognostic in the CABASTY trial regardless of the cabazitaxel regimen. Patients with a high lymphocyte count and/or a low NLR, NPR, and MDSC counts at baseline had a significantly improved PSAr, PFS and OS. In the multivariate analysis, a NPR > 1,84 and lymphocytes count < 1,2 G/L at baseline were significantly associated with OS [HR 2.007 (1.3 - 3.1)] and [HR 0.38 (0.20 - 0.73)]. Conclusions: High NLR, NPR, neutrophil and MDSC counts as well as a low lymphocyte count at baseline and during treatment predict poor outcomes in mCRPC patients treated with cabazitaxel. NPR and lymphocyte count are readily available biomarkers that may be useful for risk stratification in future clinical trials and could be incorporated into prognostic nomograms. Clinical trial information: NCT02961257 .
Lutetium-177 PSMA radioligand therapy for metastatic castration resistant prostate cancer in Germany: Population-based data with multicenter validation from 2016 to 2020.
Authors: Flegar Luka , Thoduka Smita George , Librizzi Damiano , Luster Markus , Zacharis Aristeidis , Heers Hendrik , Eisenmenger Nicole , Ahmadzadehfar Hojjat , Eiber Matthias , Weber Wolfgang A , Groeben Christer , Huber Johannes 
Published: March 2023

146 Background: Our purpose was to investigate the adoption and current trends of Lutetium-177 PSMA radioligand therapy (RLT) for metastatic castration-resistant prostate cancer (mCRPC) in Germany. Methods: We analyzed the nationwide German hospital billing database (Destatis) and the hospitals’ quality reports for 177Lutetium PSMA RLT from 2016 to 2020 using the reimbursement.INFO tool. For detection of trends over time we applied linear regression models. For validation of these billing data, we included a total of 1239 177Lu-PSMA RLT cycles from 392 patients within the WARMTH multicenter study from 2016 to 2018. Additionally, we included the 177Lu-PSMA RLT cycles from two participating institutions from 2016 to 2020 for further validation. Results: We identified 12553 cases which were treated with 177Lu-PSMA RLT. The number of 177Lu-PSMA RLTs steadily increased from 1077 to 3640 therapies during the study period (+641 RLT/year; p<0.005). In 2016, 25 departments of nuclear medicine offered this treatment, which increased to 44 nuclear medicine departments in 2020. In 2016, 16% of nuclear medicine departments (4/25) performed more than 100 177Lu-PSMA RLTs, which increased to 36% (16/44) in 2020 (p<0.005). In 2016, 88% (22/25) of 177Lu-PSMA RLTs were performed at a university hospital, which decreased to 70% (31/44) in 2020. The proportion of patients older than 65 years receiving 177Lu-PSMA RLT increased from 78% in 2016 to 81% in 2020. Conclusions: Treatment of mCRPC with 177Lu-PSMA RLT has been rapidly increasing in Germany in the recent years providing an additional therapy option. Most of the therapies are performed at academic hospitals.
Carboplatin in metastatic castrate resistant prostate cancer: A retrospective study of heavily pretreated patients (COMPACT).
Authors: Pemberton Lara , Allen Connor , Handel Eleanor , Weickhardt Andrew James , Tran Ben , Crumbaker Megan , Shapiro Jeremy David , Risbridger Gail P. , Pook David William 
Published: March 2023

158 Background: Despite a lack of up-to-date clinical trial data, many clinicians advocate the use of Carboplatin monotherapy to treat patients with advanced Castrate Resistant Prostate Cancer (CRPC) who have exhausted multiple other treatment options. The aim of this study was to determine the overall survival (OS) and response rate in patients with advanced CRPC treated with Carboplatin monotherapy after progressing on other chemotherapy agents. Methods: Retrospective multicentre study of the use of Carboplatin in advanced CRPC patients in Australia. Demographic data, PSA response rates, survival data and Carboplatin treatment protocols, such as dose and duration, were collected. Exploratory analyses on potential prognostic parameters were performed. Results: 51 patients received Carboplatin: median age 68 (range 55–86 years). Most patients (78.3%) received Carboplatin AUC 5 at 3-weekly intervals. The median number of cycles of Carboplatin was 3 (range 1-17). Median time on treatment was 63 days (range 1-441). Median overall survival was 29.4 weeks (IQR 11.7 weeks). 6 (11.8%) patients had a PSA response ≥50%. The median time to PSA progression on Carboplatin was 67 days (range 15-418). 16 patients (31%) required a dose delay or reduction and 8 patients (15.6%) ceased Carboplatin secondary to side effects/ toxicity. Conclusions: Our findings demonstrate that in heavily pre-treated CRPC, Carboplatin has a modest benefit in a minority of patients with a low rate of toxicity in the advanced prostate cancer population.
Updated results of a phase Ib single-center study of pembrolizumab in combination with chemotherapy in patients with locally advanced or metastatic small cell/neuroendocrine cancers of the prostate and urothelium.
Authors: Chin Arnold I. , Ly Ann , Rodriguez Sara , Sachdeva Ankush , Zomorodian Nazy , Zhang Hanwei , Kim Jiyoon , Li Gang , Rettig Matthew , Liu Sandy , Drakaki Alexandra 
Published: March 2023

165 Background: Small cell/neuroendocrine cancers irrespective of origin share aggressive phenotypes. Pembrolizumab (MK-3475) is a humanized antibody targeting programmed cell death protein 1 (PD-1) that has shown activity against small cell lung cancers. Preclinical studies showed molecular commonality amongst small cell cancers across multiple tissue types. This study evaluated the safety and efficacy signals of pembrolizumab and chemotherapy in patients with small cell/neuroendocrine cancer of the prostate and urothelium. Methods: Patients with locally advanced or metastatic small cell cancer of the bladder (cohort 1) and primary small cell or treatment-derived neuroendocrine prostate cancer (NEPC) (cohort 2) received pembrolizumab and standard of care chemotherapy (etoposide and cisplatin/carboplatin for cohorts 1 and 2, with option of docetaxel and carboplatin for cohort 2) with maintenance pembrolizumab for 2 years until unequivocal progressive disease or unacceptable toxicity. Primary endpoint was to estimate ORR, PFS, and OS compared to historical controls as well as safety and tolerability. Targeted gene mutation sequencing as well as sequential single cell sequencing of peripheral blood mononuclear cells (PBMCs) for immune profiling as well T cell receptor (TCR) repertoire was performed. Results: 14 patients were enrolled (7 cohort 1, 7 cohort 2) with mean age 64.9 (range 53 to 81). ORR was 43% (95% CI: 0.06, 0.80) overall and within each cohort. PFS rate at 12 months was 64% (95% CI: 0.44,0.95) across cohorts, 86% (95% CI: 0.63,1.00) within cohort 1, and 43% (95% CI: 0.18,1.00) within cohort 2. OS rate at 12 months was 79% (95% CI: 0.60,1.00) across cohorts, 86% (95% CI: 0.63,1.00) within cohort 1, and 71% (95% CI: 0.45,1.00) within cohort 2. 4 patients in cohort 1 with locally advanced disease underwent radical cystectomy, with no PD at a mean follow up of 29 months. Grade 3 or higher AEs occurred in 87% of patients, while 40% of patients experienced grade 3 or higher AEs related to pembrolizumab. In 12 patients where tissue was sufficient, all patients had genomic alterations in either p53 (75%) or Rb (58%). Single cell sequencing showed progressive enrichment of CD8+ T cells with clonal expansion of specific TCRs in responding patients. Conclusions: In patients with locally advanced or metastatic small cell/neuroendocrine prostate and bladder cancers, combination pembrolizumab with standard of care chemotherapy and maintenance pembrolizumab showed promising efficacy with tolerable adverse events. Clinical trial information: NCT03582475 .
A phase I trial of androgen deprivation, darolutamide, and ipatasertib in a safety cohort with castration-resistant prostate cancer (ADDITION).
Authors: Fenton Sarah Elizabeth , Springsdorf Rachel , Kenny Siobhan , Bere Lauren , Ross Ashley , Kocherginsky Masha , Hussain Maha H. A. , VanderWeele David James 
Published: March 2023

174 Background: Alterations activating the PI3K-AKT pathway are found in 40-50% of patients with aggressive prostate cancer. This leads to an abrogated response to therapy with androgen-receptor (AR) pathway inhibitors (ARPIs) and is associated with poor outcomes. Preclinical in vivo models suggest there is synergy between ARPIs and AKT inhibitors. Methods: This is a single-arm study of the AR inhibitor darolutamide, the AKT inhibitor ipatasertib, and androgen deprivation therapy (ADT). The phase I safety cohort included patients with castration-resistant prostate cancer (CRPC). ADT was administered per institutional standards. Patients started with a lead-in of ipatasertib for 7 days, followed by ipatasertib combined with darolutamide 600 mg BID. The starting dose of ipatasertib was 400 mg daily with plans to de-escalate if ≥ 2 dose-limiting toxicities (DLTs) were identified in the first six patients. The DLT period was the first 4 weeks of combination therapy. The primary endpoint was to identify the recommended phase II dose (RP2D) of ipatasertib. A phase II biomarker-selected cohort was planned to receive the combination neoadjuvantly. That portion of the study was terminated prior to patient enrollment due to the withdrawal of industry support. Results: Six patients with metastatic CRPC were enrolled in the phase I cohort. They had received a median of 3 prior systemic therapies in addition to ADT (range 1-6). All patients completed the DLT period, and no DLTs were observed. The RP2D of ipatasertib, when given with darolutamide, is 400mg daily. Two patients (33%) had serious adverse events (SAEs) (diarrhea; grade 3) related to ipatasertib outside the DLT period. Two patients (33%) had SAEs unrelated to study drugs; pyelonephritis (one patient; grade 3) secondary to obstruction, and respiratory failure (one patient; grade 5) attributed to disease progression. Two (33%) patients had at least a 50% decline in PSA as the best PSA response, including 2 of 3 patients with known PI3K pathway alterations. Median PSA progression free survival (PFS) was 3.35 months (95% CI 3.06-NA). Median radiographic PFS was 2.91 months (95% CI 2.79-NA). Conclusions: Combination therapy with darolutamide and ipatasertib in CRPC is safe and a RP2D of ipatasertib was established. Toxicity was similar to the therapies given alone, and the most common treatment-related SAE was diarrhea. Partial response to combination therapy was seen in men with CRPC and known PI3K alterations. Clinical trial information: NCT04737109 .
Comparative effectiveness of abiraterone and enzalutamide in the first-line treatment of metastatic castration-resistant prostate cancer (mCRPC): A retrospective cohort study in a large database of deeply curated EHR real-world data (RWD) from community oncology practices in the US.
Authors: An Huijun , Schoen Martin W. , Rider Jennifer , Schorer Anna E. , Ken Jessica , Chen Li , Alabaster Amy , Natanzon Yanina 
Published: March 2023

175 Background: Abiraterone(A) and enzalutamide(E), both oral androgen receptor targeted agents, are available as first-line treatment options for mCRPC patients. Direct comparisons of efficacy have not been performed for mCRPC patients primarily receiving their cancer care outside of academic centers or integrated health care systems. The study aims to evaluate the real-world effectiveness between first-line A and E-containing regimens in mCRPC patients primarily receiving care in the US community oncology setting. Methods: Patients were selected from ConcertAI Patient 360 Prostate data product, a large de-identified database of deeply curated EHR RWD, sourced from data sharing agreements with community oncology practices. mCRPC patients treated with a first-line A or E-cont. regimen between 1/2011 and 6/2022 were included. OS, TTNT, TTD outcomes were described using KM estimates and evaluated with Cox proportional hazard (HR) model. Confounding was addressed with inverse probability treatment weighting (IPTW) propensity scores based on age, BMI, ECOG, prior anti-androgen exposure, smoking status, comorbidities, and nadir PSA. Sensitivity analysis evaluated KM and HR for each covariate strata. Hazard ratios were also evaluated with multiple imputation by chained equations for missing covariates. Results: From 3,578 mCRPC patients, 1,210 (33.8%) received E-cont. regimen and 1,357 (37.9%) received A-cont. regimen(ref) with a median of 8 months duration for both drugs. Adjusted HR (aHR) for all three outcomes showed a slight increase in effectiveness for E albeit not significant (OS (aHR 0.99, CI 0.87-1.12), TTNT (aHR 0.98, CI 0.89-1.08). Adjusted model including imputation (iHR) supported unimputed results (OS (iHR 0.97, CI 0.88-1.07), TTNT (aHR 0.94, CI 0.9-1.10). The HRs for OS, TTNT and TTD in sicker patients were consistent (2+ ECOG TTNT (aHR 0.95, 0.81-1.12)), (BMI >30, TTNT (aHR 0.84, 0.61-1.18)), and reached significance for some models (2+ ECOG TTD (aHR 0.66, 0.48-0.91)). Conclusions: First-line E-cont. regimens consistently showed increased effectiveness in outcomes compared to A-cont. regimens in mCRPC patients treated in community oncology setting. The effects sizes are modest and did not reach significance, however analysis of the sickest patients showed a trend of consistently larger effect sizes which reached significance for some outcomes. More work needs to be done to evaluate if these results support findings from other RWD sources.
Activity of lutetium-177 PSMA (Lu-PSMA) and determinants of outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with cabazitaxel: The PACAP study.
Authors: Flippot Ronan , Telli Tugce , Velev Maud , Flechon Aude , Turpin Lea , Bergman Andre M. , Turco Fabio , Fendler Wolfgang Peter , Giraudet Anne Laure , Montravers Françoise , Vogel Wouter V. , Gillessen Silke , Berardi Simona , Herrmann Ken , Kryza David , Paone Gaetano , Garcia Camilo , Foulon Stéphanie , Pages Arnaud , Fizazi Karim 
Published: March 2023

180 Background: Cabazitaxel and Lu-PSMA both improved survival in patients with mCRPC after docetaxel and an androgen receptor pathway inhibitor (ARPI), but there is limited data regarding Lu-PSMA activity after cabazitaxel. We aimed at assessing activity of Lu-PSMA and determinants of outcomes in this setting. Methods: Consecutive mCRPC patients from 6 European centers treated with Lu-PSMA after cabazitaxel were included in this retrospective study. Endpoints included radiographic progression-free survival (rPFS), time to PSA progression (PSA-TTP), PSA decline, objective response, overall survival, and safety. Results: Of 101 patients included (median age 67y), 64% had ISUP grade 4-5 disease; 71% had bone +/- nodal (LN) metastases, 22% visceral metastases, 7% LN only. All patients and 92% had received previous docetaxel and a prior ARPI (≥ 2 in 47%) before cabazitaxel respectively. Patients had received a median number of 6 cabazitaxel cycles (range 1-26). DNA damage repair alterations (DDR) were found in 11/48 (23%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (range 1-14). With a median follow-up of 5.7 months, the median rPFS from Lu-PSMA initiation was 4.3 months (m, 95%CI 3.2-5.7) and median PSA-TTP was 3.5 m (95%CI 3.0-4.5). Overall, 44 patients (44%) experienced a PSA decline ≥ 50% (PSA50), 54 (53%) ≥ 30% (PSA30), and 67 (66%) any PSA decline. Objective response rate was 34%. Baseline characteristics associated with shorter rPFS on Lu-PSMA included ISUP grade 4-5 disease (median rPFS of 3.5 vs. 7.2m, p=0.02) and a time to castration resistance < 12 months (3.1m vs. 4.5m, p=0.04). Patients with LN only had longer rPFS compared to those with bone and visceral metastases (median NR vs. 3.6 and 3.7m, respectively, p=0.02). There was no association between activity of Lu-PSMA and DNA damage repair alterations, duration of previous cabazitaxel therapy, and number of previous ARPI. During Lu-PSMA, a profound PSA decline was associated with longer rPFS: patients achieving PSA50, PSA30 or any PSA decline had respective median rPFS rates of 9.0, 8.3 and 6.2 months, while those who did not experience any PSA decline had a median rPFS of only 2.6 months. Conclusions: Lu-PSMA demonstrated substantial PSA decline but limited duration of response after cabazitaxel in a real-life setting. Adverse baseline characteristics and absence of PSA decline may help early identification of poor responders.