bluuebunny/crossref_metadata_2025_split huggingface dataset:
The CADMUS trial: A paired cohort, blinded study comparing multiparametric ultrasound targeted biopsies with multiparametric MRI targeted biopsies in the detection of clinically significant prostate cancer.
Authors: Grey Alistair , Scott Rebecca , Shah Bina , Acher Peter , Liyanage Sidath , Pavlou Menelaos , Omar Rumana , Chinegwundoh Frank , Patki Prasad , Campbell Diane , Shah Taimur T. , Hamid Sami , Brew-Graves Chris , Arumainayagam Nim , Chapman Alex , Eldred-Evans David , Freeman Alex , Winkler Mathias , Emberton Mark , Ahmed Hashim Uddin ,   The CADMUS Study Group
Published: June 2021

5008 Background: Multiparametric MRI (mpMRI) of the prostate followed by targeted biopsy is recommended in men at risk of prostate cancer. Dissemination of this pathway may be limited by cost, variable scan and reporting quality, and contraindicated in the presence of metallic implants and claustrophobia. Multi-parametric ultrasound (mpUSS) is a point of care test with low cost that combines b-mode, colour Doppler, elastography and contrast enhancement. CADMUS compared the diagnostic performance of mpUSS to mpMRI. Methods: CADMUS recruited 370 patients from seven sites to a prospective, multicentre, paired-cohort trial (ISRCTN 38541912). Ethics committee approval was obtained. Patients underwent both mpUSS and mpMRI independently, each with a positive test defined as a Likert score of >3. Those with either a positive mpUSS or mpMRI, or both, were advised to undergo targeted biopsies. Reporting of each scan was carried out blind to the other and prior to biopsy; patients advised for biopsy were blinded to which test was positive. The order of mpUSS and mpMRI targeting was randomised. Primary outcomes were proportion of positive tests and detection of clinically significant cancer (csPCa) defined as Gleason >4+3 of any length and/or maximum cancer core length of >6mm of any grade [PROMIS definition1]. Results: 306 completed both mpUSS and mpMRI. Agreement in lesion detection between mpUSS and mpMRI was 73.2% (kappa 0.06, p = 0.14). 257 with positive results on mpUSS, mpMRI or both had targeted biopsies. Agreement on detection of csPCa was 91.1% (expected 59.8%, kappa 0.78, p < 0.01). Overall, mpUSS detected 4.3% fewer csPCa than mpMRI (95% CI = [-8.3%, -1.5%]; p = 0.042 [Bonferroni correction]). mpUSS detected 7.2% (6/83) csPCa missed by mpMRI; mpMRI detected 20.5% (17/83) csPCa that mpUSS missed. At a less stringent definition of significant cancer, Gleason grade >3+4 of any length (definition 3), agreement was 89.1% (expected 55.6%, kappa 0.75, p < 0.01) mpUSS detected 5.4% fewer definition 3 cancers than mpMRI overall. mpUSS detected 7% (7/99) definition 3 cancers that mpMRI missed; mpMRI detected 21% (21/99) definition 3 cancers that mpUSS missed. Conclusions: The CADMUS trial shows mpUSS has a diagnostic performance approaching that of mpMRI and significant cancer detection is improved by the use of both scans over mpMRI alone. Clinical trial information: 38541912. [Table: see text]
Concordance of DNA damage repair (DDR) gene mutations in paired primary and metastatic prostate cancer (PC) samples.
Authors: Schweizer Michael Thomas , Sivakumar Smruthy , Tukachinsky Hanna , Coleman Ilsa , De Sarkar Navonil , Yu Evan Y. , Konnick Eric Quentin , Nelson Peter , Pritchard Colin C. , Montgomery Robert B. 
Published: June 2021

5020 Background: Mutations in DDR genes represent actionable alterations that can be used to guide precision medicine strategies in men with advanced PC. However, acquisition of contemporary tissue samples for advanced molecular testing can be a barrier to deploying precision medicine approaches. We hypothesized that most DDR alterations represent early truncal events in PC and that archival primary tissue would faithfully reflect mutations found in cell-free circulating tumor (ctDNA) and/or metastatic tissue. Methods: Patients were included in this study if a DDR pathway mutation was detected in metastatic tissue or ctDNA and primary tissue sequencing was available for comparison. Sequencing data from three cohorts were analyzed: 1) FoundationOne, 2) University of Washington (UW-OncoPlex or SU2C/PCF International Dream Team sequencing pipelines) and 3) University of Washington rapid autopsy series. Only pathogenic somatic mutations were included and we required ≥30 days between primary tumor tissue and ctDNA/tumor tissue acquisition. Clonal hematopoiesis of indeterminant potential (CHIP) and germline events were adjudicated by an expert molecular pathologist and excluded. Variants detected only in plasma were considered likely to be CHIP or low subclones if the variant fraction was <1% and/or >5-fold less than the estimate tumor content in plasma. Results: Paired primary and ctDNA/metastatic samples were sequenced from 72 individuals with known DDR alterations. After excluding ctDNA cases where only CHIP (N=13) and/or germline events (N=7) were observed, 51 subjects remained and were included in the final analysis. The median time from acquisition of primary tissue to acquisition of ctDNA or tumor tissue was 52 mos (range: 1 – 193 mos). Concordance in DDR genes across samples was 86% (95% CI: 74-93%). Rates of concordance between metastatic-primary and ctDNA-primary pairs were similar when CHIP cases were excluded (87% and 85%, respectively). BRCA2 reversion mutations associated with resistance to PARP inhibitors and platinum chemotherapy were detected in ctDNA from two subjects. Conclusions: These data provide evidence that primary prostate tissue accurately reflect the mutational status of actionable DDR genes in men with metastatic PC, supporting the hypothesis that DDR alterations are early truncal events. After excluding likely CHIP events, ctDNA profiling accurately captured these truncal DDR mutations, while also detecting reversion alterations that may suggest potential resistance mechanisms.[Table: see text]
An open-label, pharmacokinetic study to determine the bioavailability, safety and tolerability of single dose oral docetaxel in metastatic prostate cancer (mPC) patients treated with IV docetaxel.
Authors: Jackson Christopher G. C. A. , Ou Yen-chuan , En Meng , Chao Tsu-Yi , Hung Noelyn Anne , Wang David , Cutler David , Kramer Douglas , Zhi Jay , Chan Wing Kai , Kwan Min-Fun Rudolf , Hung Tak 
Published: June 2021

5050 Background: Docetaxel has poor oral bioavailability in part due to extrusion by intestinal p-glycoprotein. To improve IV solubility, it is fomulated with the nonionic surfactant polysorbate 80, requiring steroid premedication to manage hypersensitivity type reactions. Oral administration has the potential to improve tolerability, reduce day-stay utilization and improve patient convenience and allows investigation of alternative dosing schedules. Oradoxel is a new combination of oral docetaxel capsules plus the novel gut-selective P-glycoprotein inhibitor encequidar (HM30181A). Methods: Patients with mPC receiving IV docetaxel were enrolled in 3 cohorts with a dose escalation schedule of Oradoxel 75 mg/m2 in Cohort 1, 150 mg/m2 in Cohort 2, 300mg/m2 in Cohort 3. Oradoxel was given 3 weeks before or after IV docetaxel treatment. Intensive PK samples were taken on days 1-5 for Oradoxel and days 1-4 for IV docetaxel. Dose limiting toxicity (DLT) or serious adverse events (SAE) were assessed per CTCAE v4.03. Results: 3 evaluable patients in each Cohort were studied. No DLT, MTD, or drug-related SAE were observed. PK parameters of Oradoxel vs IV docetaxel are summarized in the table below. Mean absolute bioavailability of Oradoxel was 15.9% (range 8-25%). PK became non linear at 300mg/m2. Conclusions: Oradoxel was well tolerated. Based on the results of this and related studies, Oradoxel 300mg/m2 in divided doses is being further evaluated in phase 2 studies. Clinical trial information: 12616000983404. [Table: see text]
Real-world utilization of advanced therapies and racial disparity among patients with metastatic castration-sensitive prostate cancer (mCSPC): A Medicare database analysis.
Authors: Freedland Stephen J. , Agarwal Neeraj , Ramaswamy Krishnan , Sandin Rickard , Russell Dave , Hong Agnes , Yang Hongbo , Gao Wei , Hagan Kaitlin , George Daniel J. 
Published: June 2021

5073 Background: Several randomized controlled trials have shown that adding docetaxel or novel hormonal therapy (NHT) to androgen deprivation therapy (ADT) improves survival in mCSPC patients. This study aimed to evaluate the real-world utilization of advanced therapies over time and to provide data on utilization patterns among racial minorities that are often under-represented in clinical trials. Methods: This was a retrospective analysis of a Medicare database (Jan 2009-Dec 2018). Adult men with ≥1 claim for prostate cancer (PC) who initiated ADT (index date) within 90 days prior to or any time after a metastasis diagnosis were included. The first-line (1L) treatment was grouped by PC drugs prescribed within 30 days prior to and 120 days after the index date, in 4 categories: ADT alone, ADT + first-generation anti-androgen (AA; ≥90 days to avoid capturing AA for flare control), ADT + docetaxel, and ADT + NHT (abiraterone, apalutamide, and enzalutamide). The 1L treatment distributions were described over time and stratified by race. Results: A total of 35,195 patients with mCSPC were included in the study, with a mean (SD) age of 76.5 (7.9) years. 11.8% were Black, 5.3% Hispanic, and 78.5% White. 76.4% received ADT alone as 1L treatment, 14.3% ADT + AA, 4.8% ADT + docetaxel, and 4.5% ADT + NHT. While the proportion of patients treated with ADT alone and ADT + AA slowly decreased over time, the utilization of ADT + docetaxel increased since 2015 and the utilization of ADT + NHT increased since 2017 (Table). After the emergence of NHTs for treatment of mCSPC in 2017, treatment intensification with ADT + NHT was numerically lower for Black than White patients. Data from before 2017 also suggest a similar lower use of ADT + AA in Black patients (Table). Survival analysis across treatment cohorts and race are ongoing. Conclusions: In this large and nationally representative sample of mCSPC patients, less than one-third of patients received treatment intensification by 2018, possibly due to patient/disease characteristics, provider awareness or therapeutic inertia, or cost. Importantly, the data showed less frequent treatment intensification in Black vs White patients. Further study is required to elucidate underlying reasons for this disparity.[Table: see text]
Correlation of baseline circulating tumor cells (CTC) and associated genomic profile with survival outcomes in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) in a real-world cohort.
Authors: Swami Umang , McFarland Taylor Ryan , Haaland Benjamin , Kessel Adam , Nussenzveig Roberto , Sayegh Nicolas , Hahn Andrew Warren , Rathi Nityam , Sirohi Deepika , Esther John , Li Haoran , Kohli Manish , Maughan Benjamin L. , Goldkorn Amir , Agarwal Neeraj 
Published: June 2021

5077 Background: We recently published, in the context of SWOG1216 trial in pts with mCSPC, that higher baseline CTC level were associated with inferior survival outcomes (Goldkorn. Agarwal, CCR, 2021). Here in, we validate these findings in a real world population of mCSPC and interrogate tumor genomic profile with respect to the CTC level. Methods: Eligibility criteria: new mCSPC receiving ADT without or with intensification (docetaxel or novel hormonal therapy) and enumeration of baseline CTCs by FDA cleared Cell Search CTC assay. Gene alterations were determined by comprehensive genomic profiling (CGP) of tumor tissue (Foundation Medicine). CTC counts were categorized as 0, 1-4 and ≥5/7.5 ml. Relationships between CTC counts and number (no.) of genes altered and individual gene alterations were assessed via Kruskal-Wallis and chi-squared tests, respectively. Relationships between progression-free survival (PFS), overall survival (OS) and individual mutations were assessed via log-rank tests. Relationships between CTC counts, PFS and OS were assessed by Cox proportional hazards models, both unadjusted and adjusted for multiple variables (Table). Results: Overall 103 pts were eligible. Median age: 67 yrs, Gleason score: 9, PSA at ADT initiation: 41 ng/mL. 67 (65%) pts had de-novo metastatic disease and 44 (43%) pts underwent ADT intensification therapy. Pts with greater CTC counts tended to have greater no. of altered genes (p=0.017), greater no. of total alterations (p=0.017) and higher rate of TP53 mutations (p=0.036). In univariate analyses (UVA) and multivariable analyses (MVA), both CTC counts and no. of genes altered were strongly associated with both PFS and OS (Table). CGP of tumors with respect to CTC counts will be presented in meeting. Conclusions: Herein, we validate our previous findings from SWOG1216 trial of association of higher CTC level with inferior survival outcomes in a real world mCSPC cohort. The CTC enriched population is associated with a distinct tumor genomic landscape, which may guide further drug development in this pt population at the highest risk of progression and/or death.[Table: see text]
Outcome and immune landscape of HER2-positive invasive lobular carcinoma in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) trial.
Authors: Chumsri Saranya , Li Zhuo , Shachner Tracy , Advani Pooja , Sideras Kostandinos , Moreno-Aspitia Alvaro , Colon-Otero Gerardo , Knutson Keith L. , Nassar Aziza , Perez Edith A. , Thompson E Aubrey 
Published: June 2021

535 Background: Invasive lobular carcinoma (ILC) is a rarer form of breast cancer, accounting for 10% of the disease cases. HER2 overexpression in ILC is infrequent and limited data exist regarding clinical characteristics and outcome of HER2-positive (HER2+) ILC patients (pts) treated with adjuvant trastuzumab. Methods: Patient characteristics were compared between ILC and invasive ductal carcinoma (IDC) using Wilcoxon rank sum test for continuous variables and Chi-square test for categorical variables. Kaplan-Meier (KM) method was used to estimate the freedom from mortality and recurrence. Cox regression model was used to evaluate the association between ILC and outcomes adjusted for other characteristics. NanoString technology was used to quantify mRNA to develop immune-related gene signatures. Results: From a total of 3,304 pts, 122 (3.7%) pts had ILC. Pts with ILC were significantly older (median age 54 vs. 49 years), had larger tumors, lower grade, more ER and PR positive tumors, and more lymph node involvement (25.4% had N3 disease compared to 12.7% in IDC). Overall, with KM analysis, pts with ILC had significantly worse overall survival (OS, p = 0.005) and recurrence-free survival (RFS, p = 0.046) compared to IDC. The 15-year freedom from recurrence was merely 57.67% in ILC compared to 72.68% in IDC. A significant number of hormone receptor-positive (HR+) ILC pts developed late recurrence with cumulative event rates increasing from 23% at 5 years to 42% at 15 years. Nevertheless, in multivariate Cox regression analysis adjusting for other clinical characteristics, including age, tumor size, grade, ER/PR, and lymph node status, lobular histology was not significantly associated with worse outcome for OS (HR = 1.19, 95%CI 0.67-2.1, p = 0.55) and RFS (HR = 1.5, 95%CI 0.9-2.5, p = 0.12), as compared with IDC. However, ILC pts appeared to have similar degree of benefit from trastuzumab, with RFS HR = 0.58 compared to HR = 0.67 in the entire population. For immune landscape, there was no significant difference in gene signatures related to CD45, CD8, B cells, or cytotoxic cells. However, ILC had more enrichment in mast cell gene signature and fewer macrophage, NK CD56dim, and regulatory T cell signatures compared to IDC (p < 0.05). Conclusions: HER2+ ILC has distinct clinical characteristics and immune landscape compared to IDC. ILC pts appeared to have worse outcome compared to IDC likely because ILC pts often presented with more locally advanced disease. However, similar benefit of trastuzumab was observed in ILC pts. Due to high risk of late relapse in HR+ HER2+ ILC, extended adjuvant endocrine therapy should be considered in this group of high-risk pts. Clinical trial information: NCT00005970.
Potential non-drug cost differences associated with the use of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) in the treatment of HER2-positive early breast cancer patients in Western Europe and the United States.
Authors: Manevy Federico , Filkauskas Gabriele , Levy Pierre , Fredriksson Judy , Sussell Jesse 
Published: June 2021

544 Background: In patients with HER2-positive early breast cancer (BC), pertuzumab (P) added to trastuzumab (T) and chemotherapy has been recognized as a standard-of-care, improving the risk of recurrence. P and T treatments can be given intravenously (PT IV) or, more recently, subcutaneously − via PH FDC SC. Both methods are comparable in terms of efficacy and safety profiles. However, PH FDC SC allows for a faster infusion than that of PT IV, and this can be associated with lower costs. The aim of this study is to estimate the incremental difference in non-drug costs between PH FDC SC and PT IV for a typical patient receiving treatment for HER2-positive early BC in Western Europe and the United States. Methods: A model-based cost-minimization analysis was performed to quantify mean non-drug cost differences per patient over a full course of therapy (18 cycles). Western Europe: costs in the analysis are based on an archetypal country, and explicitly include estimates for costs for patient chair time, active healthcare professional (HCP) time, usage of non-drug consumables, port-a-cath placement surgeries and patients’ productivity losses. Costs are calculated by multiplying the resource use by its corresponding unit price. Costing data were obtained from literature sources on T SC time and cost savings for Western European countries, and assumptions on PH FDC SC and PT IV times and costs. United States: non-drug costs for the two strategies were estimated using average net reimbursement amounts for relevant procedure codes for intravenous and SC therapy administration among commercial payers in the MarketScan databases. Results: PH FDC SC is estimated to reduce non-drug costs by 73% − 80% in Western Europe, and 75% in the United States. Total monetary non-drug savings per patient over 18 cycles of treatment are estimated in the range of €2,474 − €8,975 in Western Europe, and at $10,138 in the United States. In Western Europe, where the analysis allows for a disaggregation by cost category, cost savings related to savings in patient chair time (excluding patients’ productivity losses) are estimated to account for up to 62% of overall non-drug cost savings. Patients’ productivity losses are estimated to explain up to 11% of non-drug cost differences. Conclusions: The use of PH FDC SC for the treatment of HER2-positive BC can potentially result in substantial non-drug cost savings. These savings could easily derive in overall net cost savings to the healthcare system, contributing to the long-term sustainability of the healthcare spending, while still providing a safe and effective therapy.[Table: see text]
Phase 3, randomized, single-dose, open-label study to investigate the safety and efficacy of pafolacianine sodium injection (OTL38) for intraoperative imaging of folate receptor positive ovarian cancer.
Authors: Tanyi Janos Laszlo , Chon Hye Sook , Morgan Mark Aloysuis , Chambers Setsuko K. , Han Ernest Soyoung , Butler Kristina A. , Langstraat Carrie L. , Powell Matthew A. , Randall Leslie M. , Vahrmeijer Alexander L. , Winer Ira Seth , Wenham Robert Michael 
Published: June 2021

5503 Background: Pafolacianine sodium is under investigation as an adjunct to visual inspection and palpation by providing intra-operative imaging of folate receptor positive (FR+) ovarian cancer. Since complete resection (R0) is the strongest predictor of overall survival, methods to enhance detection of lesions are expected to benefit patient outcomes. Methods: For this phase 3, randomized, multicenter, single dose, open-label pivotal trial (NCT03180307), patients with ovarian cancer who were scheduled to undergo cytoreductive surgery were recruited from 11 sites in the US and Netherlands from March 2018 through April 2020. The study objectives were to confirm efficacy and safety of pafolacianine sodium (0.025 mg/kg i.v., ≥1 h prior to imaging) in combination with intraoperative near-infrared fluorescence (NIRF) imaging to detect additional lesions not detected by palpation and normal white light alone. Results: Pafolacianine sodium was administered to 150 total patients (safety analysis set); 109 patients comprised the full analysis set for efficacy analyses. Patients had primarily serous adenocarcinoma (n = 72; 68.6%) and advanced stage disease (n = 83; 76.1%). In 33% of patients (36 of 109), NIRF imaging with pafolacianine sodium identified additional lesions that were not planned for resection and were not detected by normal white light and palpation ( P < 0.001, 95% CI [0.243, 0.427]). Among patients who underwent interval debulking surgery, the rate was higher, at 39.7% of patients (23 of 58; 95% CI [0.270, 0.534]). At the individual lesion level, the accuracy of pafolacianine sodium with NIRF to detect ovarian cancer is reflected by sensitivity of 83% (95% CI [73.9, 89.4]) and a false positive rate of 32.7% (95% CI [25.6, 40.7]). Investigators reported achieving complete resection (R0) in 62.4% (68 of 109) of patients. Drug-related adverse events (AEs) were reported by 30% of patients (45 out of 150). The most frequently reported drug-related AEs were nausea (18.0%), vomiting (5.3%), and abdominal pain (4.7%). Infusion reactions at the time of the procedure were mostly (96%) mild or moderate in severity; 89% resolved within 24 hours of onset. No drug-related serious AEs or deaths were reported. Conclusions: This phase 3 trial of pafolacianine sodium with NIRF imaging met its primary endpoint, intraoperatively identifying additional cancer not planned for resection in a statistically significant number of patients. Therefore, pafolacianine sodium may offer a novel real-time adjunct to current surgical imaging practice in ovarian cancer surgery. Clinical trial information: NCT03180307.
Population-based estimates of the age-specific cumulative risk of breast cancer for pathogenic variants in CHEK2: Findings from the Australian Breast Cancer Family Registry.
Authors: Nguyen-Dumont Tu , Dowty James , Steen Jason A , Renault Anne-Laure , Hammet Fleur , Mahmoodi Maryam , Theys Derrick , Rewse Amanda , Tsimiklis Helen , Winship Ingrid , Giles Graham G. , Milne Roger L , Hopper John L. , Southey Melissa C 
Published: June 2021

551 Background: Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein truncating variant CHEK2c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. Methods: We conducted a genetic screen of CHEK2 in an Australian population-based case-control-family study of breast cancer. This study is focused on disease at an early age and participants were unselected for family history. The age-specific cumulative risk (penetrance) of breast cancer was estimated using segregation analysis. Results: The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5-9.5; p < 0.0001) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02-11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5-12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11-30%) and 33% (95% CI 21-48%) to age 60 and 80 years, respectively. Conclusions: These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.