bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of plasma androgen receptor (AR) testing to optimize docetaxel chemotherapy in castration-resistant prostate cancer (CRPC): A multicenter biomarker study.
Authors: Conteduca Vincenza , Castro Elena , Wetterskog Daniel , Scarpi Emanuela , Romero-Laorden Nuria , Gurioli Giorgia , Jayaram Anuradha , Lolli Cristian , Schepisi Giuseppe , Wingate Anna , Casadei Chiara , Lozano Rebeca , Brighi Nicole , Aragon Isabel , Marín-Aguilera Mercedes , González-Billalabeitia Enrique , Mellado Begona , Olmos David , Attard Gerhardt , De Giorgi Ugo 
Published: May 2020

5546 Background: Plasma AR status has been identified as a potential biomarker of response in CRPC patients receiving docetaxel or the AR-targeted therapies abiraterone or enzalutamide. However, the relevance of plasma AR in the overall management of CRPC patients (pts) receiving docetaxel at different dose due to the toxicity profiles and physician-patient preferences is unknown. Methods: This was a multi-institution study of associations between baseline plasma AR-copy-number status assessed by droplet digital PCR and outcome in 325 CRPC pts. Between September 2011 and July 2019 pts started treatment with docetaxel administered at standard regimen 75mg/m2 every three weeks or adapted regimen (75-80% of standard recommended dose or 30mg/m2 weekly administration) at the discretion of the treating physician. Patients were assigned randomly into 2 sets with a ratio 2:1 to either training (n=217) and internal validation (n=108) cohorts. Results: In our study, adapted regimen of docetaxel was administered in 68 (31.3%) and 35 (32.4%) of training and validation cohorts, respectively. Based on plasma AR status, 67 (30.9%) and 39 (36.1%) validation and training set pts were classified as AR gain, respectively. In men treated with standard docetaxel regimen, no difference in progression-free/overall survival (PFS/OS) was seen between plasma AR normal and gain in both cohorts. In patients treated with adapted docetaxel regimen, we observed a significantly shorter median PFS (3.9 vs. 6.4 months, HR 4.77, 95%CI 1.48-3.80, p=0.0003) and median OS (11.2 vs . 20.4 months, HR 2.87, 95%CI 1.73-2.13, p=0.0008) in the training cohort. This finding was confirmed in the validation cohort (median PFS: 4.8 vs. 7.4 months, HR 2.54, 95%CI 1.40-4.58, p=0.005, and median OS: 11.8 vs. 26.4 months, HR 5.00, 95%CI 2.59-9.65, p<0.0001). In addition, AR-gained patients were less likely than AR normal to have a PSA decline when receiving an adapted regimen in both cohorts (p=0.010 e p=0.003, respectively). Conclusions: This study suggests that plasma AR may improve clinical decision making in choosing not only between AR-directed therapies and taxanes, but also between adapted and standard regimen of docetaxel in first- and subsequent-therapy lines, providing promising clinical implications to select the proper timing and dose of docetaxel. Prospective trials to validate these findings are warranted.
Cabazitaxel versus enzalutamide/abiraterone in CARD eligible mCRPC patients with or without germline HRR defects.
Authors: Romero-Laorden Nuria , Lozano Rebeca , Llacer Perez Casilda , Piulats Rodriguez Jose Maria M. , Puente Javier , Lorente David , Medina Ana , Cattrini Carlo , Vitrone Francesca , Almagro Elena , Borrega Pablo , Lainez Nuria , Rivera Leticia , Villatoro Rosa , Hernandez Amaia , Rodriguez-Vida Alejo , López-Casas Pedro P. , Gallardo Diaz Enrique , Castro Elena , Olmos David 
Published: May 2020

5554 Background: The CARD trial proved that in mCPRC patients (pts), previously treated with docetaxel and an androgen-receptor signaling inhibitor (ARSi), cabazitaxel (CBZ) significantly improves progression-free (PFS) and Overall Survival (OS) compared with the alternative ARSi. Concurrently, the PROFOUND study showed the superiority of olaparib vs. ARSi in pts with similar prior treatment history and genetic alterations in Homologus Recombination DNA repair related genes (HRR). Methods: PROREPAIR-B (NCT03075735) is a prospective study which aimed to demonstrate the prognostic role of germline deleterious mutations in (g)HRR genes and the benefit of first (1L), second (2L) and subsequent therapy lines for mCRPC. Outcomes with 1-2L have been previously reported. Here we evaluated radiographic (r)-PFS, clinical (c)-PFS, and OS in PROREPAIR-B pts who meet CARD study eligibility criteria and who received CBZ and/or ARSi. Survival analysis were performed using Kaplan Meier method and Cox regression models. Results: 95 out of 419 mCRPC pts included in PROREPAIR-B meet CARD eligibility criteria and received CBZ (n=60) or ARSi (n=35) including 14 gHRR carriers, 8/6 treated with CBZ/ARSi, respectively. Visceral metastases were more frequent among pts treated with CBZ (p=0.01). ECOG 2, M1 at diagnosis, Abiraterone as 1st ARSi and prior radiographic PD (all p<0.05) were more frequent in our pts than in the CARD study. Overall, CBZ was superior to ARSi in terms of rPFS (median 6.0 vs. 3.7 months (m), p=0.03), cPFS (median 4.4 vs. 3.4 m, p=0.01) and PSA50 responses (39% vs. 17%, p=0.027). Differences in OS were not observed, although approximately 60% of patients in ARSi had crossed to CBZ at the time of the analyses. Results of subgroups analyses were similar to those reported by CARD. In this series, gHRR carriers had a significant worse prognosis (OS HR 1.9; rPFS HR 2.4; cPFS HR 2.6) than non-carriers. In gHRR carriers CBZ was not superior to ARSi in terms of rPFS (2.5 vs. 3.0 m, p=0.8), cPFS (2.5 vs. 2.4 m, p=0.8) and OS (4.5 vs. 3.7, p=0.8). Cox MVA models adjusted for unbalances and CARD grouping factors confirmed a significant interaction between treatment and gHRR status for rPFS and cPFS, suggesting that the benefit of CBZ was not observed in gHRR. Conclusions: Our results confirm the benefit of CBZ treatment over a second ARSi (either abiraterone or enzalutamide) in unselected mCRPC population. However, the outcomes in gHRR carriers are poor with either CBZ or ARSi supporting the need of novel therapies in this setting. Clinical trial information: NCT03075735 .
Prospective evaluation of 18F-DCFPyL PET/CT in biochemically recurrent prostate cancer: Analysis of lesion localization and distribution.
Authors: Song Hong , Duan Heying , Harrison Caitlyn , Guja Kip , Hatami Negin , Franc Benjamin Lewis , Moradi Farshad , Mari Aparici Carina , Davidzon Guido , Srinivas Sandy , Iagaru Andrei 
Published: May 2020

5556 Background: 18F-DCFPyL, a promising PET agent targeting prostate specific membrane antigen (PSMA), is prospectively evaluated in a single academic center for detecting recurrent lesions in prostate cancer patients with biochemical recurrence (BCR). Methods: We prospectively enrolled 150 men (51-91 years old, mean ± SD: 70.3±7.5) with biochemical recurrence (PSA median 2.38 ng/mL, range 0.12 to 698.4) after primary definitive treatment with prostatectomy (65%), radiotherapy (35%) or both (19%). The 18F-DCFPyL positive lesions compatible with prostate cancer were evaluated by two independent readers. Impact of 18F-DCFPyL PET/CT on patient management was recorded from clinical chart review. Results: 18F-DCFPyL PET/CT had an overall positivity rate of 83% (125 scans), which increased with higher prostate specific antigen (PSA) levels (ng/mL): 63% (PSA < 0.5), 75% (0.5≤PSA < 1), 91% (1≤PSA < 2), 95% (2≤PSA < 5) and 98% (PSA≥5), respectively. In the cohort who underwent prostatectomy, 18F-DCFPyL PET/CT had higher positivity rate in patients with shorter PSA doubling time (PSAdt) (94% in PSAdt 0-3 months vs. 53% in PSAdt > 12 months, P< 0.01). No difference of 18F-DCFPyL positivity rate was observed in post-radiation patients with different PSAdt, nor were there differences between patients with low grade (Gleason 6) or higher-grade prostate cancer (Gleason 7-10). 20 patients (13%) had lesions in the prostate bed only and 41 patients (27%) had oligometastatic disease (1-3 lesions), making them candidates for locally targeted therapy. We identified a total of 1455 18F-DCFPyL positive lesions, including 51 lesions in the prostate bed, 271 pelvic and 463 extra-pelvic lymph nodes, approximately 585 osseous lesions, including 5 patients with diffuse osseous metastases, and 85 lesions in other organs (most commonly in the lungs). 91 out of 150 patients (61%) had change in treatment after 18F-DCFPyL PET and, most noticeably, 48 of these patients (32% total) had lesions only localized on 18F-DCFPyL PET/CT despite negative conventional imaging. Conclusions: 18F-DCFPyL PET/CT holds great potential to be a “one-stop shop” diagnostic tool in the work-up of BCR prostate cancer, with high (61%) impact on the management of these patients. Clinical trial information: NCT03501940 .
Association of detectable levels of circulating tumor DNA (ctDNA) with disease burden in prostate cancer (PC).
Authors: Attard Gerhardt , Gormley Michael , Urtishak Karen , Simon Jason S. , Ricci Deborah S. , Parekh Trilok V. , Cheng Shinta , Chi Kim N. , Smith Matthew Raymond 
Published: May 2020

5562 Background: PC is characterized by a relatively low prevalence of recurrent somatic point mutations. ctDNA is shed from PC and can be analyzed to profile somatic point mutations and copy number changes. We evaluated a computational approach to detect ctDNA (ie. ctDNA+) in PC based on allele frequencies of polymorphisms and mutations. We then sought to confirm the association of this biomarker with disease burden and clinical outcome. Methods: Customized, hybrid capture, high-depth next-generation sequencing was performed on pre-treatment (PT) plasma samples from a phase 2 line 3+ metastatic castration-resistant PC (mCRPC) study (NCT02854436, GALAHAD) and PT and end of treatment (EOT) samples from randomized Phase 3 study in non-metastatic (nm) CRPC (NCT01946204, SPARTAN) and from metastatic castration-sensitive PC (mCSPC) (NCT02489318, TITAN). Associations of ctDNA+ with bone lesions (number), visceral metastases (+/-), circulating tumor cells count (CTCc), and serum prostate specific antigen (PSA), alkaline phosphatase (AP) and lactate dehydrogenase (LD) were tested. Also, associations of ctDNA+ with overall survival (OS) and second progression free survival (PFS2) were evaluated in randomized studies using Cox regression. Results: ctDNA+ at PT was 7.5% in nmCRPC, 23.7% in mCSPC and 66% in heavily pre-treated mCRPC. ctDNA+ increased from PT to EOT in nmCRPC (7.5% to 27%) and mCSPC (23.7% to 63.6%). Disease burden metrics were evaluated in ctDNA+ vs ctDNA- patients. ctDNA+ was associated with higher disease burden in mCRPC (Table), nmCRPC and mCSPC. At EOT, ctDNA+ patients had shorter OS and PFS2 in nmCRPC (HR [95% CI] OS: 2.73 [1.83, 4.08], p < 0.0001; PFS2: 2.00 [1.38, 2.90], p = 0.0002) and mCSPC (HR [95% CI] OS: 7.59 [3.22, 17.91], p < 0.0001; PFS2: 4.84 [2.47, 9.47], p < 0.0001). Conclusions: ctDNA+ assessed using our novel, composite biomarker increases with advanced disease state and disease progression, is significantly associated with disease burden and poor clinical outcome in PC and could be a clinically relevant metric for monitoring response to therapy. Clinical trial information: NCT02854436 . [Table: see text]
Association between BRCA2 status and histologic variants (intraductal [IDC] and cribriform [CRIB] histology) in prostate cancer (PC).
Authors: Castro Elena , Salles Daniela Correia , Lozano Rebeca , Thorne Heather , Aragon Isabel , Lopez Campos Fernando , Rubio Jose , Gutierrez Pecharroman Ana , Prieto Daniel , García Isabel , Pacheco Maria I , Llacer Perez Casilda , Maldonado Laneisha , Romero-Laorden Nuria , Zambrana Francisco , López-Casas Pedro P. , Sandhu Shahneen Kaur , Antonarakis Emmanuel S. , Olmos David , Lotan Tamara L. 
Published: May 2020

5579 Background: IDC histology in PC has been suggested to associate with germline BRCA2 mutations (gBRCA2) in small series, leading to the potential recommendation of genetic testing for all PC patients with IDC in the primary tumor. Methods: We conducted a case-control study in which primary PC from 58 germline BRCA2 mutation carriers ( gBRCA2) and 116 from non-carriers (NC) were matched 1:2 by Gleason score and specimen type (core biopsy/prostatectomy). Samples were independently reviewed by two expert pathologists blinded to genetic status who established the presence of IDC and/or CRIB morphology with supportive immunohistochemical stains in a subset of cases. Next-generation sequencing, aCGH and/or FISH were used to assess for somatic mono-/bi-allelic BRCA2 alterations. PTEN protein loss was determined by IHC, and TMPRSS2-ERG was detected by FISH/qRT-PCR. Chi-square tests were used to compare the frequency of IDC and cribriform histology in gBRCA2 vs NC, as well as to assess the associations with other variables. Logistic regression models were built to identify independent factors associated with IDC and CRIB histology. Results: gBRCA2 cases were younger at diagnosis (median 61.3 vs 64, p < 0.01) and had T3-4 disease more often than NC cases (31% vs 10.5%, p < 0.01), but the two groups did not differ in any other clinical-pathologic characteristics. After independent histopathological review, 79 cases demonstrated IDC histology and 81 had CRIB histology. No differences in the prevalence of IDC (50% NC vs 36% gBRCA2, p = 0.09) or CRIB (43% NC vs 53% gBRCA2, p = 0.20) patterns were observed. The probability of IDC was higher in PC with bi-allelic BRCA2 alterations (OR 5.1, 95%CI 2.1-12.6), PTEN loss (OR 5.1, 95%CI 1.9-13.5) or both (OR 23.0, 95%CI 4.9-107.2) compared to those without these alterations. Bi-allelic BRCA2 alteration was also associated with higher probability of CRIB histology (OR 7.2, 95%CI 3.1-16.4). TMPRSS2-ERG fusions were not associated with IDC or CRIB histology. MVA confirmed the independent association of bi-allelic BRCA2 alteration (p < 0.01) and PTEN loss (p < 0.01) with IDC histology. Bi-allelic BRCA2 alteration (p < 0.01) and Gleason >8 (p < 0.01) were independent risk factors for CRIB histology. Conclusions: Primary PC with bi-allelic BRCA2 alterations was significantly associated with IDC and CRIB histology, independent of other clinical-pathologic factors (while gBRCA2 status alone was not). PTEN loss in primary PC was also independently associated with IDC, but not CRIB, histology.
Next generation sequencing reveals CCNE1 amplification as an independent prognostic factor for triple negative breast cancer (TNBC) patients.
Authors: Huang Xin , Wu Huanwen M. , Zhu Changbin , Shao Di , Guo Dan , Zhou Yidong , Lin Yan , Chen Chang , Xu Ying , Zhao Bin , Song Yu , Lu Tao , Sun Qiang ,   Xiehe
Published: May 2020

558 Background: Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer due to the heterogeneity as well as lack of better therapeutic approach. It remains controversial whether BRCA status is the predictor of survival in TNBC. Besides, both germline and somatic mutation may contribute to the prognosis. This study is to explore the potential predictors and therapeutic targets based on genetic data and clinicopathological parameters. Methods: Seventy-five TNBC patients were enrolled with approximately 2:1 based on BRCA status. Genetic data was analysed by comprehensive genomic profiling 508 key cancer related genes. DAVID was applied to perform pathway enrichment analysis of significant enriched genetic alterations. Cox regression model was applied to evaluate disease-free survival (DFS) and overall survival (OS). Immuno-chemistry (IHC) was used to validate clinically meaningful genetic alteration. Results: In this study, 27 germline mutations were detected, including 26 homologous recombination repair (HRR) pathway gene mutations and 1 mismatch repair gene mutation among them 16 BRCA1 mutations and 5 BRCA2 mutations were found. Germline HRR including BRCA1/2 mutation marginally affected DFS ( p = 0.0624 and 0.15, respectively). We found 480 somatic genetic alterations including 110 copy number variations (CNV). The median value of TMB was determined to be 4.1 Muts/Mb which divided 74 TNBC patients into TMB-low (TMB-l) and TMB-high (TMB-h) group. TMB-l group had inferior DFS to TMB-h ( p = 0.0457). CCNE1 (with 5% frequency) copy number gain was specifically enriched in TMB-l group but mutually exclusive with BRCA1/2 mutation. TNBC with CCNE1 gain displayed worse DFS ( p< 0.0001). Cox multivariate regression analysis indicated CCNE1 gain was an independent risk factors for DFS [HR = 13.48 (95% CI 2.62-69.23), p= 0.002)]. Pathway analysis indicated CCNE1 harmed prognosis through regulation of transcription in G1/S phase. Expression of cyclin E1 was validated by IHC, which would be presented later. Conclusions: Comprehensive genomic profiling disclosed various potential prognostic markers for TNBC by integrating clinical characters. Especially, amplified CCNE1 may be a potential prognostic marker and therapeutic target. [Table: see text]
The impact of age on early breast cancer after breast conserving therapy: Results of a subanalysis from the accelerated partial breast irradiation IMRT Florence trial.
Authors: Meattini Icro , Saieva Calogero , Desideri Isacco , Marrazzo Livia , Simontacchi Gabriele , Bonomo Pierluigi , Pallotta Stefania , Livi Lorenzo 
Published: May 2020

566 Background: The impact of age on local recurrence rate of patients affected by early breast cancer is still unclear. The standard of care for older adult largely varies depending on patient- and tumor-related features, but also on national guidelines. We recently presented the 10 years median follow update of the APBI-IMRT Florence phase III trial. The primary aim of the present analysis is to identify the potential relationship between age and ipsilateral breast tumor recurrence (IBTR) in this setting of patients. Methods: This retrospective analysis was performed on the whole series of 520 patients who were enrolled in the trial after breast conserving surgery and randomized to receive APBI or whole breast irradiation. We analyzed patients stratified by age (70+ vs 40-69 years). Results: At a median follow up time of 10.7 years, we recorded 15 IBTR events. Four hundred and three patients (77.5%) were aged less than 70 years old (11 IBTR) and 117 patients (22.5%) were aged 70 years or older (4 IBTR). At the univariate analysis the age (70+ vs 40-69 years) was not significantly correlated with IBTR occurrence (HR 1.33, 95% CI 0.42-4.17; p=0.63). The only significant prognostic factor was adjuvant endocrine therapy, also at the multivariable analysis (HR 0.26, 95% CI 0.07-0.94; p=0.041). Main results are summarized in the table. Within the luminal-like patients (n=437; 12 IBTR events), the age did not impact on the IBTR rate (HR 0.91, 95% CI 0.19-4.31; p=0.91) and adjuvant endocrine therapy lost its significance (HR 0.32, 95% CI 0.09-1.11; p=0.072). Conclusions: Our trial subanalysis did not demonstrate a significant effect of age on IBTR rate for early breast cancer patients receiving a breast conserving therapy. Due to the low number of events, the benefit of adjuvant endocrine therapy is unclear and calls for further investigations. Clinical trial information: NCT02104895 . [Table: see text]
Factors associated with axillary conversion after neoadjuvant chemotherapy in initially node positive breast cancer patients: A transSENTINA analysis.
Authors: Kolberg Hans-Christian , Kühn Thorsten , Krajewska Maja , Bauerfeind Ingo , Fehm Tanja N. , Fleige Barbara , Helms Gisela , Lebeau Annette , Staebler Annette , Loibl Sibylle , Untch Michael , Kolberg-Liedtke Cornelia 
Published: May 2020

567 Background: Current study concepts in early breast cancer after neoadjuvant chemotherapy (NAT) are aiming at reducing morbidity by omission of axillary surgery in selected patients. Selection criteria for this strategy have to include the probability of conversion from cN1 to ycN0. We analyzed the association of clinical/pathological parameters and axillary conversion with data from arms C and D of the SENTINA trial (Kühn T et al., Lancet Oncol 2013). Methods: Patients were recruited to Arms C/D of the SENTINA trial in case they presented with clinically positive nodes before NAT. Based on their response to NAT they were then assigned to either arm C (clinically conversion to ycN0) or arm D (no clinical conversion (ycN+). In both the pre- and post-NAT scenarios, clinically involved lymph nodes were defined as palpable and/or suspect by ultrasound. Univariate logistic regression analyses were carried out to evaluate the association between clinical/pathological parameters and axillary conversion after NAT. Results: Of the 892 patients in arms C and D of the SENTINA trial 716 were evaluable for this analysis. After NAT, 593 patients converted to ycN0 and were therefore assigned to arm C; in contrast, 123 patients still had involved lymph nodes after NAT (ycN+) and were assigned to Arm D. Arms C and D were compared regarding the clinical/pathological parameters tumor diameter by ultrasound before and after NAT, grading, multifocality, ER status, PR status, HER2 status, pathological complete remission in the breast (breast pCR), morphology, lymphovascular invasion (LVI) and hemangiosis. Only small tumor diameter after NAT (p = 0.0038), achievement of breast pCR (p = 0.0001) and lack of LVI (p = 0.0009) were positively associated with axillary conversion from cN1 to ycN0 after NAT. Conclusions: Because of the small patient number in arm D, we were not able to identify an association between parameters of tumor biology (ER, PR, HER2 and TN status) and axillary conversion. However, favorable response of the primary tumor (represented both clinically by tumor diameter after NAT and pathologically by pCR in the breast) were positively associated with conversion from cN1 to ycN0. These results justify including patients with clinical and pathological response of the primary tumor in trials investigating de-escalation of axillary surgery after NAT.
4R Program results in breast cancer: the impact of 4R Care Delivery Model on timing and sequence of guideline recommended care.
Authors: Weldon Christine B. , Trosman Julia Rachel , Makower Della F. , Rapkin Bruce D. , Perez Claudia Beth , Kulkarni Swati , Schaeffer Cathleen M. , Hoskins Kent , Gallagher Christopher , Lo Shelly S. , Grace-Louthen Cathy , Throckmorton Alyssa , Krueger Editha , Van Horn Jennifer , Reaves Brieyona Chardee , Ravelo Arliene , Yu Elaine , Benson Al Bowen , Schapira Lidia , Gradishar William John 
Published: May 2020

573 Background: We previously proposed a 4R care delivery model which enables patients and care teams to manage timing and sequence of interdependent, time sensitive care with a novel multimodality 4R Care Sequence plan (NCI ASCO Teams Project; Trosman, JOP 2016). We report final results of a program which tested 4R at 10 US centers (4 academic and 6 non-academic) from 2016 to 2019. Methods: 4R Sequences were provided to stage 0-III breast cancer patients (4R cohort, N = 422) at participating centers. Analyses of clinical and patient-reported data compared the 4R cohort to a historical control cohort of patients who received care pre-4R at the same centers (N = 466). Results: We significantly improved 5 guideline recommended referral metrics and 4 referral completion metrics indicating receipt of care by patients who were referred (Table). Although significantly increased, referrals to dental visit and smoking cessation before treatment remained low (< 20% and < 10% respectively). Patient survey comments indicated that insufficient lead time to quit smoking or obtain fertility consult before cancer treatment was a key barrier for completing these referrals. Conclusions: 4R markedly improved referral and receipt of interdependent guideline recommended breast cancer care for most metrics. Future 4R program should optimize the timing of referrals within the 4R Care Sequence to allow sufficient time for smoking cessation and fertility care before treatment initiation. [Table: see text]