bluuebunny/crossref_metadata_2025_split huggingface dataset:
Are prostate cancer patients with BRCA1 and BRCA2 mutations safe for active surveillance?
Authors: Dall'era Marc , Evans Christopher P. , Pan Chong-Xian , Parikh Mamta , Lara Primo , McPherson John 
Published: March 2019

19 Background: Active surveillance (AS) is recommended as a treatment option for men presenting with low risk (Gleason 3+3) and some intermediate risk (Gleason 3+4) prostate cancer. BRCA1 or 2 germline mutations have been implicated in prostate cancer pathogenesis. It is unknown if germline BRCA1/2 mutations in AS candidacy are associated with more aggressive histologic grade, higher stage or other worse genetic alterations, such as RB1 and p53 deletions. Methods: We analyzed sequencing data from 498 men who underwent radical prostatectomy from The Cancer Genome Atlas (TCGA) data set. The primary outcome was the difference in the proportions of AS candidates among subjects with and without BRCA homodeletions. Tests for differences in the proportions were conducted using Fisher’s Exact Test. Equivalence tests for proportions of AS candidates were conducted using the two-one sided tests (TOST) method. As a secondary outcome we studied the associated coincident mutations in the men with BRCA1 and BRCA2 homodeletions. Results: Forty-one men (8%) of the cohort had homodeletion of BRCA1 or BRCA2. Ten men (2%) had complete loss of BRCA1 while 31 (6%) had loss of BRCA2. Rates of candidacy for AS based on histology and stage (defined as stage T2, Gleason 6) are not different between subjects with and without BRCA 1 or 2 homodeletions, within an equivalence margin of 10 percentage points. These findings are similar when the AS criteria are modified to add Gleason 3+4 subjects. Fifty percent of men with organ confined (pT2), 3+3 and 3+4 prostate cancer with BRCA1 or BRCA2 homodeletions had concomitant RB1 deletions compared with 16.5% of the entire cohort (p = 0.002). This was primarily driven by BRCA2 deletions co-occurrent with RB1 deletions (log OR: 2.4, p < 0.001). Twenty-nine percent of men from this group had concomitant p53 deletions compared to 7.5% of the entire cohort (p = 0.004). Conclusions: Men with prostate cancer and BRCA1 or BRCA2 homodeletions present with similar stage and grade tumors than men without these deletions. Despite having low or low intermediate grade histology, BRCA1 and BRCA2 deleted tumors are enriched with deletions in RB1 and TP53, both of which are associated with more aggressive phenotypes and treatment resistance.
Radium-223 treatment patterns in a large real-world population.
Authors: Zhao Hanson Hanqing , Howard Lauren , de Hoedt Amanda , Terris Martha K , Amling Christopher L. , Kane Christopher J. , Cooperberg Matthew R. , Aronson William J. , Polascik Thomas , Freedland Stephen J. 
Published: March 2019

190 Background: For men with symptomatic metastatic castration resistant prostate cancer (mCRPC), radium-223 was shown to improve overall survival in the phase III, double blind ALSYMPCA trial. Despite the observed benefits, the application and practice patterns of Radium-223 outside of clinical trials are largely unknown. Here we aim to better characterize the use of radium-223 in a large and heterogeneous real-world population. We identify treatment patterns associated with radium-223 and link these patterns with time to skeletal related event (SRE) and mortality. Methods: We reviewed charts of all men with diagnosed with mCRPC in the entire Veterans Affairs (VA) system alive as of January 1, 2013 who received radiun-223. We generated Kaplan Meier curves for survival and time to SRE based on treatment patterns. We examined the association between common treatment patterns and mortality and time to SRE with Cox models. Results: We identified 318 men with bone mCRPC who received radium-223. Median age at radium start was 69 ys and median follow up was 25.3 months. Median survival was 11 months. 277 patients died during the study period (87%). 50% (158/318) completed ≤4 injections. There was a significant difference mortality among four consolidated treatment patterns (p=0.005) and but no difference SRE (p=0.10). On univariable and multivariable analysis, men who received AR target + docetaxel + radium-223 had increased mortality vs. men who received AR target + radium-223 (p=0.010 and 0.005, respectively). Multivariable analysis showed that non-black race, bone pain, SRE prior to radium, and higher PSA were all linked with worse mortality. Conclusions: We described the largest known cohort of men in the real world who received radium-223. We identified common treatment patterns with differing risk for overall mortality. Further prospective studies are needed to better understand whether differences in survival are attributed to worsening disease status requiring more aggressive therapy, lead-time bias, or true differences in treatment efficacy.
Outcomes of high-dose whole pelvic simultaneous integrated boost IMRT in patients with pelvic lymph node-positive prostate cancer.
Authors: Mizowaki Takashi , Takayama Kenji , Nakamura Kiyonao , Aizawa Rihito , Inoue Takahiro , Yamasaki Toshinari , Kobayashi Takashi , Akamatsu Shusuke , Ogawa Osamu 
Published: March 2019

192 Background: Managements of prostate cancer patients with positive pelvic lymph node (N1M0) have been very challenging. We evaluated the outcomes of high-dose whole pelvic (WP) intensity-modulated radiation therapy (IMRT) by using the simultaneous integrated boost (SIB) technique, combined with long-term androgen deprivation therapy (ADT). Methods: Between May 2005 and November 2013, 52 patients with T2a-T4N1M0 prostate cancer were definitively treated by WP SIB-IMRT. Pelvic lymph node metastases were clinically diagnosed based on the following criteria; depicted swollen lymph nodes on diagnostic imaging associated with subsequent shrinkage in size on a follow-up imaging after neoadjuvant ADT (NA-ADT). The median age and initial PSA value were 66 years old (range: 52–79) and 29.7 ng/ml (4.8–251.9), respectively. NA-ADT (median: 8 months, range: 5–20) was given in all cases. SIB WP-IMRT was designed to simultaneously deliver 78 Gy, 66.3 Gy, and 58.5 Gy in 39 fractions to the prostate plus seminal vesicles, metastatic lymph nodes, and the pelvic lymph node region, respectively. Adjuvant ADT (A-ADT) was given in all patients except for one case who developed severe adverse events during NA-ADT. In 9 patients, permanent A-ADT was given due to castration after IMRT (n = 2) and development to castration resistant status during A-ADT (n = 7). The median duration of A-ADT was 24 months (range: 7–71) in the remaining 42 patients. Results: The median follow-up period was 69 months (range: 12–136). Biochemical relapse-free survival rate based on the Phoenix definition and distant metastasis-free survival rates at 5 years were 69% (95% CI = 54%–80%) and 78% (95% CI = 64%–87%), respectively. Overall survival and prostate cancer-specific survival rates at 5 years were 88% (95% CI = 74–94%) and 92% (95% CI = 79–97%), respectively. Loco-regional recurrence was not observed. 5-year cumulative incidence rates of grade 2-3 late GU and GI toxicities were both 2%. No grade 4 acute or late toxicity was observed. Conclusions: High-dose WP SIB-IMRT to patients with N1M0 prostate cancer seems promising, and warrants future prospective studies.
The Veterans Health Administration Precision Oncology Program for Advanced Prostate Cancer Patients: Expanding tumor NGS opportunities to a broader patient population.
Authors: Sokolova Alexandra , Cheng Heather H. , Hintze Bradley J , Kelley Michael J. , Spector Neil L , Duffy Jill , Lynch Julie Ann , Rettig Matthew , Montgomery Robert B. 
Published: March 2019

193 Background: Progress in understanding molecular changes in advanced prostate cancer has led to promising precision oncology opportunities; to date, most have been concentrated at tertiary research centers and urban centers and unequally available to patients. The VHA is the largest integrated healthcare system in the U.S. and provides medical care to >6 million veterans (~40% living in rural areas). The VHA has implemented a system-wide National Precision Oncology Program (NPOP) to offer tumor NGS testing to veterans with cancer. Methods: VHA patients with advanced stage cancers were offered targeted NGS gene panels (Personalis ACE Extended Cancer Panel; PGDx CancerSELECT/PlasmaSELECT) as part of clinical care. Annotated sequence data is collected by NPOP. We report preliminary findings of the participating veterans with prostate cancer. Results: 372 veterans from 81 sites underwent NGS sequencing of their prostate tumors (n=311) or cfDNA (n=61). Tumors from 165 (44%) were found to have mutations (allelic ratio ≥5%) in 47 genes. Of 372, 62 harbored mutations in TP53 (17%), 9 in NOTCH1 (2%), 16 in PTEN (4%), 16 in AR (4%), 13 in ATM (4%), 11 in BRCA2 (3%), 2 in MSH2 (0.5%), 1 in NBN (0.3%), and 1 in PALB2 (0.3%). 7 men (1.8%) had adequate tumor, but no identifiable somatic mutations. NPOP findings were compared to the existing databases SU2C/PCF (of metastatic biopsies in metastatic castration resistant disease) and TCGA (of primary tumors in localized disease), see table. Findings will be updated at presentation. Conclusions: The VA NPOP has been successfully implemented, and prostate tumors from veterans were found to carry potentially actionable mutations, including BRCA2 and ATM, for which there are precision treatment trials. The program will be expanded and will facilitate more diverse and equitable distribution of access to precision oncology diagnostics and therapeutic opportunities, in alignment with the Cancer Moonshot Initiative. (e.g. VA-ABCD clinicaltrials.gov; NCT02985021). [Table: see text]
Next Generation Sequencing (NGS) in metastatic castration resistant prostate cancer (mCRPC) to identify targets for individualized treatment: Is it feasible in daily routine?
Authors: Heidenreich Axel , Pfister David A. , Odenthal Margarete , Nestler Tim , Büttner Reinhard 
Published: March 2019

194 Background: Systemic of mCRPC consists of various approaches such as docetaxel, abiraterone, enzalutamide, Radium-223 and cabazitaxel. If all treatment options are exhausted, molecular profiling of biopsies from progressive metastases might enable an individualized approach with targeted therapies. It was the purpose of our study to examine (1) the feasibility of NGS in daily routine, (2) the frequency of treatable mutations and (3) the therapeutic outcome. Methods: From 1/2016 to 12/2017, 214 patients with mCRPC were treated; 52 pts progressed after exposure to all approved systemic therapies. All men underwent biopsies of the progressing lesions to perform mutational analysis via NGS using 9 Multiplex PCR amplicons (AR, ATM, BRCA1/2, CTNNB1, DLL3, PIK3CA, PTEN, RAD51C, TP53) which generation was done with a GeneRead DNAseq Custom Panel V2 (Qiagen). Creation of the library was done with the use of GeneRead DNA Library I Core, GeneRead DNA I Amp Kits and NEXTflex-96 DNA Barcode Adapter. Results: Following lesions were biopsied n = 8 (15.4%) liver, N = 4 (7.7%) lung, n = 4 (7.7%) bone, n = 36 (69.2%) lymph node. Sufficient material was received in all cases. 31 (59.7%) demonstrated wild type in all amplicons vorhanden, n = 21 (40.3%) demonstrated at least 1 potentially treatable mutation: BRCA1/2 or ATM n = 11, AR n = 7, DLL3 n = 3, p53 n = 9, Rad51C n = 4, CTNNB1 n = 4, PTEN/PIK3CA n = 4. Results were discussed in our molecular and clincical phase-I tumor board. Median overall survival oft he pateint cohort is 18.5 (6-34) months. Conclusions: NGS analysis of biopsy samples from progressing metastatic sites is feasible in mCRPC presuming an interdisciplinary setting in the diagnostic and therapy decision making process. NGS results in the identification of treatable mutations in more than one third of patients.
Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).
Authors: Fu Simon Yuen Fai , Ritch Elie , Yip Steven , Khalaf Daniel , Taavitsainen Sinja , Annala Matti , Vandekerkhove Gillian , Kushnir Igal , Hotte Sebastien J. , Ferrario Cristiano , Wyatt Alexander William , Chi Kim N. 
Published: March 2019

195 Background: A small proportion of metastatic PC exhibit outlier somatic mutation rates. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing of 1047 plasma cell-free DNA samples and calculated somatic mutation burden. HM samples and available matched archival tissue were additionally subjected to whole exome sequencing. Trinucleotide mutational signatures and microsatellite instability (MSI) were determined via nonnegative matrix factorization and mSINGS, respectively. We evaluated PSA decline ≥50% from baseline (PSA50), time from androgen deprivation therapy (ADT) to castration-resistant prostate cancer (CRPC), median duration of 1st line CRPC therapy (1L CRPCT) and median OS (time from CRPC to death). The control cohort consisted of 199 CRPC pts treated with 1L abiraterone + prednisone (ABI+P) or enzalutamide (ENZ). Results: 671 samples from 434 pts had ctDNA% > 2 and were evaluable. The median mutation rate was 2.59/Mb (range, 0.9 – 155.6/Mb). 32 samples from 24 pts had > 11/Mb and fell above the 95th percentile for mutational burden. 10/24 pts had biallelic loss of mismatch repair (MMR) genes MSH2/6, and a further 5 pts without confirmed MMR defects had enrichment of trinucleotide signatures associated with MMR and/or were MSI high by mSINGS. The remaining 9 pts had either BRCA2 mutations or Kataegis (localized hypermutation). Clinical data was available for 10/15 MMR defective pts. Median age was 73.6 y. At diagnosis, 70% had Gleason score ≥8, 50% with M1 disease, median PSA was 22.8 (6.8 – 820). PSA50 with ADT (n = 8) or ADT + docetaxel (n = 2) was 100% in the castration sensitive setting. 5 pts had ENZ, 4 ABI + P, and 1 cabazitaxel in 1L CRPCT. Comparing the MMR defective 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; 1L CRPCT duration was 3.9 m (95% CI 1.3 – 6.5) vs. 8.4 m (95% CI 7.2 – 9.6), p = < 0.001; median OS was 13.1 m (95% CI 0.33 – 25.9) vs. 40.1 m (95% CI 32.4 – 47.8), p < 0.001. Conclusions: HM and MMR defects can be identified in a liquid biopsy. Although these pts can have poor outcomes with standard therapy, ctDNA may help selection for immunotherapy.
Toxicity results from a novel phase I/II trial of VMAT radiotherapy to prostate and pelvic nodes plus six cycles of radium-223 in mCSPC metastatic to bone post ADT and docetaxel.
Authors: O'Sullivan Joe , Turner Philip Geoffrey , Jain Suneil , Hounsell Alan R. , Mitchell Darren M. , Biggart Sandra , Grey Arthur , Cole Aidan 
Published: March 2019

196 Background: Recent data has shown an overall survival (OS) benefit for up front Docetaxel or Abiraterone combined with androgen deprivation therapy (ADT) in metastatic castration sensitive prostate cancer (mCSPC). Data from STAMPEDE also suggests an additional OS benefit for radiotherapy to the prostate in men with low volume metastases. We hypothesised that Radium-223 + Radiotherapy to prostate and pelvic nodes following docetaxel (DOC) would be well tolerated and potentially improve OS in men with mCSPC involving bone. Methods: Men with mCSPC involving bone were treated in a single arm phase 1/2 study in which they received radical dose radiotherapy (74Gy/37) to prostate and pelvic nodes using Volumetric Modulated Arc Therapy (VMAT) radiotherapy and 6 cycles of Radium-223, 55kBq/kg following up front ADT and DOC. The primary endpoint was toxicity with secondary endpoints including time to PSA and ALP progression and radiological response. Results: We report the results of 27 men, median age 67 years treated in the study with a median follow up of 25 months post 1st ADT. 81% of men had high volume disease. The schedule was well tolerated with grade ≥3 toxicity occurring in 5 patients (18.5%). Most toxicity was short lived thrombocytopenia and leucopenia. No unexpected toxicity was observed. All but 2 patients received all 6 cycles of Radium-223. One patient died of progressive disease before completion of the course of Radium-223. To date, 6 out of 27 patients have died, actuarial survival at 24 months is 83%. To date 9 out of 27 (33%) patients have developed PSA progression. Only 1 patient had a progressive alkaline phosphatase levels during the course of Radium-223 treatment. Conclusions: In men with mCSPC involving bone, a schedule of radical dose radiotherapy to prostate and pelvis + 6 cycles of Radium-223 is well tolerated post ADT + DOC. This treatment schedule will now join as a new arm of the STAMPEDE trial with OS as primary endpoint. Clinical trial information: 2014-000273-39.
A randomized trial comparing fluorocholine-PET/CT with conventional imaging in prostate cancer.
Authors: Williams Scott , Beauregard Jean-Mathieu , Roselt Peter , Moody Kate , Fisher Richard , Drummond Elizabeth , Hicks Rodney J 
Published: March 2019

2 Background: We conducted a randomised trial comparing 18Flourocholine-PET/CT (FCH) to Computed Tomography (abdomen and pelvis) plus 99mTc-Whole Body Bone Scan (Conventional Imaging [CIm]) to determine imaging performance in prostate cancer (PC). Methods: This prospective two-arm 1:1 randomised trial enrolled men with newly diagnosed or biochemically recurrent PC to first-line imaging (FLI) with either CIm or FCH. Participants without evidence of metastases proceeded to second-line imaging (SLI) using the alternative imaging strategy. The primary aim was to determine whether FCH was more effective as a FLI approach in changing management. Secondary endpoints included incremental utility of SLI and negative predictive value (NPV) based on progression-free survival (PFS). Australian New Zealand Clinical Trials Registry ACTRN12608000641392. Results: 108 men were enrolled; 44% were for staging of newly-diagnosed PC and median follow-up 43 months. Imaging impacted clinical management in 32.4% of men (95% CI=23.7-42.1%), mostly with FLI (n=30). High-impact management changes occurred in 27.8% (95% CI=16.5-41.6%) of FCH cases compared with 11.1% (95% CI=4.2-22.6%) in the CIm arm (p=0.032). The final management plan was derived using FCH in 98.1% (95% CI = 90.1-100%) of cases and 92.6% (95%CI = 82.1-97.9%) of CIm cases (p=0.242). FLI with FCH showed unequivocally N1 or M1 disease in 22.2% (95% CI = 12-35.6%), and 16.7% (95% CI = 7.9-29.3%; p= 0.531) of CIm cases. The overall NPV for stage TxN0M0 (from all imaging) was 26.3% (95% CI: 13.9 - 41.2%), with no significant difference between arms (p=0.9). For N1M0 cases, the NPV was 14.3% (95% CI: 7.1 - 35.7%). The identification of N1M0 by FCH resulted in a longer time to identification of progressive disease, with a median PFS of 32 months (95% CI=2-68months) compared with 3 months (95% CI=1-16 months) in the CIm N1M0 cohort (p=0.05). Conclusions: FCH-PET/CT identifies more high-clinical-impact lesions than CIm as first-line imaging. All imaging modalities were poor at predicting subsequent progressive disease. Isolated node-positive disease seen with FCH is associated with a longer time to - but similarly high rates of - recurrence, suggesting a lead-time bias. Clinical trial information: ACTRN12608000641392.
Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): Preliminary results of GALAHAD.
Authors: Smith Matthew Raymond , Sandhu Shahneen Kaur , Kelly William Kevin , Scher Howard I. , Efstathiou Eleni , Lara Primo , Yu Evan Y. , George Daniel J. , Chi Kim N. , Summa Jason , Kothari Nishi , Zhao Xin , Espina Byron M. , Ricci Deborah S. , Simon Jason S. , Tran Namphuong , Fizazi Karim ,   GALAHAD Investigators
Published: March 2019

202 Background: New therapies are needed for patients (pts) with mCRPC progressing after androgen-receptor signaling inhibitors (ARSIs) and taxane therapies. Niraparib is a once daily highly selective inhibitor of poly (ADP-ribose) polymerase (PARP-1 and 2). Methods: GALAHAD is an ongoing open label Ph 2 study assessing niraparib (300 mg daily) in pts with DRD progressing on/after ARSIs and taxane chemotherapy. Using a validated plasma assay, DRD status was defined as pathogenic mutations (including homozygous deletions) of BRCA1/2, ATM, FANCA, PALB2, CHEK2, BRIP1 or HDAC2. Composite response rate (RR) was defined as an objective response by RECIST 1.1 for measurable disease, circulating tumor cell (CTC) conversion to < 5/7.5 mL blood or prostate-specific antigen (PSA) decline of ≥50% (PSA50). Here, preliminary data on RR and adverse events (AEs) are reported in pts with biallelic DRD. Results: As of 10 Sep 2018, 123 pts with mCRPC and DRD were enrolled, of whom 39 had biallelic DRD (23 BRCA1/2). The median follow-up was 5.7 mo (2.0–23.7). Table depicts RRs for pts with biallelic DRD by BRCA status. Composite and objective RRs were 65% and 38% in pts with biallelic BRCA1/2, respectively. 3/8 pts (38% [2/5 BRCA1/2 and 1/3 non-BRCA]) with measurable visceral metastases showed objective response. Among the 20 biallelic responders, the duration of treatment (tx) has exceeded 4 mo in 13 pts and 6 mo in 8 pts; 14 pts remain on tx. The most common grade 3/4 hematologic AEs were anemia (25%) and thrombocytopenia (15%) (manageable by dose reduction/interruption). The most common grade 3/4 nonhematologic AEs were asthenia (6%) and hypertension (5%). Conclusions: These results suggest niraparib has compelling activity as monotherapy for pts with treatment-resistant mCRPC, particularly those with biallelic BRCA1/2 identified by a blood assay. Clinical trial information: NCT02854436. [Table: see text]