bluuebunny/crossref_metadata_2025_split huggingface dataset:
Are patients with Gleason 6 pathology safe from developing metastatic castration-resistant prostate cancer (mCRPC)?
Authors: von Klot Christoph A. J. , Boeker Alena , Herrmann Thomas R. W. , Kramer Mario W. , Kuczyk Markus A. , Merseburger Axel S. 
Published: February 2017

110 Background: Prostate cancer may remain clinical unapparent for decades, however at the stage of metastatic castration resistant prostate cancer (mCRPC), patients have only limited survival even with new therapeutic options. Recent evidence from histology studies regarding random prostate biopsies hint toward a relationship between higher biopsy Gleason score and the development of mCRPC. A few patients with initial low risk prostate cancer also seem to develop mCRPC. However, prostate biopsy underestimates final pathology in about one third of patients. We therefore evaluated the final whole gland pathology from radical prostatectomy to better assess the risk of progressing to mCRPC for patients with Gleason 6 prostate cancer in particular. Methods: Clinical data was assessed for patients with confirmed mCRPC between 3/2007 and 10/2014. Whole gland pathology workup was not available for patients with either metastatic disease on diagnosis, external radiation therapy or no curatively intended initial therapy. Results: Out of 605 screened patients we identified a total of 77 patients with confirmed mCRPC. Mean PSA at initial diagnosis was 29.5 ng/mL (range 1 - 58 ng/mL ). Mean PSA at the end of follow up was 34.1 ng/mL (range 1 - 71 ng/mL ). A total of 30 patients died during follow up. Distribution of Gleason scores for gleason 6, 7, 8, 9 and 10 were 2, 24, 28, 18, 5 patients respectively. Pathological evaluation obtained from laparoscopic or retropubic radical prostatectomy was available in 43 of 77 cases. cases. Interestingly, out of the only two patients with a documented gleason score of 6, one had radiation/I125 brachytherapy while the other had primary anti hormonal therapy. Therefore an understaging may be possible. Out of the confirmed final pathologies, non of the patients had a Gleason score below 7. Conclusions: Our observations suggest a non significant occurrence of mCRPC during the development of prostate cancer for patients with Gleason pathology of less than 7. Our results may potentially help better counseling for patients and need further validation in a larger series.
Prostate patterns of care.
Authors: Burt Lindsay , Shrieve Dennis C. , Tward Jonathan D. 
Published: February 2017

117 Background: The aim of this study is to describe initial treatment of men diagnosed with prostate cancer in the United States (US) between 2004 and 2011. Methods: Subjects with adenocarcinoma of the prostate were identified using the National Cancer Institute’s (NCI) Surveillance, Epidemiology and End Results (SEER) Program between 2004 and 2011. Subjects were staged according the American Joint Committee on Cancer (AJCC) 7th edition criteria. The National Comprehensive Cancer Network (NCCN) risk group classifications were used to stratify subjects into low risk (LR) including very low risk, intermediate risk (IR), high risk (HR) and very high (VHR) groups. Surgical intervention was grouped into no surgery, prostatectomy or other which included cyroablative therapy, hyperthermia, laser ablation, TURP, etc. Descriptive statistics and analysis were performed using Microsoft Office 2013 Excel. Results: There were 306,694 PC subjects with sufficient data to be risk categorized. Overall, 35.0% of subjects had LR, 36.1% had IR, 22.5% had HR, 1.2% had VHR, 0.6% had node positive and 4.6% had metastatic disease. Table 1 reveals the surgical and radiation treatment distribution for each risk group. Between 2004 and 2011 the use of prostatectomy, no treatment and external beam RT (EBRT) increased and the use of brachy including brachy monotherapy and brachytherapy in combination with EBRT decreased. Age is a strong influence on treatment delivered. Conclusions: This patterns of care study shows the heterogeneity of therapy for PC stratified by risk group in a contemporary series. Trends in treatment may reflect the development of new technology and findings from randomized trials. [Table: see text]
Combined HDR brachytherapy boost plus external beam radiotherapy by IMRT versus external beam radiotherapy alone IMRT in intermediate- and high-risk prostate cancer: Dosimetric analysis from a randomized control trial.
Authors: Annamalai Manikandan , MA Laviraj , Kunhiparambath Haresh , Sharma Dayanand , Gupta Subhash , Mallick Supriya , Julka Pramod Kumar , Rath Goura Kishor 
Published: February 2017

134 Background: Dose escalation by IMRT or brachytherapy significantly improves biochemical control in localized prostate cancer. In this prospective randomized study we compared dose conformity between two modalities HDR brachytherapy and IMRT to deliver a boost to the prostate after External beam Radiotherapy (EBRT). Methods: 20 patients with localized prostate cancer were randomized to receive IMRT alone or IMRT plus brachytherapy. After randomization, all patients received EBRT 45Gy/25#/5 weeks by IMRT in phase I. In phase II patients received either HDR brachytherapy 19Gy/2# (Arm A) or EBRT 29Gy/15#/3weeks (Arm B) and EQD2–DVH parameters were calculated for comparison. EQD2 was calculated with α/β ratio of 1.5Gy and 3Gy for prostate & 3Gy for rectum and bladder. Results: The median age, stage distribution, Gleason score, PSA and prostate volume of the cohort were 69.5 years, T2b–T3b, 7, 38.5ng/ml and 47.4cc respectively.The HDR BT delivered higher mean doses to PTV. In phase II, HDR BT vs IMRT the mean EQD2 for 95% of prostate volume, 33% of rectal volume was 45.7Gy vs 28.4Gy, 6.8Gy vs 17.4 Gy respectively; Dmean of rectum and bladder was 7.4 Gy vs 13.5Gy and 5.4Gy vs 12.7Gy respectively. Conclusions: HDR BT produced more conformal plan and lower OAR doses than IMRT. Dose escalation for prostate tumors by HDR BT may be preferred as easily achievable. [Table: see text]
Current state of genetic biomarkers for prostate cancer.
Authors: Cooper Meghan Anastasia , Lee Jae K , Pow-Sang Julio 
Published: February 2017

135 Background: The heterogeneity of prostate cancer presents a challenge in accurately predicting disease behavior. Several biomarker models have recently been developed to allow better risk stratification and more definitive treatment. Methods: We surveyed the literature to find relevant articles on three commercially available prostate cancer biomarkers: Prolaris, Decipher and Oncotype DX. Articles were chosen based on the following criteria: adequate sample size for reliable statistical analysis, original and validation studies utilizing datasets from independent patient cohorts, and studies reporting appropriate statistical evaluations. Results: After screening 32 articles, eight were chosen for review that met the aforementioned criteria. Hazard ratio, odds ratio, area under the curve (AUC), or precision and reproducibility were used to quantify the assay’s predictive capability (Table). Conclusions: From our independent review we concluded that these biomarker models have not yet fully justified their claimed clinical utilities. Also, it is difficult to directly compare performance of these markers and no prospective studies have been reported to validate these assays. [Table: see text]
Predictive biomarkers of sensitivity to androgen receptor signaling (ARS) and taxane-based chemotherapy in circulating tumor cells (CTCs) of patients (pts) with metastatic castration resistant prostate cancer (mCRPC).
Authors: Scher Howard I. , Louw Jessica , Jendrisak Adam , Bambury Richard Martin , Danila Daniel Costin , Rathkopf Dana E. , Arslan Zaina , Schreiber Nicole A. , Lu David , Krupa Rachel , Marrinucci Dena , Landers Mark , Dittamore Ryan Vance 
Published: February 2017

147 Background: The optimal sequence to administer approved life prolonging ARS inhibitors: Abiraterone (A) and Enzalutamide (E),and taxanes: Docetaxel (D) and Cabazitaxel (C), to maximize individual pt benefit is an unmet medical need. Sensitivity to an individual agent is dependent on the intrinsic biology of the tumor and the treatment to which it has been exposed. For each agent, response rates are lower in pts who have received prior treatment with any of the other drugs, but for the individual, sensitivity to one does not necessarily predict sensitivity to the other. We sought to develop response and resistance signatures to A & E or D & C from a baseline blood sample. Methods: 91 pt blood samples collected from 79 pts for CTC analysis with the Epic Sciences platform prior to treatment (27 pre-A, 28 pre-E, 28 pre-D, 8 pre-C). Epic analysis identified traditional CTCs (CK+, CD45-, intact nuclei, morph distinct), CK- CTCs (CK-, CD45-, intact nuclei, morph distinct), small CTCs (CK+, CD45-, intact nuclei, small cell size), and CTC clusters. IF staining for AR N, AR C exp were performed, digital pathology algorithms analyzed CTC morphology. A classifier was developed to associate clinical phenotypes with outcome to a specific agent. Results: A and E signatures included: AR N/C exp. and presence of CK+, AR+, Nucleoli+ CTCs. D and C signatures by: presence of CK+, small, AR-, Nucleoli+ CTCs. Multivariate algorithms for A and E and D & C were statistically associated with de novo resistance. Line of therapy was not a univariate predictor of response. Conclusions: Characterization of CTCs identified predictive biomarkers of sensitivity to ARS Tx and taxane chemotherapy in mCRPC pts. The proposed A&E signature differs from C and D, providing the opportunity to better guide treatment selection and improve patient outcomes using a real-time, non-invasive blood biopsy. Prospective trials to validate results are planned. [Table: see text]
Statin use at the time of initiation of androgen deprivation therapy (ADT) and time to progression (TTP) in patients with hormone-sensitive prostate cancer.
Authors: Harshman Lauren Christine , Nakabayashi Mari , Xie Wanling , Wang Xiaodong , Valenca Loana , Werner Lillian , Mucci Lorelei A. , Lee Gwo-Shu Mary , Sweeney Christopher , Pomerantz Mark , Kantoff Philip W. 
Published: February 2017

148 Background: Statin use has been associated with a decreased risk of recurrence after local therapy and a lower risk of prostate cancer mortality. There is little known about the association between statin use and prostate cancer progression among men newly initiating ADT. We undertook an analysis of the association between statin use at the time of ADT initiation and TTP. Methods: We queried our institutional clinical database (Prostate CRIS), which captures clinicodemographic data, treatment details, and clinical outcomes of our prostate cancer patients (pts), to identify pts treated with ADT for biochemical recurrence or metastatic disease. Date of progression and statin use at ADT initiation were collected by medical record review. Progression was defined as 3 PSA rises. Date of progression was defined as date of first rise (nadir + >0.02 ng/ml). The association between statin use and TTP on ADT was estimated from multivariable Cox regression, adjusting for known prognostic factors: biopsy Gleason score, primary therapy type, metastatic status, and PSA at ADT initiation. Results: Of the 926 patients eligible for analysis, 283 (31%) were taking a statin at ADT initiation. Statin users were less likely to have M1 (11 vs. 18%) or N1 (5 vs 10%) disease at diagnosis and more likely to have received local therapy +/-ADT compared to nonusers. They were also less likely to have metastases at ADT initiation (53 vs 63%). Median PSA at diagnosis and at ADT initiation were lower among statin users. Duration from diagnosis to ADT initiation was longer in users. After a median follow-up of 5.8 years, 644 pts (70%) had progressed on ADT and median TTP on ADT was 20.3 months (95% CI: 18,24). Men on statins had a longer median TTP on ADT compared to nonusers (27.5 vs 17.4 months). The association remained statistically significant after adjusting for known prognostic factors [adjusted HR=0.83 (p=.039)]. Conclusions: In our cohort, statin use at the time of ADT initiation was associated with a significant increase in TTP on ADT even after adjusting for established prognostic factors. Further investigation into the mechanisms behind this observation is planned.
Phase II trial of abiraterone acetate (AA) treatment for metastatic prostate cancer (PC) patients with a PSA of more than four following initial androgen deprivation therapy: SWOG S1014.
Authors: Flaig Thomas W. , Tangen Catherine M. , Hussain Maha , Agarwal Neeraj , Mitsiades Nicholas , Deshpande Hari Anant , Vaishampayan Ulka N. , Thompson Ian Murchie 
Published: February 2017

152 Background: Metastatic PC patients with a poor response to initial androgen deprivation therapy (ADT) as reflected by a PSA > 4 ng/ml after 7 months of ADT have a poor prognosis. In the S9346 trial, about 25% of all enrolled patients had a PSA > 4 ng/ml after 7 months of ADT with a subsequent median survival (OS) of 13 months. S1014 examined the efficacy of AA in this setting. Methods: Eligible patients with metastatic PC and a PSA of > 4ng/ml between 6-12 months after starting ADT were treated with 1,000 mg of AA daily + 5 mg of prednisone twice daily. PSA could be rising or falling at the time of enrollment, but had to be > 4 ng/ml. No chemotherapy or secondary hormonal therapies were allowed, except in patients receiving an anti-androgen at the time of enrollment, who were continued on this therapy. The primary endpoint was a PSA of ≤ 0.2ng/ml within 12 months of starting AA. The null hypothesis was a 5% rate and alternative was 20%, requiring 6 or more patients with PSA < 0.2 ng/ml to conclude the regimen is promising (one-sided α=0.048, power=0.92). Results: Forty-one patients were enrolled between 7/2012 and 7/2013. One patient was deemed not analyzable due to not receiving any protocol treatment. Fourteen patients remain on treatment. Five (13%) patients achieved an undetectable PSA of ≤ 0.2ng/ml (95% CI 4%, 27%). Nine (23%) additional patients had PSA level > 0.2 but < 4 ng/ml. Twenty-one patients had no PSA response and six were not assessable and assumed to be non-responders. The median progression-free survival (PFS) was 17.4 months. There was one incident each of Grade 4 ALT elevation and rectal bleeding. Twelve patients reported Grade 3 adverse events as their worst level of severity. Conclusions: Although encouraged by 5 patients attaining “undetectable” PSA responses to AA in this poor prognosis setting, this study did not reach the protocol pre-specified level of 6 responses. OS and PFS will be updated with further follow-up. The therapy was generally well tolerated, without any clear signal of any unexpected toxicity. Clinical trial information: NCT01309672.
Precision medicine program for whole-exome sequencing (WES) provides new insight on platinum sensitivity in advanced prostate cancer (PCa).
Authors: Beltran Himisha , Sboner Andrea , Mosquera Juan Miguel , Rickman David , Eng Kenneth , Prandi Davide , Kossai Myriam , Faltas Bishoy , Pauli Chantal , Fontugne Jacqueline , Collins Colin , Gleave Martin , Wang Yuzhuo , Robinson Brian D. , Romanel Alessandro , Nanus David M. , Tagawa Scott T. , Demichelis Francesca , Elemento Olivier , Rubin Mark A. 
Published: February 2017

158 Background: WES has provided insight into the genomic landscape of PCa. The next step for precision medicine requires prospective patient (pt) follow-up and clinical and functional validation of both common and low frequency mutations. We describe a precision medicine WES program and illustrate how this can be used to identify novel biomarkers associated with response. Methods: Metastatic PCa pts were prospectively enrolled. WES of metastatic biopsies or rapid autopsies and normal DNA were sequenced by Illumina HiSeq 2500. Results: Tumor-normal pairs from 71 pts with metastatic PCa (11 hormone naïve, 38 CRPC, 23 NEPC) were sequenced including 3 rapid autopsies, with a biopsy success rate of >95%, avg tumor purity 10-95%, avg coverage 85X. The spectrum of mutations across metastatic PCa and how serial biopsies and rapid autopsies were used to assess heterogeneity and clonal evolution will be presented. WES from a metastatic PCa pt (PM12) with exceptional response to platinum with complete remission of liver and lung metastases at 2 years follow-up, demonstrated a hypermutated genotype and hemizygous deletion of the DNA repair gene FANCA in both his primary and metastatic PCa. A loss of function germline variant was detected within the second allele, and only the mutated allele was expressed in his tumor. Genome editing of FANCA using CRISPR in PCa cell lines resulted in cisplatin hypersensitivity and a significant decrease in FANC complex formation. In patient derived xenograft (PDX) models, PM12’s PDX was significantly more sensitive to cisplatin compared to a control Pca PDX of similar morphology but lacking FANCA deletion. By screening larger cohorts, FANCA loss was detected by FISH in 16% of localized PCa (n= 69), 14% metastatic Pca (n= 29), and not detected in any benign prostate (n=69). Conclusions: Our study provides a proof of principle for developing a precision medicine approach to cancer care with the capability to identify potential biomarkers of response. Our findings suggest that a subset of PCa with FANCA loss may be particularly vulnerable to cytotoxic therapy and provides biologic rationale to help explain the exceptional response of pt PM12 to platinum chemotherapy.
Risk for death from prostate cancer predicted from complete family history of lethal prostate cancer (LPC).
Authors: Albright Frederick S. , Agarwal Neeraj , Lowrance William Thomas , Stephenson Robert A , Alex Anitha , Cannon-Albright Lisa A 
Published: February 2017

175 Background: There are few published reports of relative risk (RR) for LPC based on family history of prostate cancer (PC) lethality. This study provides LPC RR using complete LPC family history data obtained from a statewide Cancer Registry linked to a genealogy database. Methods: The Utah Population Data Base (UPDB), which includes a statewide SEER cancer registry, includes 1,192,768 individuals with at least 12 of their 14 immediate ancestors. All males (probands) with specific LPC constellations were identified in the UPDB, and the observed number of LPC cases among these probands was compared to the expected number of LPC cases using internal cohort-specific rates from Utah death certificates including all deceased males with no 1st, 2nd, or 3rd degree relatives with LPC. LPC Family history was estimated for 1st degree to 3rd degree relatives for: number of LPC relatives affected, paternal versus maternal family history, and age at first PC diagnosis. Results: 3,921 individuals in UPDB were diagnosed with histologically confirmed PC, and had a Utah death certificate indicating PC as a cause of death and were designated LPC. The RR for LPC was significantly elevated with each additional first-degree relative (FDR) with LPC; even in the absence of FDR family history of LPC, significantly increased risk for LPC was observed in the presence of at least 1 LPC affected second degree relative (SDR). In the absence of positive FDR and SDR family history for LPC, there was still increased risk for LPC for males with 2 or more third degree relatives with LPC. Early age PC diagnosis in the LPC relative did not appear to affect LPC RR. Higher risks of LPC were associated with the maternal compared to the paternal lineages. Conclusions: Examination of lethal prostate cancer family history (in FDRs through TDRs) may be useful in identifying the cohort of men with prostate cancer most at risk for death from prostate cancer. Focused screening and treatment of this cohort holds potential to decrease the rates of undertreatment of lethal disease while avoiding over diagnosis and overtreatment in inconsequential disease.
Comparison of active surveillance with other treatment options for low-risk prostate cancer.
Authors: Musunuru Hima Bindu , Morton Gerard , Klotz Laurence , Vespirini Danny , Cheung Patrick , Chung Hans T. , Zhang Liying , Mamedov Alexandre , Sethukavalan Perakaa , Jethava Vibhuti , D'Alimonte Laura , Deabreu Andrea , Jain Suneil , Yamamoto Toshihiro , Loblaw D. Andrew 
Published: February 2017

178 Background: To evaluate outcomes and treatment history of low risk (LR) prostate cancer patients(pts) diagnosed between 2006-2008 in a single academic institute. Methods: Treatment and toxicity details were retrieved through retrospective chart review,apart from surgery where toxicity data was not available in detail.Biochemical RFS following primary and salvage treatments and CSS were computed.Pts who underwent salvage treatment for local failure and subsequently remained under biochemical control were censored as disease free for the salvage bRFS. Results: 594 pts were eligible for this study. Treatment options were active surveillance (AS=178 pts), low dose rate brachytherapy (LDR=192 pts, I-125 implant), stereotactic ablative body radiotherapy (SABR =84 pts; 35Gy in 5 weekly fractions), external beam radiation (EBRT=81 pts; 76Gy ) and radical prostatectomy (RP=59 pts). Median follow was > 70 months in all cohorts. 17.9% on AS protocol underwent active treatment. Biochemical failures were detected in 9 (5%), 10 (5.2%), 3 (3.5%), 6 (7.4%) and 9 (15.3%) pts respectively. Out of these, 4 pts in AS cohort, 2 in SABR group, and 7 in RP underwent local/salvage treatment. The 7-year bRFS was 94.4%, 93.6%, 95.8%, 90.1% and 89.5% for primary treatment and 95.7%, 93.6%, 98.7%, 90.1% and 98.3% following salvage treatment. 1 pt in AS, 2 in LDR, 1 pt in SABR and EBRT group developed metastatic disease. The 6 year CSS was 100% in all groups apart from LDR (99.4%) and EBRT (98.8%). Significant dysuria (20.8%) and hematochezia (7.4%) were noticed in EBRT cohort (Table). One grade 4 toxicity was noted in LDR, SABR and EBRT pts. Conclusions: AS has CSS comparable to other treatment options in LR prostate cancer setting with minimal toxicity. In the primary setting all treatment modalities apart from RP and EBRT have 7-year bRFS >93%. Differences in bRFS following salvage treatment might be due to pt and treatment selection. [Table: see text]