bluuebunny/crossref_metadata_2025_split huggingface dataset:
A circulating tumor cell specific RNA assay for assessment of androgen receptor signaling inhibitor sensitivity in metastatic castration-resistant prostate cancer.
Authors: Teng Pai-Chi , Jan Yu Jen , Yoon Junhee , Chen Pin-Jung , Chen Jie-Fu , Yao Nu , Cheng Shirley , Lozano Amber , Freeman Michael , You Sungyong , Tseng Hsian-Rong , Posadas Edwin M. 
Published: May 2019

5059 Background: Our objective is to develop a circulating tumor cell (CTC)-RNA assay for characterizing clinically relevant RNA signatures for the assessment of androgen receptor signaling inhibitors (ARSIs) sensitivity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: We developed NanoVelcro CTC-RNA Assay by combining Thermoresponsive(TR)-NanoVelcro CTC purification system with NanoString nCounter platform for CTC purification and RNA analysis. Based on the well-validated, tissue-based Prostate Cancer Classification System (PCS), we selected the most aggressive and ARSI-resistant subtype- the PCS1, for CTC analysis. We applied a rigorous bioinformatic process to develop a CTC-PCS1 panel that is specific to PC CTCs. We validated NanoVelcro CTC-RNA Assay and CTC-PCS1 panel with PC cell lines to demonstrate sensitivity and specificity of the PCS1 Z score (the likelihood estimate of the PCS1 subtype) for identifying PCS1 subtype and ARSI resistance. We then selected 31 blood samples from 23 PC patients receiving ARSIs to test in our assay. The PCS1 Z score of each sample was computed and compared with ARSI treatment sensitivity. Results: We established a 16-gene CTC-PCS1 panel that consists of CTC-specific RNA signatures. The validation studies using PC cell lines showed that the assay can detect the RNA transcripts with high sensitivity and scalability in the range of 1-100 cells. We also showed that the genes in CTC-PCS1 panel is highly expressed in PC cells. We further demonstrated that the CTC-PCS1 panel is highly specific in identifying PCS1-like samples, and the high PCS1 Z score is associated with ARSI resistance. In patient bloods, ARSI-resistant samples (ARSI-R, n=14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n=17) (Rank-sum test, P=0.003). In 8 patients who were initially sensitive to ARSI (ARSI-S) and later developed resistance (ARSI-R), we found that the PCS1 Z score increased from the time of ARSI-S to the time of ARSI-R (Pairwise T-test, P=0.016). Conclusions: Using our new methodology, we developed a first-in-class CTC-RNA assay and demonstrated the feasibility of transforming clinically-relevant tissue-based RNA profiling into CTC tests. This approach allows for detecting RNA expression relevant to clinical drug resistance in a non-invasive fashion, which can facilitate patient-specific treatment selection and early detection of drug resistance- a goal in precision oncology.
Computerized histomorphometric features of glandular architecture predict risk of biochemical recurrence following radical prostatectomy: A multisite study.
Authors: Leo Patrick , Janowczyk Andrew , Elliott Robin , Janaki Nafiseh , Shiradkar Rakesh , Farrè Xavier , Yamoah Kosj , Rebbeck Timothy , Shih Natalie , Khani Francesca , Robinson Brian D. , Eklund Lauri , Ettala Otto , Taimen Pekka , Bostrom Peter , Feldman Michael D , Gupta Sanjay , Lal Priti , Madabhushi Anant 
Published: May 2019

5060 Background: Following a radical prostatectomy (RP) for prostate cancer, a patient may experience biochemical recurrence (BCR), defined as two consecutive prostate specific antigen (PSA) readings > 0.2 ng/mL. BCR is correlated with metastasis and disease specific survival. Extant molecular based companion diagnostic tests for predicting risk of BCR and disease progression tend to be expensive and tissue destructive. We sought to evaluate whether computer extracted features of glandular architecture from routine digitized H&E slides could predict post-RP BCR risk. Methods: RP specimens from 683 patients (184 with BCR, 499 without) with post-surgical PSA follow-up information were gathered from six sites. Median non-BCR follow-up was 3.2 years. A representative tumor area was annotated on the diagnostic H&E slide of each patient. 324 (131 BCR) patients from two sites formed the training set. The other 359 (53 BCR) patients formed the validation set. Glands were segmented by a deep learning model. 216 features describing gland arrangement, shape, and disorder were then extracted. An elastic net Cox proportional hazards model was constructed from the training set using the top 10 stable features identified via feature selection. Risk score thresholds were chosen on the training set to stratify patients into low-, medium-, or high-risk. Validation set results were evaluated by the log-rank test and hazard ratio. For the 172 (37 BCR) patients for whom Gleason grade and preoperative PSA values were available, risk classifications were compared using Cox proportional hazards regression. Results: Nine of the top features were gland shape features and one was a gland arrangement feature. The hazard ratio between the low- and high-risk groups on the validation set was 3.04 (p < 0.05). The histomorphometric classifier was predictive of BCR (p < 0.05, hazard ratio = 1.63) independent of Gleason grade group and preoperative PSA in multivariate testing. Conclusions: Computer extracted features of gland morphology can stratify post-RP patients by BCR risk. Our computerized histomorphometric model could serve as a prognostic tool in the post-RP setting.[Table: see text]
Evolving natural history of metastatic prostate cancer.
Authors: Nafissi Nellie , Bryce Alan Haruo , Kosiorek Heidi E. , Butterfield Richard , Ho Thai Huu , Singh Parminder , Tan Winston , Costello Brian Addis 
Published: May 2019

5063 Background: The systemic therapies available to patients with metastatic prostate cancer (mPC) have improved dramatically over the past decade. Prior to 2010, the only agents with a proven survival benefit for patients with metastatic disease were androgen deprivation therapy and docetaxel. Since then, five new agents have been FDA approved and have proven survival benefit in phase III trials. Anecdotal experience suggests that the increased available lines of therapy have changed the profile of mPC to include a higher prevalence of visceral metastases. Methods: A retrospective review of 474 patients with prostate cancer who died in 2009 and in 2016 was performed. Patients with metastatic disease who had imaging within 6 months of death were included. A total of 164 patients were eligible for analysis. Results: Mean age at death overall was 77.4 years (SD 9.5) and did not differ signifiantly by cohort. Overall rates of visceral and distant metastases to include lung, liver, adrenal, brain, renal, spleen, and thyroid, were higher in patients who died in 2016 as compared to those who died in 2009 (40.0% and 26.1%, respectively, p = 0.07). Lung metastases were more prevalent in patients who died in 2016 versus in 2009 at 26.3% and 13.0%, respectively (p = 0.05). Patients who died in 2009 received a median of 3 (range 1-10) systemic treatments versus 4 (range 0-13) in those who died in 2016 (p = 0.005). Forty-four percent of patients who died in 2016 used five or more lines of systemic treatments compared to 26.1% of patients in 2009. Conclusions: The emergence of new systemic therapies for mPC is changing the natural history of the disease. Forty percent of patients now develop visceral metastases compared to 26% in the past. These changes will drive the need for new treatment approaches targeting visceral metastases. [Table: see text]
Ductal (PDC), acinar (PAC) and neuroendocrine (PNC) carcinomas of the prostate: A comparative comprehensive genomic profiling (CGP) study.
Authors: Bratslavsky Gennady , Jacob Joseph , Shapiro Oleg , Liu Nick , Ferry Elizabeth Kate , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Ali Siraj Mahamed , Chung Jon , Schrock Alexa Betzig , Reddy Prasanth , Millis Sherri Z. , Alexander Brian , Necchi Andrea , Ross Jeffrey S. 
Published: May 2019

5064 Background: PDC, PAC and PNC are histologic subtypes of prostate cancer (PC). We queried whether these subsets would share similar genomic alterations (GA) reflecting their disease biology and clinical features. Methods: CGP was performed using a hybrid capture-based assay on 61 PDC, 4,132 PAC and 217 PNC. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The age, GA per tumor and TP53 GA of PDC, PAC and PNC were similar (Table). RB1 GA were predominant in PNC. TMPRSS2:ERG fusions were most frequent in PNC, intermediate in PAC and lowest in PDC. AR GA were more often identified in PAC than PDC or PNC whereas PTEN GA were most frequent in PDC than PAC or PNC. Targetable GA were identified in all 3 groups when focused on BRCA2 (PARP inhibitors) and PIK3CA (MTOR inhibitors). ATM GA (PARP inhibitors) were more common in PAC than PDC or PNC. BRAF GA (BRAF/MEK inhibitors) were more frequent in PDC and PAC than PNC. CDK12 GA potentially associated with immunotherapy (IO) benefit were similar in PDC and PAC and low in PNC. Low frequencies of MSI-High and low median TMB levels were similar in all 3 groups. Conclusions: The pathologic features of PDC, PAC and PNC have been classically maintained as representative of 3 different tumor types with potentially contrasting histogenesis. In the current CGP based study, all 3 tumor types did not display significant differences in genomic signatures other than the high RB1 GA. CGP may reveal biomarkers that could direct patients to targeted (PARP, MTOR and BRAF/MEK inhibitors) or immunotherapies ( CDK12 GA, MSI-High or high TMB status) especially in PDC and PAC. [Table: see text]
Randomized phase II trial of presurgical androgen deprivation therapy (ADT) with or without axitinib in prostate cancer (PCa) presenting with lymph node (LN) metastasis.
Authors: Zurita Amado J. , Slack Tidwell Rebecca , Troncoso Patricia , Chapin Brian Francis , Harris Deborah , Pisters Louis L. , Araujo John C. , Pettaway Curtis Alvin , Aparicio Ana , Tu Shi-Ming , Papadopoulos John N. , Wang Jennifer , Logothetis Christopher , Pagliaro Lance C. , Davis John W. 
Published: May 2019

5078 Background: Strategies integrating androgen targeted and locoregional therapies are being increasingly used in PCa with regional spread, but are rarely curative. Angiogenesis inhibitors delay progression in castration resistant PCa and may synergize with ADT through endothelial cell apoptosis in hormone naïve patients (pts). We hypothesized that the frontline combination of ADT with the potent VEGF inhibitor Axi would improve PCa control relative to ADT alone and allow for meaningful time off systemic therapy after surgical consolidation. Methods: Pts with either clinically detected LN+ (TxN1M0 or TxNxM1a) or very high risk for LN PCa were treated with ADT for 2 mos and then randomized 2:1 to respectively add open label Axi (5 mg PO bid) vs. continue ADT alone for 4 mos until surgery. Those responding with PSA ≤5 ng/mL were offered prostatectomy and extended pelvic lymphadenectomy (RP). ADT +/- Axi was withheld postoperatively and PSA measured q3 mos until 1 y. Primary objective: proportion of pts progression free (FFP) 12 mos after RP, defined as PSA ≤1.0 ng/mL and no radiation or ADT, aiming to detect a 35% difference favoring ADT+Axi. Results: 72 pts completed accrual. We report on the 54 pts with LN+ disease: median age 62 y (range 42-76), pretreatment PSA 22.9 ng/mL (range 3.6 - 404.4), 38 N1 / 16 M1a. Table shows presurgical therapy outcomes. Path responses in the prostate were similar between arms, but in 5 ADT+Axi vs. 0 ADT LN+ pts there was no residual nodal disease. Testosterone recovery: 24/26 ADT+Axi and 9/9 ADT RP pts by 6 mos. 21/36 ADT+Axi and 15/18 ADT pts have failed; 1 y FFP estimates 48.0% (SE 8.6%) and 16.7% (SE 8.3%), respectively (p = 0.02). 1 y undetectable PSA 9 pts (6 ADT+Axi). No grade 4 toxicities or unexpected side-effects were observed. Conclusions: 1 year after RP, ADT+Axi resulted in proportionally greater number of LN+ PCa pts off treatment and progression free than ADT alone. Tissue analysis is evaluating predictors of benefit to further develop angiogenesis inhibition as part of combination strategies for hormone naïve PCa. Clinical trial information: NCT01409200. [Table: see text]
Contemporary trends in treatment for low-risk prostate cancer.
Authors: Frankel Jason , Caumont Fernando , Pervin Ari , Porter Christopher R. , Flores John Paul 
Published: May 2019

5082 Background: Active surveillance (AS) is the preferred management of low risk (LR) prostate cancer (PCa) to decrease morbidity associated with overtreatment. We hypothesized management trends would show AS increasing and initial definitive treatment decreasing for men with LR PCa. This study describes contemporary trends in initial treatment for LR PCa using the National Cancer Database (NCDB), which includes ~50% of new PCa diagnoses in the United States per year. Methods: NCDB was queried for all patients with LR localized PCa (2010-2015), defined as non-metastatic PCa with PSA<10 ng/mL, Gleason ≤6 and clinical T1-T2a primary tumor. Staging was assigned using 2018 American Joint Committee on Cancer guidelines. Patients refusing treatment, unable to be treated due to comorbidity or with unknown treatment status were excluded. Men were grouped based on NCDB codes for initial treatment including prostatectomy (PR), radiation (RT), AS and no treatment. Those receiving initial definitive treatment were compared to those who were not using logistic regression. Multivariable analysis was conducted for factors possibly correlating with management choice. Results: Of the 645,932 patients identified, 134,540 met inclusion criteria. Of these patients, 114,183 (84.9%) underwent PR or RT compared to 20,357 (15.1%) that did not. When examined over time, 92.4% of patients underwent initial PR or RT in 2010 vs. 73.9% in 2015 (p<0.001). 90% of patients seen at community cancer centers underwent definitive initial treatment compared to 78% of those seen at academic centers (p<0.001). Conclusions: In this national, hospital-based cohort overall rates of definitive initial treatment for LR PCa remain high, though seem to be decreasing over time. Overtreatment of LR PCa remains a concern and illustrates the relatively slow incorporation of guideline recommendations into clinical practice at the national level. [Table: see text]
Human prostate cancer immune phenotypes after androgen deprivation therapy.
Authors: Dallos Matthew , Obradovic Aleksandar , Chowdhury Nivi , Lopez Bujanda Zoila , Aggen David Henry , Hawley Jessica , Rathkopf Dana E. , Drake Charles G. 
Published: May 2019

5083 Background: The prostate tumor microenvironment (TME) is generally non-inflamed. However, we previously showed in pre-clinical models that androgen deprivation therapy (ADT) induces a complex immune cell infiltrate. Whether ADT similarly promotes inflammation in patients remains unclear. Therefore, we collected specimens from patients with localized prostate cancer treated with neoadjuvant degarelix and hypothesized that we could decipher key changes in the immune TME after ADT utilizing a novel cancer systems biology approach. Methods: We identified a cohort of patients treated with neoadjuvant degarelix (240mg SQ) as part of two clinical trials (NCT01696877, NCT01542021). Patients were treated with degarelix either 4 days (N = 13), 7 days (N = 17) or 14 days (N = 8) prior to radical prostatectomy. RNA was extracted from FFPE tissue and analyzed by RNAseq. To deconvolute fractional contributions of different immune cell subsets we performed CIBERSORT and Uniform Manifold Approximation and Projection (UMAP) analysis. Treatment groups were compared to a cohort of untreated matched controls (N = 37). Results: Degarelix induced a complex immune cell infiltrate in human primary prostate tumors with an increase in both pro- and anti-inflammatory cells subsets and changes in expression of immune checkpoints compared to untreated matched controls. Degarelix therapy also significant changed associated gene signatures within the lymphoid and myeloid compartments over time. Conclusions: ADT leads to profound immune remodeling within the prostate TME. Our analysis of human primary prostate tumors supports the hypothesis that the optimal time for immunologic intervention is the peri-castration period. These data also suggest that combinatorial immunotherapy strategies that target particular immune cell subsets will likely be required to successfully promote robust anti-tumor immune responses in prostate cancer.
Immunophenotype and proliferation to predict for response to neoadjuvant chemotherapy in TNBC: Results from BrighTNess phase III study.
Authors: Metzger Filho Otto , Stover Daniel G. , Asad Sarah , Ansell Peter J , Watson Mark , Loibl Sibylle , Geyer Charles E. , O'Shaughnessy Joyce , Untch Michael , Rugo Hope S. , Huober Jens Bodo , Golshan Mehra , Sikov William M. , Von Minckwitz Gunter , Rastogi Priya , Maag David , Wolmark Norman , Denkert Carsten , Symmans William Fraser 
Published: May 2019

510 Background: In TNBC, the interplay between immunophenotype, tumor proliferation (prolif) and achievement of pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) remains unknown. Methods: RNA seq was performed on pre-tx research biopsies of stage II/III TNBC enrolled in BrighTNess. NAC regimens included paclitaxel alone or with carboplatin (Cb) or Cb plus veliparib, followed by AC. Computational analysis included subtyping (i.e. PAM50, Pietenpol), prolif (PAM50) and GeparSixto immune signature (GSIS). Cb-containing arms were combined due to similar pCR. Results: High quality RNA seq data was obtained from 482 of 634 pts. PAM50 classified 80.1% of tumors as basal-like. TNBC subtypes were mostly BL1 or BL2 (23.3%), IM (22.4%) or M/MSL (31.7%); 6% were LAR. pCR was higher for basal vs non-basal tumors (52.3% vs 35.4%, p = 0.003). IM had the highest pCR rate (64.2%, 95% CI 59.9%,68.5%). Basal-like was not a significant predictor for Cb benefit (p-interaction = 0.8). Prolif (OR = 0.30 p < 0.001) and GSIS (OR 0.68 p < 0.001) were significantly correlated with pCR but did not correlate with each other (Pearson’s r2 = 0.027). In multivariate analysis, prolif (HR = 0.36 95% CI, 0.21-0.61 p = 0.0002) and GSIS (HR = 0.62 95% CI, 0.49-0.79 p < 0.0001) increased the ability to predict pCR beyond standard clinico-pathologic variables (likelihood ratio = 14.9, p = 0.0001115). Among all pts, those above the median for both prolif. and GSIS had the highest pCR (67%; 84/125) while those below the median for both had the lowest pCR rate (34%; 42/125). Tumors with higher inferred CD8+ T-cell infiltration demonstrated greater benefit from Cb using either TIMER (HR = 0.83 [0.73-0.95]) or CIBERSORT (HR = 0.83 [0.76-0.91]). Tumors with higher inferred total macrophages, particularly immune suppressive M2 macrophages had a higher pCR rate on the non-Cb arm (AC-T) using CIBERSORT (HR = 1.27 [1.07,1.50]). Conclusions: Immunophenotype and proliferation are independent predictors of pCR to standard NAC regimens in TNBC. PAM50 is not a significant predictor of Cb benefit. Exploratory findings suggest that tumor infiltrating immunophenotype (i.e. CD8 T cells and macrophages) may predict response to specific NAC regimens in TNBC. Clinical trial information: NCT02032277.
Clinical validity of CTS5 for estimating risk of late recurrence in unselected, non-trial patients with early ER+ breast cancer.
Authors: Richman Juliet , Ring Alistair E. , Dowsett Mitchell , Sestak Ivana 
Published: May 2019

514 Background: The Clinical Treatment Score at 5 years (CTS5) is a prognostic tool using clinicopathological data to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with estrogen receptor positive (ER+) breast cancer. It was developed and validated in the ATAC and BIG 1-98 trials. Methods: The validity of CTS5 was tested in a retrospective cohort of unselected, non-trial patients diagnosed with early ER+ breast cancer at the Royal Marsden Hospital from 2000-2007 who were alive and distant recurrence-free at 5 years. The primary endpoint was time to late DR (5-10 years). Cox regression models were used to determine the prognostic value of CTS5 and to produce Kaplan-Meier curves with associated 10-year DR risks (%). Results: A total of 2428 women were included with a median follow-up of 9.34 years from diagnosis. The CTS5 was significantly prognostic for late DR in post- and premenopausal women (Table). Risk stratification by CTS5 of the postmenopausal cohort was comparable with the development cohort. 42.1% of postmenopausal women were categorised into the low risk group with a late DR risk of 4.9% and these women had significantly lower risk of late DR compared to those in the intermediate or high-risk groups (Table). Amongst the premenopausal cohort, 41% were categorised as low risk with a late DR risk of 4.9%. The prognostic effect of CTS5 was seen for chemotherapy treated (HR=2.26, 95% CI (1.68-3.03)) and untreated patients (HR=1.93, 95% (1.32-2.82)). Conclusions: CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected, non-trial patients that included premenopausal women. The low risk cohort identified by the CTS5 represents a group of women whose risk of late DR is so low as to not warrant extended endocrine therapy to ten years. [Table: see text]
Event-free survival analysis of the prospectively randomized phase III ETNA study with neoadjuvant nab-paclitaxel (nab-P) versus paclitaxel (P) followed by anthracycline regimens in women with HER2-negative high-risk breast cancer.
Authors: Gianni Luca , Mansutti Mauro , Anton Antonio , Calvo Martínez Lourdes , Bisagni Giancarlo , Bermejo Begoña , Semiglazov Vladimir , Thill Marc , Chacon Jose Ignacio , Chan Arlene , Morales Serafin , Alvarez Isabel , Lahuerta Ainhara , Zambetti Milvia , Redfern Andrew D. , Dent Rebecca Alexandra , Barlera Simona , Valagussa Pinuccia , Tusquets Ignasi 
Published: May 2019

515 Background: The ETNA study showed that substituting P with nab-P did not significantly increase the overall rate of pathological complete response (pCR) (P 18.6%, nab-P 22.5%, p = 0.19). The multivariate analysis revealed that tumor subtype (triple negative vs luminal B-like) was the most significant factor (OR 4.85) influencing treatment outcome (Gianni L et al, JAMA Oncol 2018). Methods: This multicenter open label study (NCT01822314) in collaboration with GEICAM and BCRC-WA randomized 695 patients with centrally-confirmed HER2-negative breast cancer to nab-P 125 mg/m2 (346 patients) or P 90 mg/m2 (349 patients). The two drugs were given on weeks 1, 2 and 3 followed by 1-week rest for 4 cycles before 4 cycles of an anthracycline regimen as per investigator choice. The primary endpoint was pCR (absence of invasive cells in breast and nodes). A secondary endpoint is event-free survival (EFS) defined as the time from randomization to the first date of disease progression while on primary therapy or disease recurrence (local, regional, distant, invasive contralateral breast cancer) after surgery or death due to any cause. Results: The ITT analysis of the secondary endpoint EFS at 5 years is reported below: Clinical trial information: NCT01822314. Overall 5-year survival was 84.8% after P and 87.3% for nab-P. No serious adverse events were documented during the follow-up. Conclusions: The improved 5-year EFS after nab-P failed to reach statistical significance (unadjusted P = 0.245). In the analysis by subgroup the numerical improvement was almost exclusively observed in luminal B and not in TN tumors. So far the data do not support substitution of P with nab-P in the schedule and doses adopted in the ETNA trial. Additional analyses will be based on ongoing molecular studies.[Table: see text]