bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in prostate cancer circulating tumor cell (CTC) numeration and gamma H2AX positivity before and after treatment with radium 223 for metastatic castrate resistant prostate cancer.
Authors: Zhang Jingsong , Mocha Jesse , El-Haddad Ghassan 
Published: February 2018

211 Background: As an alpha-particle emitting radiopharmaceutical, R is indicated for symptomatic mCRPC patients with bone predominant metastases and no visceral metastases. The current R administration dose was calculated based on body weight and decay factor. This may not be an ideal dose to individual patient (pt) with different body mass and different burdens of bone metastases. We hypothesize that changes in CTC # and the DNA damage marker, γH2AX, could serve as readout for on target effects of R and conducted a pilot prospective biomarker study. Methods: Pts who received R as standard of care for mCRPC and had a baseline CTC # of ≥ 2 were eligible. CTC samples were collected prior to and between 24 and 96 hours post dose 1, 3 and 6 of R. CTC # and γH2AX positivity were performed by Janssen Diagnostics Lab. Results: 10 pts were enrolled and all had > 15 bone metastases at enrollment. 7/10 pts had prior Taxane-based chemotherapy. The median CTC # and γH2AX positivity prior to R were 21 (range: 3-250), and 33% (range: 3% to 80%) respectively. 8 pts completed all 6 doses of R; 2 pts completed 2 doses then elected to hospice due to rapid clinical decline. Among pts completed R, 4 (50%) had bone scan progression within 1 month. No decline in ALKP, PSA, CTC # or increase in gamma H2AX positivity were seen during treatment with R in these 4 pts. 2 pts had CTC # conversion to 0 after dose 3 R at week 9. Both pts had ALKP decline, but no PSA decline during treatment. 1 of these 2 pts had 100% positivity for gamma H2AX after dose 6 R and had prolonged post R PSA response with stable bone scans at last follow up 24 months after the first dose of R. Increases in CTCs’ γH2AX positivity, and > 50% decline of ALKP were observed in 2 pts with germline deleterious mutations in BRCA2 and PALB2. Both pts, however, had a rapid surge in CTC # and PSA after dose 3. Despite stable bone scans, both proceeded with chemotherapy within 2 months after completing dose 6 R. Conclusions: Increase in CTC # and no increase in γH2AX positivity were associated with lack of response to R. The lack of increase in the DNA damage marker, γH2AX, in pts without declines in ALKP, PSA, and CTC # suggests their R doses may need to be increased. Clinical trial information: NCT02981797.
Clinical outcome of patients with germline DNA repair mutations: Results from a retrospective international study.
Authors: Mateo Joaquin , Cheng Heather H. , Beltran Himisha , Dolling David , Xu Wen , Pritchard Colin , Mossop Helen , Rescigno Pasquale , Perez-Lopez Raquel , Sailer Verena , Kolinsky Michael Paul , Balasopoulou Ada , Bertan Claudia , Carreira Suzanne , Thorne Heather , Montgomery Robert B. , Sandhu Shahneen Kaur , Rubin Mark A. , Nelson Peter , De Bono Johann S. 
Published: February 2018

218 Background: CRPC is enriched for germline mutations in DNA damage repair genes (gDDRm). BRCA2 mutations (g BRCA2m) associate with poor prognosis from localized PC, but prognostic and predictive value for standard therapy in CRPC is unclear. We reviewed clinical outcome of 390 patients previously tested for gDDRm. Methods: Patient records were reviewed for 372 patients from 3 institutions (Royal Marsden UK, Weill-Cornell NY, University of Washington, WA) with gDDRm status previously published (Pritchard et al, NEJM 2016) and 18 g BRCA1/2m carriers from KConFab consortium (Australia). Baseline characteristics and survival were annotated. Response (PSA50%/RECIST) and PFS (RECIST/PSA progression or start of a new therapy due to clinical progression) were collected for Abiraterone, Enzalutamide and Docetaxel. To account for potential differences between cohorts, a mixed effect model (Weibull distribution) with random intercept per cohort was pursued. Results: dDDRm status was available for n = 390 (60 gDDRm+, including 37 g BRCA2m, and 330 gDDRm-). Overall, 74% and 69% received Docetaxel and Abiraterone/Enzalutamide respectively; 47% gDDRm+ and 34% gDDRm- received PARPi and/or platinum. Median overall survival from CRPC was 3.0 vs 3.2 years in gDDRm+ vs gDDRm- (p = 0.73; g BRCA2m = 3.0 years, p = 0.72). Age and Gleason score at diagnosis were associated with survival from castration-resistance in multivariate analysis. Median PFS on Docetaxel for gDDRm+ (6.8 months; 6.3 for g BRCA2m) and gDDRm- (5.1 months) were not significantly different (p = 0.2). Similarly, RR to Docetaxel was similar for the two groups (61% vs 54% in gDDRm+ vs gDDRm-; 63% g BRCA2m). Median PFS and RR on first Abiraterone/Enzalutamide were similar across groups (PFS: 8.3 months gDDRm+, 8.3 months for gDDRm-; p = 0.9; RR 46% vs 56% respectively) The Interaction of PARPi/platinum therapy among gDDRm+ patients resulted in an aHR for OS from CRPC of 0.59 (95%CI 0.28-1.25; p = 0.17). Conclusions: In this retrospective analysis, CRPC patients with gDDRm still benefited from standard therapies similarly to non-mutation carriers; interpretation of survival data should consider the high proportion treated with PARPi/platinum.
Effect of germline DNA repair gene mutations on outcomes in men with metastatic castration-resistant prostate cancer receiving first-line abiraterone and enzalutamide.
Authors: Antonarakis Emmanuel S. , Lu Changxue , Luber Brandon , Wang Hao , Chen Yan , Silberstein John , Piana Danilo , Lai Zhao , Chen Yidong , Isaacs William B. , Luo Jun 
Published: February 2018

221 Background: Inherited DNA repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. Here we investigated the clinical significance of germline DNA repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line novel hormonal therapy (NHT), with a particular emphasis on BRCA1/2 and ATM mutations. Methods: We interrogated 50 DNA repair genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT: abiraterone or enzalutamide. We assessed the impact of germline DNA repair gene mutation status on ≥50% and ≥90% PSA response rates, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results: Among 172 mCRPC patients, germline mutations (in any DNA repair gene) were found in 12.8% (22/172) of men, and germline BRCA/ATM mutations were found in 5.2% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs. no mutations) with respect to ≥90% PSA responses (78% vs. 28%, P = 0.004), PSA-PFS (HR 0.47, P = 0.061), PFS (HR 0.50, P = 0.090) and OS (HR 0.28, P = 0.059). In propensity score-weighted multivariable analyses, outcomes remained superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95%CI 0.25–0.92, P = 0.027), PFS (HR 0.52, 95%CI 0.28–0.98, P = 0.044) and OS (HR 0.34, 95%CI 0.12–0.99, P = 0.048), but this was not true for men with non- BRCA/ATM germline mutations (all endpoints, P > 0.10). Conclusions: Outcomes to first line NHT appeared better in mCRPC patients harboring germline BRCA/ATM mutations (vs. no mutations), but not for patients with other non- BRCA/ATM germline mutations. These results support the hypothesis that AR may promote DNA repair, and that inhibiting AR in the context of homologous recombination deficiency may lead to synthetic lethality.
Patterns of progression in bone and soft tissue following treatment with Ra-223 in metastatic castrate resistant prostate cancer (mCRPC).
Authors: McNamara Megan Ann , Ritz Michala , Chin Bennett , Oldan Jorge , Anand Aseem , Oyekunle Taofik , Anand Monika , Armstrong Andrew J. , George Daniel J. 
Published: February 2018

222 Background: Bone scans were not obtained in the phase 3 ALSYMPCA trial, and retrospective series have reported varying rates of development of new lesions and resolution of existing lesions, following treatment with Radium-223 (Ra-223). Methods: We performed a retrospective chart review of all men with mCRPC who received at least one dose of Ra-223 at Duke Cancer Institute from June 1, 2013 to June 1, 2015, in order to specifically describe radiographic changes on bone scan and CT during and following treatment. Radionuclide bone scans were reviewed by two radiologists prior to, during, and following Ra-223 treatment. The automated bone scan index (aBSI) was generated at each time point using EXINI boneBSI v. 2. Results: We identified 61 men with mCRPC (72% white, 28% black, median age 70) who received ≥ 1 dose of Ra-223 (median 5 doses, range 1-6). Prior treatments included: abiraterone (71%), enzalutamide (71%), sipuleucel-T (59%), docetaxel (56%), and cabazitaxel (18%). At baseline, 46% of men had nodal metastases, 3% had liver metastases, and 3% had lung metastases. Post-treatment bone scans demonstrated 0, 1-4, 5-9, 10-20, and > 20 new bone lesions in 15%, 10%, 8%, 8%, and 18%, respectively; 10% had resolution of 1-4 bone lesions. Median aBSI was 2.56 at baseline and 3.07 post-treatment. Progression in soft tissue included lymph node (31%), liver (23%), lung (5%), and epidural (8%). Of men with available imaging during treatment, 10 of 14 (71%) had new lesions on bone scan, 15 of 27 (56%) progressed on CT, and 3 of 14 (21%) progressed on both bone scan and CT; these proportions were 44%, 16%, and 24% following treatment, respectively. Men with prior chemotherapy (n = 33) had higher rates of progression on CT during (73%) and after treatment (40%), compared to men with no prior chemotherapy (36% and 25%, respectively). Conclusions: In a heavily treated population of men with mCRPC, radiographic progression in bone and/or soft tissue is common during and shortly after completion of Ra-223 treatment. Patients with prior chemotherapy have higher rates of non-bone progression, compared to patients with no prior chemotherapy. Bone scan and CT imaging are recommended during and after Ra-223.
First interim results of the Radium-223 (Ra-223) reassure observational study in metastatic castration-resistant prostate cancer (mCRPC): Safety and baseline (BL) characteristics of U.S. patients (Pts) by prior/concomitant treatment (Tx).
Authors: Harshman Lauren Christine , Sartor A. Oliver , Richardson Timothy , Sylvester John , Song Daniel Y. , Mantz Constantine , Brookland Robert K. , Perlmutter Mark , Given Robert , Kalinovsky Jan , Babajanyan Svetlana , De Sanctis Yoriko , Higano Celestia S. 
Published: February 2018

233 Background: Ra-223, a targeted alpha therapy, extended survival and had a favorable safety profile at 3 years’ follow up in pts with mCRPC in the pivotal phase 3 ALSYMPCA trial. The maturing global, prospective, single-arm, observational REASSURE study, designed to evaluate long-term safety at 7 years’ follow up, enrolled pts with mCRPC with bone metastases planned to receive Ra-223. Methods: We performed a descriptive analysis of safety and BL characteristics of US pts according to prior or concomitant abiraterone/enzalutamide (abi/enza) or prior docetaxel/cabazitaxel (chemo) using data from the first planned interim analysis (pts receiving ≥1 Ra-223 dose; median follow up 8 mo). Results: 244 US pts were included; 80% had no prior chemo. Prior abi/enza and/or chemo pts had higher median BL PSA and were less likely to complete 5-6 doses (Table). Subgroups had similar median ALP, LDH and Hb. Overall, drug-related tx-emergent AEs occurred in 71 pts (29%) and serious AEs in 9 (3.7%). Most common AEs were diarrhea, fatigue and anemia. AE incidence was numerically higher in pts who received prior chemo and/or abi/enza. Clinical trial information: NCT02141438. Conclusions: To date, REASSURE has not revealed any new safety findings and most pts complete 5-6 Ra-223 doses in routine US clinical practice. Pts with prior tx lines had lower Ra-223 tx completion and higher AE incidence, likely reflecting greater disease burden, as evidenced by higher median BL PSA.[Table: see text]
Immunological and genomic correlates of response to anti-PD1 checkpoint therapy in mismatch proficient and deficient patients with metastasized castration resistant prostate cancer.
Authors: Smits Minke , van der Doelen Maarten Johannes , Westdorp Harm , van Oort Inge M. , Sedelaar Michiel , Van Der Heijden Antoine , Witjes Alfred , Schalken Jack A. , De Vries Jolanda , Gerritsen Winald R. , Gulley James L. , Mehra Niven 
Published: February 2018

248 Background: Response to anti-PD1/PDL1 checkpoint therapy has been witnessed in only a minority of patients with castration-resistant prostate cancer (CRPC). Microsatellite instability (MSI) is the only biomarker predictive of response; additional immune and genomic correlates are needed to improve the proportion of patients that may benefit from checkpoint immunotherapy. Methods: CRPC patients were treated with anti-PD1 checkpoint immunotherapy in two basket-studies, depending on PDL1-positivity ( > 1%) or presence of MSI, and consented to prospective immune-oncology biomarker study. Genomic and immune correlates of response were studied in both MSI as microsatellite stable CRPC patients, and included PDL1 expression , whole genome sequencing on a baseline fresh metastatic biopsy, tumor microenvironment (immuno)profiling using multi-color immunohistochemistry, computational prediction of neoantigens, T-cell receptor sequencing and MHC-tetramer staining. Response was evaluated according to PCWG3 criteria and treatment was continued until radiological progression with lack of clinical benefit or toxicity. Results: At present 11 CRPC patients were included in the program and treated with nivolumab (n = 4) and pembrolizumab (n = 7). Treatment is currently ongoing in 7/11 (64%) of patients, with treatment discontinuation due to immune-related colitis (n = 2) and disease progression (n = 2). Biochemical PSA ( > 50%) responses were seen in both MSI and PDL1 positive patients. Median progression-free survival has not yet been reached. Translational studies on genomic and immune correlates of response will be presented in detail. Conclusions: Encouraging responses to anti-PD1 checkpoint immunotherapy were seen in CRPC patients selected for PDL1-positivity and MSI. An integrative biomarker suite will likely be needed to predict response to anti-PD1 therapy in CRPC.
Pembrolizumab for recurrent or advanced prostate cancer.
Authors: Higa Juliana , Wilenius Kirk , Weidhaas Joanne B. , Larsen Claire , Lam Richard Y. , Turner Jeffrey , Scholz Mark C. 
Published: February 2018

250 Background: Two previous Phase II trials studying pembrolizumab (Pembro) in 38 patients suggest it may be efficacious for prostate cancer (PC). Methods: Fifty-four consecutive men with recurrent or advanced prostate cancer were treated with 1 to 9 cycles of Pembro 200 mg every 3 weeks with or without SBRT at a private medical oncology clinic specializing in PC. Charts were retrospectively reviewed for response and toxicity. Definitions: Response (R) = >50% PSA decline; Progressive Disease (PD) = >50 % PSA increase. Stable Disease (SD)= neither response or progression. Results: 43 men completed 3 cycles of Pembro and were evaluable for toxicity. Toxicity was comparable to reports with other cancers besides PC, with 30.2% (13/43) having Grade 2 or higher toxicity. 31 men completed 4 cycles of Pembro and were evaluable for response. For the 31, the median Gleason score was 4+4=8. Treatment prior to Pembro was enzalutamide (26), abiraterone (18), and sipuleucel-t (23) and docetaxel (20). All but 4 men were castrate resistant (CRPC). Ten men got SBRT to a metastasis shortly before or during Pembro. Number of mutations were determined by the Guardant 360 assay. 17/31 (55%) were responders (19%) or had stable disease (35%). Characteristics of the two subgroups, R (6/31) + SD (11/31) versus PD (14/31), are presented in the table. Conclusions: Disease stabilization or response occurred in slightly more than half of the men treated with 4 or more cycles of Pembro. These positive responses were more common in men with lower PSA, fewer bone mets, fewer mutations, less previous chemotherapy, and there was a trend toward greater benefit in castrate sensitive disease and older men. In a separate abstract related to this patient cohort, the predictive ability of inherited mutations disrupting microRNA signaling were assessed for their capacity to predict toxicity (n=40). The table shows medians of the subgroups in the left 5 columns and the total number of patients in the right 3 columns for the 31 patients evaluable for response. [Table: see text]
Cotargeting AR signaling and cell cycle: A randomized phase II study of androgen deprivation therapy with or without palbociclib in RB-positive metastatic hormone sensitive prostate cancer (mHSPC).
Authors: Palmbos Phillip Lee , Tomlins Scott A. , Agarwal Neeraj , Twardowski Przemyslaw , Morgans Alicia K. , Kelly William Kevin , Arora Vivek , Antonarakis Emmanuel S. , Siddiqui Javed , Daignault Stephanie , Knudsen Karen E. , Feng Felix Y , Hussain Maha 
Published: February 2018

251 Background: Palbociclib, a CDK4/6 inhibitor, blocked proliferation and promoted G1 arrest in an Rb and Cyclin D dependent manner in preclinical models of HSPC. Alterations in this pathway contribute to the development of CRPC. We hypothesized that co-targeting AR (ADT) and cell cycle (palbociclib) would improve outcomes including PSA RR at 28 weeks in mHSPC pts. Methods: mHSPC pts with Rb intact tumors based on IHC of metastatic biopsy were stratified and randomized (1:2) to Arm A: ADT or Arm B: ADT+ palbociclib (125mg 3 weeks on, 1 week off). Primary endpoint is confirmed PSA RR (≤ 4 ng/mL) after 28 weeks of therapy. With 20 patients randomized to ADT and 40 to ADT + palbociclib there is a 64.2% power to detect a 20% difference in proportions with a one-sided type I error of 0.10 using the mid p-value method of the Fisher’s exact test. Secondary endpoints include safety/tolerability, biochemical and clinical PFS, PSA and radiographic RR and exploratory biomarkers (circulating DNA, tumor cells and transcriptome). Results: 72 eligible pts (median age 67, PSA 73ng/mL) with newly diagnosed mHSPC were registered and underwent biopsy (41 soft tissue, 31 bone). 64/72 (90%) had adequate tissue for RB assessment and 62/64 (97%) retained RB expression (IHC). 62 pts were stratified by disease extent and early initiation of ADT, and randomized. 60 pts initiated therapy (Arm A: 20; Arm B: 40). Neutropenia was the most common G3/4 AE (Arm A: 0% Arm B: 33%). 80% of pts (Arm A: 16/20, Arm B: 32/40; p = 0.87) on both arms met primary PSA endpoint (≤4ng/mL at 28 weeks). PSA undetectable rate at 28 weeks was Arm A: 50% (10/20) and Arm B: 43% (17/40; p = 0.5). Measurable disease RR: Arm A: 78% and Arm B: 74%. 12-month biochemical PFS was Arm A 69% (95%CI: 43-85%), Arm B 74% (95%CI: 56-85%). Clinical PFS is not mature and correlative biomarker studies are ongoing. Conclusions: Co-targeting of AR signaling and cell cycle in a tissue biomarker preselected trial is feasible in mHSPC. RB loss was rare in this population. PSA RR at 28 weeks was not impacted by addition of palbociclib to ADT. Important clinical PFS data will be reported when mature. Clinical trial information: NCT02059213.
Cell-free DNA (cfDNA) analysis and evaluation of BRAF amplifications and mutations in metastatic castration-resistant prostate cancer.
Authors: Steinwald Peter , Ledet Elisa , Christensen Bryce Raymon , Moses Marcus Marie , Chapman Lynne , Shahbandi Ashkan , Cotogno Patrick , Schiff Joshua , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver 
Published: February 2018

255 Background: Cell-free DNA (cfDNA) is an accessible method for characterizing tumoral alterations. We report cfDNA screenings of prostate cancer pts positive for BRAF amplifications/mutations in pts with metastatic CRPC. Methods: Guardant360 testing (Guardant Health, Inc.) assesses cell-free DNA analysis using sequencing to identify genomic alterations in 73 cancer-related genes in circulation. A total of 133 metastatic castrate resistant prostate cancer (mCRPC) pts in various stages of therapy had Guardant cfDNA analyses. Treatment histories prior to testing and concurrent cfDNA alterations were analyzed. Results: BRAF amplifications were detected in 32 (24%) mCRPC pts; 5 pts had concurrent BRAF mutations. Of the mutations detected, only one (K601E, n = 2) was a known activating mutation while all others were variants of unknown significance (VUS). One K601E mutation pt had no other cfDNA alterations. Additionally, 4 pts without BRAF amplification had VUS BRAF mutations. BRAF amplification pts had ≥ 2 concurrent gene amplifications/alterations with the median being 8. The most common recurrent amplifications/alterations were AR (75%), p53 (59%), CDK6 (53%), MET (50%), and MYC (50%). Abiraterone (Abi) and/or Enzalutamide (Enza) resistance was associated with BRAF amplification (p = 0.0042). Non-Abi/Enza resistance pts were less likely to have BRAF amplification. The 2 pts with BRAF K601E mutation were treated with targeted protocol therapy without success however one K601E pts was subsequently treated with cabazitaxel+carboplatin which produced a positive clinical response and a 99.79% reduction in PSA. Conclusions: Pts resistant to Abi/Enza have an increased risk of developing BRAF amplifications. BRAF amplifications arise in the context of multiple additional detectable cfDNA alterations. Identification of actionable mutations, such as BRAF K601E, illustrates the potential for cfDNA testing to direct pt treatment. As cfDNA profiling continues to expand, the ability translate alterations into clinically actionable strategies is critical.
Minority Equity and Recruitment Into Trials program: Self-assessment of disease-specific cancer clinical trial recruitment patterns at a comprehensive cancer center.
Authors: Borno Hala , McGuire Joseph P. , Griffin Ann C. , Ryan Charles J. , Kaplan Celia , Small Eric Jay 
Published: February 2018

267 Background: Prostate cancer disparities research has largely focused on access to care, treatment, and outcomes. Disparities based on race/ethnicity in clinical trial (CT) participation are less well understood. African American men are known to have an increased risk of developing and dying from prostate cancer compared to their white counterparts yet remain underrepresented in prostate cancer CTs. The goal of this study was to examine the demographic accrual patterns in prostate cancer CTs at an academic cancer center. Methods: A retrospective analysis of demographic data of cancer cases per year was performed from: 1) the central cancer registry of California, Surveillance, Epidemiology, and End Results; 2) new patients (“analytic cases”) identified in the University of California, San Francisco (UCSF) cancer registry; and (3) the UCSF Clinical Trials Management System database. The Catchment Area for the center was prospectively defined, and patients from this region comprised 98% of all cancer cases seen at UCSF. Descriptive statistics were applied to characterize CT accruals for men with prostate cancer relative to cases in our Catchment Area. Results: Overall there were 67,046 new cancer cases of all types in the Catchment Area, of which 6,558 were prostate cancer cases. The distribution of patients with prostate cancer by ethnicity/minority status are summarized (Table). Conclusions: The distribution of minority accruals to prostate cancer CTs conducted at academic cancer centers may not reflect overall accruals to all CTs. At UCSF, the accrual of Latino men with prostate cancer to CTs was representative of the Catchment Area, whereas Asian and Black men were under-represented. These results suggest that tailored, disease-specific interventions are required to achieve equitable CT recruitment.[Table: see text]