bluuebunny/crossref_metadata_2025_split huggingface dataset:
PROREPAIR-A: Clinical and molecular characterization study of prostate cancer (PC) patients with and without previously known germline BRCA1/2 mutations.
Authors: Lozano Rebeca , Castro Elena , Aragon Isabel , Thorne Heather , López-Campos Fernando , Sanz Alejandro , Alonso Concepción , Anido Urbano , maria Jose Juan , Gutierrez Pecharroman Ana , Ramirez-Backhaus Miguel , Balmana Gelpi Judith , Chirivella Isabel , Llort Gemma , Romero-Laorden Nuria , Arevalo Sara , Rubio Jose , Di Domenico Tomás , Sandhu Shahneen Kaur , Olmos David 
Published: May 2020

5511 Background: Germline BRCA1/2 (g BRCA1/2) mutations are associated with poor clinical outcomes in PC. Previous studies showed that g BRCA2 carriers present more CNV in several genes associated with more aggressive disease. These aberrations may explain the poor clinical outcomes of these patients, but larger studies are needed to confirm these findings. Methods: PROREPAIR-A is a multicenter case-control study in which g BRCA2 carriers with available diagnostic timor-tissue were matched 1:2 by Gleason and stage at diagnosis (M0 vs M1) with known non-carriers (NC). A minimum of 120 controls-60 cases were required to prove a 5yr Cause Specific Survival (CSS)-rate of 85% vs 60%. The primary endpoint was to confirm the independent prognostic value of g BRCA2 in PC CSS. In addition, we explored the prognostic role of g BRCA1 and somatic events in BRCA2, RB1, MYC, PTEN and TMPRSS2-ERG by FISH. Χ2, Kaplan-Meier, log-rank and cox-regression models were carried out to identify associations with baseline characteristics and outcomes: Metastases Free Survival (MFS), Time to Castration-Resistance (TTCR) and CSS. Results: A total of 80:160 matched cases-controls were initially included, but tumor tissue and clinical data were only available in 73 g BRCA2 and 127 NC. 14 g BRCA1 were also included. At diagnosis, g BRCA2 were younger (median 62.6 vs 64.5, p = 0.02) and had cT3-4 disease more often than NC (31.5% vs 9.4%, p < 0.01), but no other significant differences were found. Somatic BRCA2-RB1 codeletion (40.8% vs 11.8%, p < 0.01) and MYC amplification (51.4% vs 22.8%, p < 0.01) were more frequent in g BRCA2 compared to NC, but no significant differences in PTEN and TMPRSS2-ERG were observed. g BRCA2 mutations as well as somatic BRCA2-RB1 codel and MYC amplif were significantly associated with shorter CSS, MFS and TTCR (Table). MVA model confirmed the independent prognostic value of g BRCA2 (HR 1.94, p = 0.03), BRCA2-RB1 codel (HR 3.16, p < 0.01), MYC amplif (HR 2.36, p < 0.01), Gleason ≥8 (p < 0.01) and M1 at diagnosis (p < 0.01) for CSS. Conclusions: PROREPAIR-A confirmed the independent prognostic value of g BRCA2 for CSS. Somatic BRCA2, RB1 and MYC aberrations were more frequent in g BRCA2 carriers. Those alterations are associated with shorter CSS, MFS and TTCR, and may contribute to poor clinical outcomes in g BRCA2 and NC. [Table: see text]
Population-based prostate cancer screening using a prospective, blinded, paired screen-positive comparison of PSA and fast MRI: The IP1-PROSTAGRAM study.
Authors: Eldred-Evans David , Burak Paula , Connor Martin John , Day Emily , Evans Martin , Fiorentino Francesca , Gammon Martin , Hosking-Jervis Feargus , Klimowska- Nassar Natalia , McGuire William , Padhani Anwar R , Price Derek , Prevost Toby , Sokhi Heminder , Tam Henry , Winkler Mathias , Ahmed Hashim Uddin 
Published: May 2020

5513 Background: The prostate-specific antigen (PSA) test can lead to under- and over-diagnosis of prostate cancer and has not been recommended for population screening. A fast MRI scan might overcome the limitations of PSA. IP1-PROSTAGRAM is the first study to evaluate the performance of a 15-minute non-contrast MRI for prostate cancer screening in comparison to PSA. Methods: IP1-PROSTAGRAM was a prospective, population-based, screen-positive paired-cohort study. Men aged 50-69 years in the UK were invited for prostate cancer screening through seven primary care practices or community-based recruitment. Participants underwent a PSA and MRI scan (T2-weighted and diffusion). MRI was scored using PIRADS version 2.0 without knowledge of PSA; screen-positive MRI (defined as either PIRADS score 3-5 or 4-5) were compared against a screen-positive PSA defined as ≥3ng/ml. If any test was screen-positive, a systematic 12-core biopsy was performed with MRI-ultrasound image-fusion targeted biopsy to MRI suspicious areas, as appropriate. Clinically-significant cancer was defined as any Gleason score ≥3+4. The primary outcome was the proportion of screen-positive MRI at different scores; important secondary outcomes were the number of clinically-significant and insignificant cancers detected. Results: 2034 men were invited to participate of whom 408 consented and 406 were screened by both PSA and MRI (10/Oct/2018-15/May/2019). The proportion with a screen-positive MRI (score 3-5) was higher than the proportion with a screen-positive PSA (17.7% [95%CI 14.3-21.8] vs. 9.9% [95%CI 7.3-13.2]; p < 0.001). A screen-positive MRI (score 4-5) was similar to a screen-positive PSA (10.6% [95%CI 7.9-14.0] vs. 9.9% [95%CI 7.3-13.2], p = 0.71). An MRI score 3-5 or 4-5 used to denote a screen-positive MRI, compared to PSA alone, detected 14, 11 and 7 clinically-significant cancers, respectively. There were 7, 5 and 6 clinically-insignificant cancers detected, respectively. No serious adverse events occurred. Conclusions: When screening the general population for prostate cancer, MRI using a score of 4-5 to define a screen-positive test, compared to PSA alone at ≥3ng/ml, could lead to more men diagnosed with clinically-significant cancer without increasing the number of men biopsied or diagnosed with clinically-insignificant cancer. Clinical trial information: NCT03702439 .
Final overall survival (OS) from PROSPER: A phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Sternberg Cora N. , Fizazi Karim , Saad Fred , Shore Neal D. , De Giorgi Ugo , Penson David F. , Ferreira Ubirajara , Ivashchenko Petro , Efstathiou Eleni , Madziarska Katarzyna , Kolinsky Michael Paul , Cubero Daniel Iracema , Noerby Bettina , Zohren Fabian , Lin Xun , Modelska Katharina , Sugg Jennifer , Steinberg Joyce Leta , Hussain Maha H. A. 
Published: May 2020

5515 Background: PROSPER previously demonstrated a statistically significant and clinically meaningful improvement in metastasis-free survival (MFS) (hazard ratio [HR] 0.29; 95% CI 0.24-0.35; P < .001) in men with nmCRPC and rapidly rising prostate-specific antigen (PSA) who received ENZA. When first reported, OS was immature with only 165 of 596 (28%) prespecified deaths. Here we report results from the final OS analysis. Methods: Men with nmCRPC, PSA doubling time ≤ 10 mo, and PSA ≥ 2 ng/mL at screening continued androgen deprivation therapy (ADT) and were randomized 2:1 to ENZA 160 mg or PBO. OS treatment effect was assessed using a group sequential testing procedure with O’Brien-Fleming-type alpha spending function ( P ≤ .021 required for statistical significance). Medians were estimated using the Kaplan-Meier method; 95% CIs using a stratified Cox regression model. Results: As of Oct 15, 2019 (median follow-up ≈ 48 mo), there were 466 deaths (288 [30.9%] and 178 [38.0%] in the ENZA and PBO arms, respectively). ENZA significantly prolonged OS compared with PBO (HR 0.73; 95% CI 0.61-0.89; P = .0011). Median OS was 67.0 mo (95% CI 64.0-not reached) in the ENZA arm and 56.3 mo (95% CI 54.4-63.0) in the PBO arm. Subsequent antineoplastic therapies were initiated after treatment discontinuation by 310 (33%) men in the ENZA arm vs 303 (65%) in the PBO arm. Median duration of treatment was 33.9 mo vs 14.2 mo with ENZA vs PBO, respectively. Grade ≥ 3 adverse events (AEs) were reported by 48% of men in the ENZA arm vs 27% in the PBO arm (16% vs 6% were drug related, respectively). AEs with event rates per 100 patient-yr that were ≥ 2 points higher with ENZA vs PBO were falls (9 vs 4), fatigue (14 vs 12), and hypertension (7 vs 5). Conclusions: ENZA treatment resulted in a statistically significant 27% reduced risk of death compared with PBO, demonstrating that initiation of ENZA + ADT before the onset of detectable metastasis improves OS in men with CRPC and rapidly rising PSA. This OS benefit ensues despite crossover from the PBO arm to ENZA and higher rates of subsequent antineoplastic therapies in men from the PBO arm. Safety was consistent with previous clinical trials. This final OS analysis from PROSPER provides prospective validation of MFS as a potential surrogate endpoint for OS in nmCRPC and supports the continued use of ENZA + ADT as a standard of care in men with nmCRPC and rapidly rising PSA. Clinical trial information: NCT02003924 .
Bone metabolism biomarkers (BMB) and progression-free survival (PFS) in men with metastatic hormone-sensitive prostate cancer (HSPC): SWOG S1216, a phase III trial of androgen deprivation therapy (ADT) with or without orteronel.
Authors: Lara Primo , Mayerson Edward , Gertz Erik , Tangen Catherine , Goldkorn Amir , Van Loan Marta , Hussain Maha H. A. , Gupta Shilpa , Zhang Jingsong , Twardowski Przemyslaw , Quinn David I. , Vogelzang Nicholas J. , Thompson Ian Murchie , Agarwal Neeraj 
Published: May 2020

5523 Background: We previously reported that baseline BMB are independently prognostic for overall survival (OS) in men with castration resistant prostate cancer. We correlated BMB with outcomes in mHSPC as part of S1216, a phase III trial of ADT +/- the novel CYP17 inhibitor orteronel. Methods: Blood was obtained at study entry for bone resorption [C-telopeptide(CTx) & Pyridinoline(PYD)] & formation markers [C-terminal collagen propeptide(CICP) & bone alkaline phosphatase(BAP)]. With prior DSMC approval, patients were sampled to mask potential treatment effect. Logistic regression was used to assess if BMB elevation above median was prognostic for a PFS event w/in 2 years across pooled study treatment arms, adjusting for baseline variables (including disease extent, PSA, age, pre-randomization ADT, & presence of bone mets). An additional interaction term between BMB elevation & presence of bone mets was included; if significant, separate models were developed for men +/- bone mets. Results: Of 1,313 men, 656 were included in this analysis. All 4 BMB levels were higher in men with a PFS event w/in 2 years vs. those with no PFS event. The odds ratio (OR) for a PFS event was significantly higher in men w/ elevated baseline BMB (see table). For BAP, a significant interaction between marker elevation and bone mets was seen (p = 0.003); men w/ bone mets and BAP elevation had an OR of 1.83 for a PFS event in 2 years. Conclusions: In men with newly diagnosed HSPC, elevated baseline levels of BMB were significantly associated with PFS, with about a two-fold increased risk of a progression event w/in 2 years. For CICP, CTx, & PYD, this association was independent of the presence of bone metastases. Baseline BMB levels have strong prognostic value in the mHSPC context. Correlative analysis of BMB & OS is planned. Clinical trial information: NCT01809691 . [Table: see text]
Health-related quality of life (HRQoL) for olaparib versus enzalutamide or abiraterone in metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations: PROfound.
Authors: Thiery-Vuillemin Antoine , De Bono Johann S. , Saad Fred , Procopio Giuseppe , Shore Neal D. , Fizazi Karim , Roubaud Guilhem , Anjos Gabriel dos , Gravis Gwenaelle , Joung Jae Young , Matsubara Nobuaki , Castellano Daniel , Degboe Arnold , Gresty Christopher , Kang Jinyu , Allen Allison , Burgents Joseph E , Hussain Maha H. A. 
Published: May 2020

5539 Background: In the randomized Phase III PROfound trial (NCT02987543), olaparib significantly prolonged radiographic progression-free survival compared with physician’s choice of new hormonal agent (pcNHA, enzalutamide or abiraterone) in men with mCRPC and HRR gene alterations, whose disease had progressed on prior NHA. Olaparib significantly improved time to pain progression in Cohort A. We report additional patient reported outcome measures of HRQoL in the overall study population (Cohorts A+B). Methods: HRQoL was assessed in the overall study population using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, comprising 5 subscales: physical wellbeing (PWB), functional wellbeing (FWB), emotional wellbeing, social wellbeing, and prostate cancer subscale (PCS). The Trial Outcome Index (TOI; PWB+FWB+PCS) and FACT Advanced Prostate Symptom Index (FAPSI-6: derived from 6 FACT-P items) were also calculated. Adjusted mean change and time to deterioration in scores were statistically analyzed. Results: Baseline FACT-P total score was similar for both treatment arms. FACT-P total and subscale scores during treatment were all higher for olaparib vs pcNHA, with clinically meaningful differences between treatment arms in the adjusted least square (LS) mean changes from baseline in all but FWB and FAPSI-6 (Table). The time to deterioration in FACT-P total and TOI, FAPSI-6, PWB and PCS scores favored olaparib but were not statistically significant, with hazard ratios ranging from 0.68 to 0.94. Further HRQoL results for cohort A will also be presented. Conclusions: Olaparib delayed deterioration in HRQoL scores vs pcNHA and was associated with better HRQoL functioning over time compared with pcNHA in men with mCRPC and HRR gene alterations. Clinical trial information: NCT02987543 . [Table: see text]
Radium-223 (Rad) and niraparib (Nira) treatment (tx) in castrate-resistant prostate cancer (CRPC) patients (pts) with and without prior chemotherapy (chemo).
Authors: Kelly William Kevin , Leiby Benjamin , Einstein David Johnson , Szmulewitz Russell Zelig , Sartor A. Oliver , Yang Eddy Shih-Hsin , Sonpavde Guru 
Published: May 2020

5540 Background: Despite multimodality txs such as surgery, radiotherapy, hormonal tx and chemo, metastatic CRPC (mCRPC) prognosis remains poor. Research suggests PARP-1 is a key regulator of androgen receptor (AR) signaling and transition to lethal CRPC. Nira is a safe, potent and selective PARP-1/2 inhibitor that has shown single agent clinical activity in CRPC, and Rad is an alpha particle emitter. Addition of PARP inhibition may further enhance the clinical benefit of Rad. Nira has a favorable safety profile however, data on safety, tolerability and efficacy of Nira plus radiotherapy is limited. We hypothesize that targeting the PARP-1/AR axis in combination with radiation is safe and will improve mCRPC management. Methods: This is a phase (ph) Ib dose finding study (NCT03076203) of pts with progressive mCRPC using Time-to-Event Continual Reassessment Method (TITE-CRM). The primary objective is to determine the optimum ph II dose of Nira plus Rad (55 kBq/kg of body weight) in pts with and without prior chemo. Secondary endpoints include PSA reduction at 12 weeks (wks) and radiographic progression-free survival at 6 months. Pts enrolled to one of three dose levels of Nira (100, 200, and 300 mg PO daily). After completing 6 cycles of Rad, pts continued on Nira alone until objective progression, tx intolerance or pt decision. TITE-CRM identifies the maximum tolerated dose (MTD) based on toxicities observed over 12 wks of tx. Results: Between Oct 2017 and Jan 2020, 30 pts were enrolled (15 per stratum). Median age was 70 years; ECOG performance status was 0. The MTD of Nira was 100 mg in the chemo-exposed arm and 200 mg in the chemo-naïve arm. 19 Grade ≥ 3 adverse events were possibly related to tx: lymphocyte count decrease (n = 4, 13%), neutrophil count decrease (n = 3, 10%), anemia (n = 3, 10%), hypertension (n = 3, 10%), platelet count decrease (n = 2, 7%), creatinine increase (n = 1, 3%), hydronephrosis (n = 1, 3%), nausea (n = 1, 3%), white blood cell count decrease (n = 1, 3%). Tx duration and PSA response are shown in the table. Conclusions: Nira plus Rad was determined to be safe and tolerable. The MTD of Nira was identified and is pending ph II investigation. Managed by: Prostate Cancer Clinical Trials Consortium; Funded by: Janssen Scientific Affairs and Bayer Healthcare Pharmaceuticals, Inc Clinical trial information: NCT03076203 . [Table: see text]
Prognostic markers for overall survival and outcome to LuPSMA radionuclide treatment in patients with metastatic castration-resistant prostate cancer.
Authors: Gafita Andrei , Calais Jeremie , Wang Hui , Weber Manuel , Rathke Hendrik , Kratochwil Clemens , Esfandiari Rouzbeh , Armstrong Wesley R , Sandhu Shahneen Kaur , Tauber Robert , Delpassand Ebrahim , Haberkorn Uwe , Weber Wolfgang A , Herrmann Ken , Czernin Johannes , Hofman Michael S , Fendler Wolfgang Peter , Eiber Matthias 
Published: May 2020

5548 Background: The aim of this international multicenter retrospective analysis was to identify prognostic markers for the clinical outcome in late-stage mCRPC patients treated with 177Lutetium-prostate-specific membrane antigen (LuPSMA) radionuclide treatment. Methods: Patients with progressive mCRPC treated with LuPSMA at six centers in Germany, USA, and Australia were considered for inclusion. Eligible patients had 24 predefined, pretherapeutic covariates (demographics, prior mCRPC treatments, and PSMA PET/CT derived parameters) and survival data available. Endpoints included overall survival (OS) and PSA progression-free survival (PSA-PFS). Covariates were tested using univariate and mulitvariate proportional hazards regression Cox models. Results: 267/414 (64%) patients met inclusion criteria and were analyzed. 113 patients participated in clinical trials (ACTRN12615000912583, NCT03042312), while 154 were enrolled in compassionate-access programs. After a median follow-up of 22.5 months, median OS was 13.0 months (95%CI 11.6-14.4); 83% of the patients died. Median PSA-PFS was 4.0 months (95%CI 3.2-4.7). In the multivariate analysis, factors associated with shorter OS were: shorter time since diagnosis of prostate cancer (HR=2.04; p=0.002), lower number of prior systemic therapies (≤3; HR=1.56; p=0.006), prior exposure to chemotherapy (HR=1.42; p=0.05), lower hemoglobin levels (HR=1.13; p=0.002), higher number of lesions (≥20: HR=1.53; p=0.009), multiple sites of metastases (bone/LN only vs. bone + LN; HR=1.39; p=0.03) and visceral involvement (M1c) (HR=1.45; p=0.01). Factors associated with longer PSA-PFS were: longer time since diagnosis of prostate cancer (HR=0.44; p<0.001), higher hemoglobin levels (HR=0.32; p=0.03), presence of pelvic lymph nodes (LN) metastasis (N1) (HR=0.68; p=0.01), no distant lymph node metastases (M1a) (HR=0.66; p=0.01), no skeleton involvement (HR=0.44; p=0.01), no visceral metastases (M1c) (HR=0.51; p<0.001), higher PSMA-positive tumor volume (HR=0.87; p=0.04), and higher SUVmean (HR=0.94; p=0.002). Conclusions: This retrospective analysis identified prognostic factors for survival and treatment response to LuPSMA. Along with the conventional risk factors in mCRPC, PSMA PET/CT can be a useful tool for stratifying patients and guide patient’s selection for LuPSMA radionuclide treatment.
Modulation by treatment of tumor infiltrating lymphocytes (TILs) and PDL1 expression in triple-negative breast cancer in the ETNA trial.
Authors: Bianchini Giampaolo , Smart Chanel , Mansutti Mauro , Lück Hans-Joachim , Zambelli Stefania , Olier Clara , Anton Antonio , Bisagni Giancarlo , Merlini Laura , Murillo Serafin Morales , Calvo Martínez Lourdes , Chacon Jose Ignacio , Semiglazov Vladimir , Thill Marc , Chan Arlene , Tusquets Ignasi , Licata Luca , Valagussa Pinuccia , Viale Giuseppe , Gianni Luca 
Published: May 2020

555 Background: We assessed TILs and PDL1 expression before, during and after neoadjuvant treatment in TNBC patients enrolled in the ETNA study, and investigated associations with clinical outcome. Methods: In ETNA patients randomly received paclitaxel or nab-paclitaxel followed by 4 cycles of an anthracycline regimen, including 219 centrally confirmed TNBC. We successfully measured stromal and intratumoral TILs (sTILs, iTILs) and PDL1 status (Ventana SP142, IC≥1%) on biopsies before [n = 186/213 (84.9%)], on d1 cycle 2 (d1c2) of therapy [n = 41/186 (22.0%)], and at surgery [SX, n = 65/129 (34.9%)]. We investigated the expression and modulation over time of TILs and PDL1 and their association with pCR and event-free survival (EFS). Results: Prevalence of PDL1+ was 35.5% (baseline), 20.6% (d1c2) and 30.1% (SX). At each time-point sTILs and iTILs were higher in PDL1+ cases (p≤0.01). An effect of age of the tumor blocks (5-7.5 years) or pre-analytical issues could not be ruled out for the relatively low rate of PDL1 positivity. Paired PDL1 at baseline and d1c2 showed conversion in 25.7% (pos to neg [11.4%] or neg to pos [14.3%]). Comparing PDL1 at baseline and SX, the conversion rate was 30% (pos to neg [8.3%] or neg to pos [21.6%]). sTILs and iTILs significantly increased at cycle 2, more significantly in pCR (p≤0.001) than in RD (p≤0.05) cases, and a not significant trend of decrease was observed at surgery PDL1+ tumors had a higher pCR rate (54.7% vs 32.5%, p = 0.004). PDL1 retained significance (OR 2.00 [1.04-3.88], p = 0.039) after adjustment for sTILs (OR 1.21 [1.03-1.42], p = 0.021). High iTILs and sTILs at d1c2, but not PDL1 status, were predictive of pCR. Notably, adjusting for sTILs, PDL1+ tumors at d1c2 showed a trend for association with lower pCR rate (OR 0.06 [0.01-1.15], p = 0.062). sTILs at cycle 2 was the most informative variable (OR 1.61 [1.28-1.61], p = 0.004) and provided independent information to baseline biomarkers. Baseline PDL1 and biomarkers at cycle 2 were not associated with EFS. In surgical samples with RD, higher sTILs, but not iTILs and PDL1 status, were associated with a trend for a lower risk of recurrence (HR 0.19 [0.02-1.39], p = 0.068). Conclusions: sTILs assessment on core biopsies after one cycle of taxane is a promising early biomarker of pCR. PDL1, as well as sTILs and iTILs, provided independent prediction of pCR and were strongly modulated by treatment. The modulation of PDL1 expression should be considered whenever PDL1 is assessed in view of identifying candidates to atezolizumab in 1st line advanced setting.