bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATM loss in primary prostate cancer: Analysis of >1000 cases using a validated clinical-grade immunohistochemistry (IHC) assay.
Authors: Antonarakis Emmanuel S. , Kaur Harsimar B , Hicks Jessica , Pritchard Colin C. , De Marzo Angelo M , Isaacs William B. , Lotan Tamara L. 
Published: May 2019

5069 Background: ATM is a protein kinase acting as the main signal transducer of double-strand DNA break repair, in addition to mediating other cellular functions. Germline and somatic pathogenic mutations in ATM occur in a significant fraction of prostate cancers, and targeted therapies for ATM-deficient tumors ( e.g. ATR inhibitors) appear promising. Because DNA sequencing assays frequently cannot distinguish mono-allelic from bi-allelic ATM alterations, a clinical-grade protein IHC assay for ATM loss is needed to select men for these trials and better characterize ATM-deficient tumors. Methods: We validated an automated dichotomously-scored IHC assay to detect ATM protein loss in primary prostate cancer using prostate cancer cell lines with and without bi-allelic ATM inactivation and 49 high-grade (primary Gleason pattern 5) prostate tumors with known ATM genomic status. We then examined the frequency of ATM loss among 23 tumors with pathogenic germline ATM mutations, as well as > 1000 additional primary prostate carcinomas using tissue microarrays (TMA). Results: ATM loss by IHC was found in 14% (7/49) of primary Gleason pattern 5 (5+4 = 9 and 5+5 = 10) tumors. Of these, all cases with adequate tumor content and DNA yield had underlying pathogenic ATM mutations. Of the remaining 42 cases without ATM protein loss, none had ATM alterations. Among men with pathogenic germline ATM mutations, 74% (17/23) had ATM loss by IHC. Of these, 76% (13/17) had homogeneous loss of ATM protein in all tumor cells within a dominant tumor nodule, suggesting that ATM loss was an early clonal event. On TMA analysis, 90% (944/1044) of tumors were evaluable for ATM status by IHC. Among these, ATM loss was seen in 3.3% (31/944), and was significantly more common in tumors with Gleason scores 9-10 (20/198; 10.1%) than in those of all other Gleason grades (11/746; 1.5%) ( P< 0.0001). Conclusions: Validated ATM IHC is a sensitive assay for detecting underlying genomic ATM alterations. ATM protein loss appears to be an early event occurring in the majority of tumors with underlying germline pathogenic ATM mutations, and is significantly enriched in high-grade prostate cancers (especially Gleason grades 9-10).
Implications of the United States Preventive Services Task Force (USPSTF) recommendations on prostate cancer (PCa) stage migration.
Authors: Sheng Iris Yeong- Fung , Chen Yu-Wei , Ornstein Moshe Chaim , Gilligan Timothy D. , Rini Brian I. , Garcia Jorge A. 
Published: May 2019

5071 Background: Prostate specific antigen (PSA) screening has been controversial, given unrefined screening guidelines leading to overdiagnosis and overtreatment of “indolent” PCa. In 2008, the USPSTF recommended against PSA screening for men aged ≥75 and in 2012 broadened this recommendation to include all men. The impact of these changes is unstudied. We hypothesize that these screening changes could delay the diagnosis of advanced PCa. Methods: The Surveillance, Epidemiology and End Results Program (SEER) was used to identify men (age 55-69) diagnosed with PCa between 2004-2015. PCa stage was categorized as nodal (N1M0) and metastatic (NxM1). Trend analysis was stratified based on year 2004-2008 (group 1), 2009-2012 (group 2), and 2012-2015 (group 3). Using group 2 as a reference, multivariable logistic regression was used to identify predictors for N1M0 and NxM1 in each group. Results: From 2004-2015, there were 603,323 eligible men diagnosed with PCa (group 1: 262,240 men, group 2: 210,045 men, group 3: 131,038 men). In group 1, 1.4% had N1M0 and 2.8% had NxM1. In group 2, 1.6% had N1M0 and 3.7% had NxM1. In group 3, 1.4% had N1M0, and 6.1% had NxM1. The adjusted odds ratio (AOR) of N1M0 was 0.78 (95%CI 0.74-0.82; p<0.0001) in group 1 and 1.71 (95%CI 1.63-1.80; p<0.0001) in group 3. Similar AOR trends were seen in NxM1 (group 1, 0.71; 95%CI 0.68-0.73, p< 0.0001 vs. group 3, 1.70; 95% CI 1.63-1.75, p<0.0001). (Table) Subset analysis of non-eligible patients (age >70 and <55) showed a similar stage migration. Conclusions: With each USPSTF recommendation, there have been significantly more diagnoses of advanced PCa; suggesting stage migration. The sequelae of having advanced PCa include more aggressive treatments, increased financial burden, and reduced quality of life. Future population studies are warranted to investigate whether the updated 2018 USPSTF recommendation now encapsulates the best target population.[Table: see text]
Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).
Authors: Fu Simon Yuen Fai , Ritch Elie , Herberts Cameron , Yip Steven , Khalaf Daniel , Warner Evan W , Taavitsainen Sinja , Annala Matti , Vandekerkhove Gillian , Kushnir Igal , Ferrario Cristiano , Wyatt Alexander William , Chi Kim N. 
Published: May 2019

5072 Background: A small proportion of metastatic PC exhibit outlier somatic mutation (mut) rates exceeding the average of 4.4 mut/Mb. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing from a panel of PC genes using plasma cell-free DNA samples collected from metastatic castration-resistant prostate cancer (mCRPC) pts and calculated somatic mutation burden. HM samples were additionally subjected to whole exome sequencing to determine trinucleotide mutational signatures and microsatellite instability (MSI). Clinical data was retrospectively collected and compared to a control cohort of 199 mCRPC pts. Results: 671 samples from 434 pts had ctDNA > 2% and were evaluable. 32 samples from 24 pts had > 11 mut/Mb and fell above the 95th percentile for mutation burden with a median mutation burden of 34 mut/Mb. 11 pts had deleterious mutations or homozygous deletions in mismatch repair (MMR) genes and 4 further pts had evidence of MMR deficiency (MMRd) from mutational signatures and MSI status. The remaining 9 pts had either BRCA2 mutations (n = 4), Kataegis (localized hypermutation, n = 3), or undefined causes for HM (n = 2). The incidence of MMRd was 3.5% (15/434), and germline MMRd was 0.2% (1/434). For MMRd pts with available clinical data (10/15) at diagnosis, the median age was 73.6 y, 70% had Gleason score ≥8, and 50% presented with M1 disease. Comparing the MMRd with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9–11.4) vs. 18.2 m (95% CI 15.1–21.3), p = 0.001; median time from CRPC to death was 13.1 m (95% CI 0.3–25.9) vs. 40.1 m (95% CI 32.4–47.8), p < 0.001. Conclusions: HM and MMRd can be identified using liquid biopsy and could help to select pts for immunotherapy.
The rate of tumor growth, g, as a biomarker for overall survival (OS) in prostate cancer (PC) in clinical trials as well as in real-world data from the Veterans Administration Medical Centers (VAMCs).
Authors: Leuva Harshraj , Zhou Mengxi , Wilkerson Julia , Sigel Keith , Hsu Ta-Chueh , Aggen David Henry , Langhoff Erik , Park Yeun-Hee Anna , Bates Susan Elaine , Fojo Antonio Tito 
Published: May 2019

5074 Background: Novel assessments of efficacy are needed to improve determination of treatment outcomes in clinical trials and in real-world settings. Methods: Cancer treatments usually lead to concurrent regression and growth of the drug-sensitive and drug-resistant fractions of a tumor, respectively. We have exploited novel methods of analysis that assess these two simultaneous processes and have estimated rates of tumor growth ( g) and regression ( d) in over 30,000 patients (pts) with diverse tumors. Results: In prostate cancer (PC) we have analyzed both clinical trial and real-world data from Veterans. Using clinical trial data from 6819 pts enrolled in 15 treatment arms we have established separately and by combining all the data that g correlates highly (p<0.0001) with overall survival (OS) – slower g associated with better OS. In PC, abiraterone (ABI) and docetaxel (DOC) are superior to placebo, prednisone and mitoxantrone. ABI (median g =0.0017) is superior to DOC ( g=0.0021) in first line (p=0.0013); and ABI in 2nd line ( g=0.0034) is inferior to ABI in 1st line ( g=0.0017; p<0.0001). Finally, using combined clinical trial data as a benchmark we could assess the efficacy of novel therapies in as few as 30-40 patients. Amongst 7457 Veterans, the median g on a taxane ( g=0.0022) was similar to that from clinical trials ( g=0.0012). Although only 258 Veterans received cabazitaxel (CAB), g values for CAB ( g=0.0018) and DOC ( g=0.0023) were indistinguishable (p=0.3) consistent with their identical mechanism of action. Finally, outcomes with DOC in African American (AA) ( g=0.00212) and Caucasian ( g=0.00205) Veterans were indistinguishable (p=0.9) and comparable across all VAMCs. Conclusions: The rate of tumor growth, g, is an excellent biomarker for OS both in clinical trials and in real-world settings. g allows comparisons between trials and for large trial data sets to be used as benchmarks of efficacy. Real-world outcomes in the VAMCs are similar to those in clinical trials. In the egalitarian VAMCs DOC efficacy in PC is comparable in AA and Caucasian Veterans -- indicating inferior outcomes reported in AAs are likely due to differential health care access, not differences in biology.
Assessment of 2,000 patients presenting to a multidisciplinary prostate cancer clinic in the United Kingdom.
Authors: Rudd Pandora , Hines John , Watkins Eleanor , Powles Thomas , Tipples Karen 
Published: May 2019

5077 Background: Multidisciplinary clinics (MDCs) involving both oncologists and urologists are recommended for managing radical prostate cancer patients. The effectiveness of MDCs in arriving at best treatment decisions is unknown. We analysed patient characteristics and management decisions over 8 years in a MDC at Bart’s Hospital, London. Methods: Clinical data were collected in real time and analysed retrospectively, including demographics, tumour stage and grade, D’amico risk group, treatment choice and first clinician seen. We compared variables in 1000 consecutive patients presenting between 2011-2015 (cohort A) to 1000 patients presenting 2016-18 (cohort B) to investigate trends over time. Results: 2000 patients were included, age 65.2 ± 8.6 years and 65.9 ± 9.1 years (p=0.08), with presenting PSA 9.0 (6.3-14.4) and 9.2 (6.4-15.0) ng/ml (p=0.36), in cohort A and B respectively. Disease severity and initial treatment decision are shown in the table. In low risk disease, 126 (75%) patients had active surveillance in cohort A, and 158 (90%) in cohort B (p=0.0003). In high risk disease, 202 (59%) patients had radiotherapy compared to 194 (50%) in cohort B (p=0.011). In cohort B, 127 (39%) patients seeing oncology first had radiotherapy compared to 143 (25%) patients who saw urology first (p<0.0001). 76 (23%) and 154 (27%) patients had surgery, that saw oncology and urology first, respectively (p=0.11). Conclusions: In 2000 patients presenting to a prostate MDC over 8 years, active surveillance in low risk disease increased, radiotherapy in high risk disease reduced, and the proportion undergoing surgery was unchanged. The initial clinician seen influenced treatment choice; having both specialists in the same consultation may improve consistency of treatment decisions. Disease severity and treatment choice before and after 2016. [Table: see text]
Patient-reported outcomes (PROs) in NRG oncology/NSABP B-39/RTOG 0413: A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) in stage 0, I, or II breast cancer.
Authors: Ganz Patricia A. , Cecchini Reena S. , White Julia R. , Vicini Frank , Julian Thomas B. , Arthur Douglas W , Rabinovitch Rachel , Kuske Robert R. , Parda David S. , Scheier Michael , Winter Kathryn A. , Paik Soonmyung , Kuerer Henry Mark , Vallow Laura , Pierce Lori J. , Mamounas Eleftherios P. , Costantino Joseph P. , McCormick Beryl , Curran Walter John , Wolmark Norman 
Published: May 2019

508 Background: PBI is an alternative to WBI, with potentially greater therapy (tx) compliance, and better integration with chemotherapy (CTX). NSABP B-39/RTOG 0413 clinical outcome results from 2018 did not show equivalence of PBI to WBI in local tumor control; PBI was statistically inferior, but with clinically small differences. PBI may be an acceptable alternative to WBI for some women. Understanding cosmesis and quality of life (QOL) treatment outcomes is important. Methods: B-39/0413 included a prospective QOL substudy with PRO evaluation of breast cancer treatment outcomes (cosmesis, function, pain) and fatigue using BCTOS and SF-36 vitality scales. Secondary QOL parameters included treatment related symptoms, perceived convenience of care, and the BPI pain scale. The study sample was stratified by CTX or not, as CTX is given before WBI but after PBI. PRO assessments occurred before randomization, the last day of adjuvant tx [CTX or radiation], 4 wks later, and 6, 12, 24, and 36 mo later. Primary aims included comparisons of change in fatigue from baseline to end of tx and equivalency of change in cosmesis from baseline to 36 mo for PBI v WBI. Separate analyses were done for CTX and non-CTX pts, controlling for axillary dissection. Each comparison used α=0.0125. Planned sample size was 964. Results: From 3-23-05 to 5-27-09, 975 pts were enrolled in the PRO study; 950 had follow-up data. 504 did not receive CTX and 446 received CTX. In non-CTX pts, PBI had less fatigue (p=0.011) and did not meet criteria for cosmesis equivalence (97.5% CI, -0.02 to 0.22; ∆=0.20). In CTX pts, PBI had worse fatigue (p=0.011) and equivalent cosmesis to WBI (97.5% CI, -0.09 to 0.21; ∆=0.24). In both groups, PBI pts reported less pain at end of tx. In non-CTX pts, PBI had more pain at 36 mo but in CTX pts, there was no difference. Convenience of care and treatment related symptom outcomes will be presented. Conclusions: In non-CTX pts, PBI is more convenient with less fatigue and slightly poorer cosmesis at 36 mo. Cosmesis was equivalent at 36 mo in CTX pts. Support: U10CA180868, -180822, UG1CA189867. Clinical trial information: NCT00103181.
IMRT pelvic radiotherapy with simultaneous integrated boost in high-risk prostate cancer: Results after 10 years.
Authors: Ekanger Christian , Dahl Olav 
Published: May 2019

5084 Background: To report 10 year results after image guided intensity-modulated radiotherapy (IMRT) with hypofractionated simultaneous integrated boost (SIB) in high-risk prostate cancer. Methods: Between 2007 and 2009, 97 patients with an estimated risk of lymph node metastases above 15% (Roach equation) were prospectively included in a phase II study. Patients were treated with 2-2.7 Gy to the prostate, vesicula seminalis and elective pelvic field in 25 fractions over 5 weeks with androgen deprivation therapy for 2 years. Toxicity was scored according to RTOG criteria and biochemical free survival (BFS) using the Phoenix definition. Patients were divided into three groups; very high-risk patients (VHR) according to NCCN 2015 criteria (n=50), high-risk patients (HR) (n=32), and patients with N+ disease and/or pretreatment s-PSA ≥100 (n=15). Differences were examined using Kaplan Meier estimates with log rank test. Results: Ten year BFS in the entire cohort was 63%. Metastasis-free survival (MFS) was 77% and prostate-cancer-specific-survival (PCSS) 88%. Overall survival (OS) was 69% and local failure rate was 11%. VHR vs. HR subgroups had significant different BFS; 58% vs 84% (p=0.01) respectively. MFS and PCSS in the VHR group compared to the HR group was 78% vs 91% (p=0.108) and 86% vs 97% (p=0.157) respectively. Patients with N+ and/or PSA>100 had worse outcome compared to the HR/VHR groups, but not all had treatment failure. BFS was 33% vs 68% (p=0.001), MFS 47% vs 83% (p=0.000) and PCSS 73 % vs 90% (p=0.04), respectively. Patients who reached a PSA nadir value below 0.1 (n=80) had significant better outcomes, with PCSS 93% vs 65% (p= 0.001) and BFS 74% vs 12% (p=0.000), respectively. Acute gr 2 GI and GU toxicity was observed in 27% and 40%, gr 3 GI and GU toxicity in 1% and 3%. Late gr 2 GI and GU toxicity at 3 years appeared in 3% and 4% with no gr 3 toxicity. Conclusions: High-risk prostate cancer patients treated with IMRT with SIB obtained favorable outcomes with few serious side effects. There were significant better results in the HR versus the VHR group, both better than the N+/PSA≥100 group.
Differential impact of endocrine therapy (ET) and chemotherapy (CT) on quality of life (QoL) of 4,262 breast cancer (BC) survivors: A prospective patient-reported outcomes (PRO) analysis.
Authors: Ferreira Arlindo R. , Di Meglio Antonio , Pistilli Barbara , Gbenou Arnauld S. , El-Mouhebb Mayssam , Everhard Sibille , Coutant Charles , Cottu Paul-Henri , Lerebours Florence , Petit Thierry , Dalenc Florence , Rouanet Philippe , Arnaud Antoine , Martin Anne-Laure , Ganz Patricia A. , Partridge Ann H. , Delaloge Suzette , Michiels Stefan , Andre Fabrice , Luis Ines Maria Vaz Duarte 
Published: May 2019

512 Background: We recently witnessed a trend to de-escalate CT and escalate ET in adjuvant BC treatment (tx). However, there has been limited prior research investigating the differential impact on QoL of tx classes. We aimed to test the impact of CT and ET on QoL PROs 2 yrs after diagnosis (dx). Methods: CANTO (NCT01993498) is a multicenter prospective longitudinal study of stage I-III BC pts that characterizes long-term toxicities of BC tx. For this analysis we included 4262 pts recruited from 2012-14. QoL was extensively evaluated using the EORTC QLQ C30 and BR23. Linear regression modeling was performed, adjusting for demographic and clinical factors, with use of CT and/or ET as independent variables. Analyses were stratified by menopausal status due to different tx patterns and sequelae of CT. Results: Median age at dx was 56 yrs, 63% of pts were post (PostM) and 37% premenopausal (PreM), 80% had Charlson score 0, 91% stage I-II. 26% received mastectomy, 52% CT (preM 68%, postM 44%; 86% anthracycline+taxane) and 82% ET (preM 89% tamoxifen; postM 88% aromatase inhibitor). 32% preM pts had menses 1 year after ET initiation. Overall, QoL deteriorates 2 yrs after dx. ET negatively impacts more QoL domains than CT at 2 yrs. Also, young age, smoking, income, aggressive local tx and physiological distress are often associated with low QoL. In the stratified analyses, in postM pts, mostly ET (not CT) is associated with deteriorated QoL. In contrast, in preM pts, mostly CT (not ET) is associated with deteriorated QoL. Table shows eg of associations. Conclusions: In a large prospective cohort of BC survivors, detrimental QoL 2 yrs after dx is mostly associated with ET; however, negative effects of CT persist on preM. This differential effect on QOL should be considered when choosing optimal adjuvant therapy and appropriate selection of pts for ET escalation should be a research priority. [Table: see text]
Avoiding peg-filgrastim (Peg-F) prophylaxis during the paclitaxel (T) portion of the dose-dense (DD) doxorubicin-cyclophosphamide (AC)-T regimen: A prospective study.
Authors: Barroso-Sousa Romualdo , Luis Ines Maria Vaz Duarte , Di Meglio Antonio , Hu Jiani , Rees Rebecca , Sinclair Natalie Faye , Milisits Lindsey , Leone Jose Pablo , Constantine Michael , Faggen Meredith Gail , Briccetti Frederick , Block Caroline Cole , Partridge Ann H. , Burstein Harold J. , Waks Adrienne Gropper , Trippa Lorenzo , Tolaney Sara M. , Hassett Michael J. , Winer Eric P. , Lin Nancy U. 
Published: May 2019

517 Background: Use of growth factors (GF) adds considerable expense and some toxicity to adjuvant breast cancer chemotherapy. We tested the feasibility and safety of omitting routine GF use during the T portion of DD AC-T. Methods: This is a prospective, single-arm study in which patients (pts) who completed 4 cycles of DD-AC proceeded to DD-T 175 mg/m2 every two weeks (wks) without routine GF (NCT02698891). Key inclusion: age≤ 65, ECOG PS≤1, absolute neutrophil count (ANC) ≥1500/mm3, and no febrile neutropenia (FN) during DD-AC. Criteria to treat for T included ANC ≥1000/mm3. Peg-F was given only if pts had FN in a prior cycle, or at investigator discretion if infection or treatment delay > 1 wk. Once Peg-F was given, pts received it in all future cycles. The primary endpoint was the rate of T completion ≤ 7 wks from cycle 1 day 1 (C1D1) to C4D1. Secondary endpoints included total use of Peg-F, rates of hematologic toxicity and FN, reasons for dose modification or hold. If ≥85% of pts completed T on time, the regimen would be considered feasible. If the true on-time completion rate is 75%, the chance the regimen would be declared infeasible is 91%, and if it is 85% the chance that the regimen is falsely declared infeasible is 10% (power = 0.899). ≥100/125 pts had to complete T on time for the regimen to be deemed successful. Results: Among 127 pts enrolled, 125 received ≥1 dose of protocol therapy and are included in the analysis. Median age at registration was 46 (range 21-65). Median C1D1 ANC was 7500/mm3 (range 1500-20500). 112 (90%) (95% CI 83-94%) pts completed DD-T ≤ 7 wks, and 3 (2%) completed within > 7 wks (2 due to neutropenia); 10 (8%) did not complete all cycles of T. Omission of Peg-F was not causally related to non-completion of T in any pts. The most common reasons for dose reduction or delays were non-hematologic. One pt had FN but was able to complete T on time. Eight (6.4%) pts received Peg-F during the trial. Conclusions: Omission of routine GF use during DD-T according to a pre-specified algorithm appears safe, feasible, and was associated with a 95.7% reduction in use of Peg-F, relative to the current standard of care. Additional analyses including cost implications are ongoing. Clinical trial information: NCT02698891.