bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I, first-in-human study of AbGn-107, a novel antibody-drug conjugate (ADC), in patients with gastric, colorectal, pancreatic or biliary cancers.
Authors: Ko Andrew H. , Coveler Andrew L. , Schlechter Benjamin L. , Bekaii-Saab Tanios S. , Wolpin Brian M. , Clark Jeffrey William , Bockorny Bruno , Bai Li-Yuan , Cheng Yi-Lin , Cheng Ting-Ying , Langecker Peter J. , Lin Shih-Yao
Published: May 2020

e16771

Background: AbGn-107 is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric (G), colorectal (CRC), pancreatic (PDA), and biliary (BIL) cancers. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a Phase Ia trial in patients with the aforementioned GI malignancies. Methods: Standard 3+3 dose escalation was used. Key eligibility included locally advanced or metastatic G, CRC, PDA, or BIL cancer, previously treated, ECOG PS 0-1; positive AG-7 expression was not required. Two dosing intervals were tested: AbGn-107 administered i.v. Q4 weeks (at doses ranging from 0.1-1.2 mg/kg) and Q2 weeks (at doses from 0.8-1.0 mg/kg). Dose limiting toxicities (DLT) were based on grade 3/4 hematologic and non-heme AEs occurring during the initial 4-week rx window. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments Q8 weeks. 1o objectives: safety and MTD; 2o objectives: PK, immunogenicity, and efficacy defined by ORR (RECIST 1.1). Results: 35 patients were enrolled across 6 dose levels (median age 61.5 yo (range 40 – 81); G (0)/CRC (12)/PDA (20)/BIL (3); median # lines of prior rx = 3 (range 1-7). Safety: 5 patients experienced Grade 3 or 4 neutropenia, all at higher dose levels, inc. 1 episode of febrile neutropenia. Other frequent drug-related AEs, mostly grade 1/2, inc. fatigue (29%), nausea (20%), and diarrhea (14%). DLTs included grade 4 CK elevation (n = 1) at 0.8 mg/kg Q4W and grade 3 arthralgias (n = 1) at 1.2 mg/kg Q4W. Based on safety profile and PK data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase. Efficacy: Median duration of treatment = 56 days (range, 8 – 225 days). Six pts have demonstrated a minor response by RECIST (range, -1.3 to -21.1%); 4 pts (all PDA) have had durable dz control > 180 days. Conclusions: Overall, AbGn-107 appears well-tolerated with encouraging prelim signs of efficacy in unselected pts with heavily pre-treated advanced GI cancers. Updated safety and efficacy data will be provided at the time of the meeting for the cohort expansion phase of this study (currently open across multiple sites in U.S. and Taiwan), in which subjects with G, CRC, PDA, and BIL cancers are pre-screened for high levels of AG-7 tumor expression. Clinical trial information: NCT02908451 .
Expectations of overall survival for patients with metastatic pancreatic cancer (mPC).
Authors: Willey Joanne P. , Buettner Arden , Britton Susan Lynne , Lankford Maria L. , Scharf Mitchell , Singh Bhavana Pendurthi , Rocha Lima Caio Max Sao Pedro
Published: May 2020

e16788

Background: Pancreatic cancer is the 4th leading cause of cancer-related death in the U.S. Metastatic pancreatic cancer has typically had a poor prognosis. However, the use of combination chemotherapy with novel agents have improved outcomes. First line therapy with either FOLFIRINOX (2011) or gemcitabine (gem)/nab-paclitaxel (2013) improved response rates (RR), progression-free survival (PFS) and OS versus (vs) gem alone. In 2015, second-line therapy with nanoliposomal irinotecan and fluorouracil (5FU) also improved RR, PFS, and OS vs 5FU. Since 2017, several newer agents have been approved for targeted patient populations – pembrolizumab for MSI-H/dMMR tumors, larotrectinib and entrectinib for NTRK gene fusion positive pts, and olaparib for germline BRCA-mutated pts. As more treatment (Tx) options become available, pts are more likely to receive Tx in later lines. A population-based study found that of mPC pts who completed 1st-line (1L) chemotherapy prior to December 31, 2014, 49% went on to receive 2nd-line (2L) Tx and 17% received 3rd-line (3L) Tx6. Methods: Prescribing patterns of 569 U.S.-based oncologists were studied using a validated, proprietary, case-based market research tool (Challenging Cases). Data were acquired using blinded, audience-response iPad technology at 8 live events during 2018-2019. Results: Estimate of mPC patients treated with 2L and 3L Tx in 2019 Estimates for mPC pts treated with 2L therapy rose from 2018 to 2019, with 46% treating > 60% of mPC patients with 2L in 2018 compared to 54% in 2019. Oncologists estimated median survivals to be 7.4 months (mos) from the regimens they prescribe in 1L, 4.3 mos in 2L, and 2.3 mos in 3L. Conclusions: With the addition of new and more effective treatments for mPC, more patients are treated in the 2L and 3L settings. However, oncologists may underestimate the survival expectation with novel agents or regimens, particularly in later lines of therapy. [Table: see text]
Cost-effectiveness of neoadjuvant FOLFIRINOX versus gemcitabine plus nab-paclitaxel in locally advanced/borderline resectable pancreatic cancer patients.
Authors: Ingram Myles , Lauren Brianna N , Pumpalova Yoanna S , Manji Gulam Abbas , Bates Susan Elaine , Hur Chin
Published: May 2020

e16793

Background: The 2019 NCCN guidelines recommend neoadjuvant FOLFIRINOX or neoadjuvant gemcitabine plus nab-paclitaxel (G-nP) for locally advanced and borderline resectable pancreatic ductal adenocarcinoma (BR/LA PDAC). Neoadjuvant FOLFIRINOX and G-nP have yet to be directly compared in a prospective, randomized trial with BR/LA PDAC patients. The purpose of our study was to incorporate treatment outcomes, toxicity profiles, costs, and quality-of-life measures to further inform clinical decision-making. Methods: We developed a decision-analytic mathematical model to compare the total cost and health outcomes of neoadjuvant FOLFIRINOX against G-nP over twelve years. Adjuvant gemcitabine (GEM) was used as a comparator. The inputs for the model were estimated using clinical trial data and published literature. We used single-institution retrospective studies to estimate our survival data in the absence of a prospective trial. The primary endpoint was incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay (WTP) threshold of $100,000 per quality-adjusted-life-year (QALY). Secondary endpoints included overall (OS) and progression-free survival (PFS), total cost of care (USD), QALYs, patient resection rate, and monthly treatment-related adverse events (TRAE) costs (USD). Results: FOLFIRINOX was the cost-effective strategy, totaling incremental QALYs of 0.21 at a cost of $52,845.96 per QALY when compared to G-nP. G-nP was also on the efficiency frontier with an ICER of $46,430.73 compared to GEM. More patients received resection with FOLFIRINOX (82.15% vs. 72.40%), but had higher TRAE costs than G-nP ($12,051.26 vs. $4,666.97). A one-way sensitivity analysis found that the FOLFIRINOX ICER exceeds the WTP threshold when TRAE costs are higher and resection rates are lower. Conclusions: Our modeling analysis finds FOLFIRNOX is the cost-effective treatment compared to G-nP for BR/LA PDAC despite having a higher cost of total care due to TRAE costs. Trial data with sufficient follow-up are needed to confirm our findings. [Table: see text]
Phase I trial of nab-paclitaxel administered concurrently with radiotherapy in patients with locally advanced inoperable pancreatic adenocarcinoma (ART in LAP).
Authors: Roy Amitesh Chandra , Abbas Muhammad Nazim , Price Timothy Jay , Singhal Nimit , Vatandoust Sina , Leung John , Kichenadasse Ganessan , Koczwara Bogda , Sukumaran Shawgi , Kumar Rajiv , Woodman Richard John , Richards Alison , Scott-Hoy Alex , Karapetis Christos Stelios
Published: May 2020

e16796

Background: Locally advanced pancreatic adenocarcinoma (LAPC) carries a poor prognosis with median overall survival of 12-18m. The optimal treatment is controversial. Nab-paclitaxel is active in advanced pancreatic cancer and has exhibited radio-sensitising anti-tumour efficacy. Methods: We conducted an investigator-initiated open-label, phase-I dose escalation trial of nab-paclitaxel with standard external beam radiotherapy (EBRT). All patients had biopsy-proven, untreated, localised, inoperable pancreatic adenocarcinoma; Patients received nab-paclitaxel on a weekly schedule for 6 weeks, concurrently with EBRT. A 3+3 cohort design was employed, with doses of nab-paclitaxel increasing from 25 mg/m2 (cohort 1), to 50 mg/m2 (cohort 2), 75 mg/m2 (cohort 3) and 100 mg/m2 (cohort 4). This principal objective of the trial was to establish the maximum tolerated dose (MTD) of nab-paclitaxel given concurrently with radiotherapy. Secondary objectives included safety and efficacy evaluation, including response rate, median PFS, median and 1- year OS. Results: Fourteen patients were recruited to the study, with a median age of 69 (range 40-86). 69% had a head or neck of pancreas tumour. Majority of patients had grade 1 or 2 toxicities with nausea (92%), fatigue (69%), diarrhoea (54%) and vomiting (54%) being the most common. Three patients were recruited in each of the first three cohorts, without any dose limiting toxicities (DLT). In cohort 4, DLT of febrile neutropenia and enterocolitis was observed in patient 1. The cohort was expanded with a subsequent DLT of febrile neutropenia and enterocolitis observed in patient 5. Both DLT events lead to death (grade 5). The MTD and recommended phase II study dose has been established as 75mg/ m2. The disease control (PR and SD) rate was 67%, median PFS 4.7 months (95% CI 2.5-27.5), 1 year OS 43% and median OS 11.4 months (95%CI 6.37-25.2). Conclusions: The combination of weekly nab-paclitaxel and fractionated radiation was generally well-tolerated at doses of nab-paclitaxel below 100 mg/m2. There were two treatment related DLTs leading to death in the nab-paclitaxel 100 mg/m2 cohort. The MTD and recommended phase II study dose for nab-paclitaxel combined with radiation therapy in the treatment of LAPC is 75mg/m2. Clinical trial information: ACTRN12613001013752 .
Genome-wide association study on genetic variations associated with treatment failure after intravesical bacillus Calmette–Guérin therapy for non-muscle invasive bladder cancer.
Authors: Shiota Masaki , Fujimoto Naohiro , Yamamoto Yoshiaki , Takeuchi Ario , Tatsugami Katsunori , Uchiumi Takeshi , Matsuyama Hideyasu , Eto Masatoshi
Published: May 2020

e17000

Background: Bacillus Calmette–Guérin (BCG) instillation is a key therapy to manage non-muscle invasive bladder cancer (NMIBC). However, intravesical BCG therapy fails in approximately half of patients, leading to recurrence and progression. We aimed to reveal the genetic variations associated with treatment failure after intravesical BCG therapy for NMIBC. Methods: This study included 91 Japanese patients treated with BCG instillation for NMIBC. Genomic DNA was obtained from patient whole blood samples, and a genome-wide association study and genotyping for target regions were performed. The association between genetic variation and treatment failure was analyzed by genome-wide association in 44 patients as the discovery cohort. As a validation study, candidate single nucleotide polymorphisms (SNPs) were examined among 47 patients in the distinct cohort. Results: The genome-wide association study indicated 19 candidate SNPs associated with BCG failure. Consistent results were obtained in six of these SNPs in the validation cohort. Following the combinational use of validated SNPs, 2-gene (rs73520681 and rs61094339) and 4-gene (rs4250, rs11894207, rs73520681, and rs61094339) models successfully predicted treatment failure after intravesical BCG therapy. Conclusions: This study showed that several SNPs were associated with outcome after intravesical BCG therapy in a Japanese population with NMIBC. The combinational use of these SNPs may have value in clinical applications, although this should be confirmed in future studies.
Treatment of metastatic recurrence of urothelial carcinoma after previous cisplatin-based chemotherapy: A retrospective comparison of different chemotherapy regimens.
Authors: Do Olivia A , Ferris Lorin , Holt Sarah K , Ramos Jorge , Harshman Lauren C , Plimack Elizabeth R. , Crabb Simon J. , Pal Sumanta K. , De Giorgi Ugo , Ladoire Sylvain , Baniel Jack , Necchi Andrea , Vaishampayan Ulka N. , Golshayan Ali Reza , Bamias Aristotelis , Bellmunt Joaquim , Srinivas Sandy , Dorff Tanya B. , Galsky Matt D. , Yu Evan Y.
Published: May 2020

e17005

Background: The optimal choice of first-line chemotherapy for urothelial carcinoma (UC) patients who recur after previous cisplatin-based chemotherapy for locally-advanced disease is unclear. Our objective is to compare the efficacy of platinum (PBC) versus non-platinum (NPBC) based first-line chemotherapy regimens for such patients after metastatic recurrence. Methods: Data was collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database consisting of patients with muscle-invasive or advanced UC from 28 centers between 2005 and 2012. Patient inclusion criteria included: 1) UC with no initial metastases (cT2-4, cN0-N3, and cM0), 3) receipt of cisplatin in the locally advanced setting, and 4) receipt of chemotherapy in the first-line metastatic setting. Overall survival (OS) was the primary endpoint. Secondary endpoints included progression-free survival (PFS) and response to chemotherapy. Kaplan-Meier and Cox regression models estimated OS, PFS, and response, adjusting for age, gender, Eastern Cooperative Oncology Group (ECOG-PS), Charlson comorbidity index (CCI), surgery, T and N stage, albumin, creatinine clearance, number of initial cisplatin cycles, and time from last chemotherapy. Results: 152 patients with metastatic UC (88 PBC and 64 NPBC) were analyzed. Twelve (7.9%) patients received local definitive radiation and 7 of these 12 also underwent cystectomy. The most common NPBC regimens included taxanes, gemcitabine, or pemetrexed. The median OS was 8.70 (95% CI: 7.53 to 11.16) and 10.27 months (95% CI: 7.37 to 13.10) for PBC and NPBC (HR: 1.04, 95% CI: .67 – 1.61, p = 0.86), respectively. Multivariable analysis showed an independent prognostic effect on OS for number of previous chemotherapy cycles (3-4 vs. 1-2) (HR: 0.44, 95% CI 0.20 – 0.96, P = 0.03) and whether surgery was performed (HR: 0.44, 95% CI 0.26 – 0.75, P = 0.003). Time from last chemotherapy was not prognostic for OS (HR: 0.99, 95% CI: 0.99 – 1.00, p = 0.19). There were no significant differences for both investigator-designated PFS (HR: 0.84, 95% CI: 0.57 – 1.24, p = .39) and response to chemotherapy between PBC and NPBC (p = 0.57). Conclusions: There is no significant outcome difference between PBC vs. NPBC in patients with metastatic-recurrent urothelial carcinoma who previously received cisplatin-based chemotherapy for locally advanced disease. Those who previously underwent radical surgery or who received 3-4 cycles of cisplatin had better OS with PBC.
Perioperative blood transfusion and postoperative outcomes in patients undergoing radical cystectomy for bladder cancer.
Authors: Diamantopoulos Leonidas Nikolaos , Sekar Rishi Robert , Khaki Ali Raza , Miller Natalie , Gadzinski Adam John , Psutka Sarah P. , Gore John L. , Schade George R. , Lin Daniel W. , Tretiakova Maria S. , Vakar-Lopez Funda , True Lawrence D. , Hsieh Andrew Caleb , Cheng Heather H. , Yu Evan Y. , Schweizer Michael Thomas , Yezefski Todd , Montgomery Robert B. , Grivas Petros , Wright Jonathan L.
Published: May 2020

e17012

Background: Perioperative blood transfusion (PBT) has been associated with worse outcomes in surgical oncology across tumor types. We report our institutional experience of postoperative outcomes related to PBT utilization, in patients (pts) with bladder cancer (BC) treated with radical cystectomy (RC). We hypothesized that PBT is associated with worse clinical outcomes. Methods: Pts with BC treated with RC were retrospectively identified. Clinicopathologic and peri/post-operative data were extracted. PBT was defined as red blood cell transfusion during RC or postoperative hospitalization. Overall survival (OS, diagnosis to death) and recurrence free survival (RFS, RC to recurrence/death) were estimated with the KM method. T-test, χ2 and log-rank test were used for group comparison analysis. Univariate/multivariate logistic (LR) and Cox regression (CR) were used to identify variables associated with dependent dichotomous outcomes and OS/RFS, respectively. Results: 784 consecutive pts (78% men; median age 67) were identified. At least one post-operative complication (POC) occurred in 407 (52%) pts; most common were pyelonephritis and sepsis (11% each). PBT was administered to 238 pts (30%). Those with PBT had a higher proportion of POCs (35% vs 28%, p = .02). Median follow-up, OS and RFS were 66 (95% CI: 60 - 72), 94 (95% CI: 79 - 109) and 66 months (95% CI: 50 – 82), respectively. Pts who received PBT had shorter OS (51 vs 130 months, p < .001) and RFS (27 vs 86 months, p < .001). In multivariate LR and CR, PBT was independently associated with higher odds of POCs (OR 1.5, 95% CI: 1.03 – 2.2, p = .03), length of hospital stay (LOS) > 10 days (OR 2.0, 95% CI 1.1 – 3.5, p = .02), shorter OS (HR 1.6, 95% CI 1.2-2.0, p = .001), and RFS (HR 1.5, 95% CI 1.2 - 1.9, p = .001), after adjustment for other relevant clinicopathologic variables (age, gender, performance status, neoadjuvant chemotherapy, baseline hemoglobin, open/robotic approach, pT/N stage, surgical margins, lymphovascular invasion at RC, variant histologies). Conclusions: Pts who received PBT had higher odds of POC, longer LOS and poor outcomes after RC. This is hypothesis-generating due to inherent study limitations. Further studies are needed to validate this finding, explain underlying mechanisms and explore putative interventions to improve outcomes.
Impact of previous nephrectomy on clinical outcome of metastatic renal carcinoma treated with immune-oncology (I-O):A real-world study on behalf of Meet-URO group (MeetUro-7b).
Authors: Stellato Marco , Santini Daniele , De Giorgi Ugo , Verzoni Elena , Casadei Chiara , Fornarini Giuseppe , Maruzzo Marco , Napolitano Andrea , Sbrana Andrea , Di Lorenzo Giuseppe , Soraru' Mariella , Naglieri Emanuele , Buti Sebastiano , De Vivo Rocco , Vignani Francesca , Mucciarini Claudia , Grillone Francesco , Roviello Giandomenico , Pignata Sandro , Procopio Giuseppe
Published: May 2020

e17088

Background: Immuno-oncology (IO) treatment demonstrated to improve Overall Survival (OS) in metastatic renal cell carcinoma (mRCC). The prognostic impact of previous citoreductive nephrectomy (CN) and radical nephrectomy with curative intent in patients (pts) treated with IO is not well defined. Methods: 229 eligible pts, with a least one radiological assessment of response according to the RECIST 1:1 criteria, were retrospectively collected from 16 Italian referral centers. Baseline characteristics, outcome data including progression-free survival (PFS) and OS were collected. Kaplan-Meier method and log-rank test were performed to compare PFS and OS between groups. Results: 153(66.8%) pts received IO as second line, 61(26.6%) as third line and 15(6.6%) pts as further line. 54 pts (23.6%) were good risk, 144(62.9%) were intermediate and 31(13.5%) were poor risk according to IMDC score. 189(82.5%) pts underwent nephrectomy (of them 72(32.4%) pts had synchronous metastatic disease and underwent CN), while 40(17.4%) pts did not. Nephrectomy was performed before IO treatment. ECOG PS, at the beginning of IO, was 0 for 167 pts (72.9%), the other 62 (27.1%) had ECOG PS 1 or 2. At a median follow up time of 17.5 months (mo), 13 (5.7%) pts are still in treatment while 216 (94.3%) experienced progression. 81 (35.3%) pts were treated after IO progression with mTOR and VEGFR inhibitors. 63 (27.5%) pts continued IO beyond progression. G3-G4 iAE were reported in 46 pts (20%). Median IO-PFS was 4.5 months in pts who did not undergo nephrectomy and 2.9 mo in pts who did (HR log rank 0.713, 95%CI 0.4788 to 1.063; p= 0.0582). Median IO-OS was 18.4 mo in pts who underwent nephrectomy and 10.3 mo in pts who did not (HR log rank 1.915, 95%CI 1.118 to 3.281; p= 0.0024). The difference in OS was irrespective of the IMDC criteria and the lines of treatment. Conclusions: In our real world experience, in mRCC pts treated with IO, previous nephrectomy was associated with a better outcome in terms of OS with all the limitations of a retrospective collection.
Underrepresentation of genitourinary cancers in studies of venous thromboembolism (VTE) prophylaxis.
Authors: Perlmutt Max S , Rose Tracy L , Kumar Vaibhav , Milowsky Matthew I.
Published: May 2020

e17115

Background: Significant advances in the management of VTE in cancer have led to a recent ASCO clinical practice update for VTE prophylaxis and treatment in patients with cancer. Genitourinary (GU) cancers (including bladder, kidney, prostate, testicular) have a high incidence of VTE, but also frequent bleeding complications, and it is not clear if patients with GU cancers are adequately represented in studies of VTE prophylaxis. We sought to determine the frequency of inclusion of patients with GU cancers in prospective studies of VTE prophylaxis. Methods: A systematic review of the literature using MEDLINE (inception to January 2020) was conducted. We included randomized controlled trials that compared thromboprophylaxis to placebo or best supportive care in patients with an established diagnosis of cancer. Observational studies, case series, and case reports were excluded. The primary outcome was proportion of patients with GU malignancies included within the trials. Results: A total of 137 articles were identified under the original search and 7 underwent full text review. A total of 6066 patients were included in 7 thromboprophylaxis trials, of which only 119 (2.0%) had a defined GU malignancy (Table). Given the heterogeneity of the GU cancers represented in each study, and the small numbers of patients included with GU cancers, a patient-level meta-analysis among GU patients in this population was not performed. Conclusions: In spite of the high risk for VTE in GU cancers, in particular bladder and testicular cancer, GU cancers are underrepresented in prospective randomized trials investigating VTE prophylaxis. To ensure appropriate decision making for each individual patient, future prospective trials must ensure adequate representation of patients with GU cancers to better understand the potential role for VTE prophylaxis in this high-risk population.[Table: see text]
Changes in ki-67 and cleaved caspase-3 (CC3) with short term androgen deprivation therapy (ADT) prior to prostatectomy as part of a trial in intermediate and high-risk prostate cancer (PC).
Authors: Vargas Pivato de Almeida Daniel , Chen Ying-Bei , Autio Karen A. , Carver Brett Stewart , Slovin Susan F. , Danila Daniel Costin , Scher Howard I. , Touijer Karim A. , Rathkopf Dana E.
Published: May 2020

e17502

Background: Ki-67 and CC3 are markers of cellular proliferation and apoptosis and have been associated with prognosis in localized PC. Testosterone suppression promotes a time-dependent modulation of these indices. We explored changes in Ki-67 and CC3 at different timepoints in a pilot trial using short-term ADT prior to radical prostatectomy (RP). Methods: Pts with intermediate and high-risk localized PC were randomized to receive a single dose of neoadjuvant degarelix (240 mg SC) either 4 ± 1 days (Cohort A) or 7 ± 1 days (Cohort B) prior to RP. Anatomically matched tumor foci from the pre-treatment diagnostic biopsy and the prostatectomy specimens were assessed by immunohistochemistry (IHC) for Ki-67, CC3, and PTEN expression. Results: 32 pts were randomized: 15 to Cohort A and 17 to Cohort B. Ki-67 and CC3 expression in the pre- and post-treatment samples for both cohorts are summarized in the table. A significant reduction in Ki-67 and increase in CC3 expression occurred in both cohorts (all p-values < 0.05). No difference was found when the absolute difference of Ki-67 expression was compared between Cohort A and Cohort B (p = 0.7). A significant reduction of Ki-67 and increase in CC3 expression occurred in pts independent of PTEN status. Conclusions: A reduction of Ki-67 and an increase in CC3 expression was achieved in both cohorts following a single dose of degarelix within 1 week of RP. Although loss of PTEN has been associated with androgen-independent progression, reduction of proliferation and increase in apoptosis levels were achieved independent of PTEN status in this small cohort. Further analyses are ongoing to correlate the pathologic findings with clinical outcomes. Clinical trial information: NCT01542021 . [Table: see text]
Development of a circulating tumor cell-based RNA classifier for patients with castration-resistant prostate cancer: CTC-PCS/PAM50.
Authors: Teng Pai-Chi , Jan Yu Jen , Kim Minhyung , Chen Jie-Fu , Yoon Junhee , Wang Jasmine Jiemei , Chen Pin-Jung , Yao Nu , Lee Yi-Te , Lozano Amber , Gadilov Ruslan , Freeman Michael , You Sungyong , Tseng Hsian-Rong , Posadas Edwin Melencio
Published: May 2020

e17509

Background: Genomic profiling has strongly impacted the contemporary understanding of prostate cancer (PCa). Clinical trials are now testing the utility of genomic classifiers such as the PCS (You, Ca Res 2016) and PAM50 (Zhao, JAMA Onc 2017) systems to optimize therapy selection. As contemporary tissue is not always readily available, especially in metastatic, castration-resistant PCa (mCRPC), a blood-based test would be better suited for assessing patients and predicting treatment response. Methods: The CTC-RNA assay combines the Thermoresponsive (TR)-NanoVelcro system with the NanoString nCounter platform. This allows for CTC purification and RNA analysis. Using a novel bioinformatics approach that accounts for differences in background signals between tissue and blood, we reconstructed the PCS and PAM50 panels to recapitulate both classifiers in this blood-based assay. A weighted Z-score and nearest centroid classifier were used to calculate gene expression and to assign PCS and PAM50 subtypes. Performance of the revised signatures and CTC-RNA assay was benchmarked on simulated spiked-blood specimens. An initial clinical test was performed using clinically annotated, banked blood specimens within the Translational Oncology Program Blood and Biospecimen Bank. Results: CTC-RNA profiles of C4-2B AR signaling inhibitor (ARSI)-resistant sublines were compared to parental C4-2B. C4-2B ARSI-resistant cells had significantly higher PCS1 Z scores, PCS1 probability, and basal probability compared to the parental C4-2B cells. Blood samples from 34 mCRPC patients prior to initiation of therapy with ARSIs (abiraterone, enzalutamide, or apalutamide) were then analyzed. Samples were classified as PCS1 (n = 3), PCS2 (n = 20), and PCS3 (n = 11); luminal A (n = 12), luminal B (n = 11), and basal (n = 11). The biochemical progression-free survival (bPFS) on ARSI and overall survival (OS) for PCS1/Basal vs. other are shown in the table. Conclusions: The CTC-RNA assay is capable of generating luminal-basal classifications such as those in the PCS and PAM50 systems. Given early data of these classifiers and their potential to guide therapeutic decisions, this approach may be useful as an alternative to biopsy to facilitate such decisions. Larger prospective studies will be needed to confirm and validate its clinical utility. [Table: see text]
Landscape of somatic DNA damage repair (DDR) gene mutations in genitourinary cancer in China.
Authors: Yang Kaiwei , Tang Qi , Mi Yue , Yu Wei , Song Yi , Zhang Yanrui , Wang Huina , Lou Feng , Cao Shanbo , He Zhisong
Published: May 2020

e17516

Background: DDR gene alterations(GAs) are prevalent in cancer and play key roles in tumorigenesis, progression and therapeutic response. However, the molecular profile of DDR in genitourinary cancer is still lacking in Asian. In this study, we assessed DDR GAs for better understanding therapeutic implications. Methods: Patients(pts) diagnosed with genitourinary cancer were enrolled. Tumors and plasma samples were collected for next-generation sequencing with Acornmed panel(2.0 Mbp) containing 808 cancer-related genes, including 34 DDR genes(Jonathan, et al.). OncoKB and COSMIC were used to identify GAs status including deleterious, unknown significance, and wild type(wt). Results: A total of 140 pts were enrolled with 56 pts of prostate cancer(PC), 55 pts of renal cell cancer(RCC) and 29 pts of urothelial cancer(UC). Metastatic diseases were accounted for 33.5%. A total of 127 tumor tissues and 109 baseline plasma samples were collected, including 96 matched tissue/plasma samples. A total of 109 pts(77.9%) harbored at least one GA in DDR pathway. UC carried the most DDR GAs(93.1 %), followed by PC(75%) and RCC(72.7%). After stratifying GA status, the most commonly deleterious GAs were ATM(n = 5); FANCA(n = 4); ERCC2, BRCA1, ATR, CHEK2(n = 2 each); MSH6, ERCC4, BRCA2, PALB2(n = 1 each).Tumor mutation burden(TMB) was significantly different among pts with deleterious, unknown significance and wt in PC(Mean: 17.8 vs 9.065 vs 4.468; p = 0.0003). Notably, DDR GAs were more likely to present in pts with metastatic disease(80.95% vs 62.50%), deleterious DDR GAs as well(14.29% vs 8.33%). Conclusions: DDR pathways are frequently altered in genitourinary cancer, especially UC in China. DDR GAs were significantly associated with higher TMB in PC. A higher prevalence was identified in metastatic disease. Comprehensive genomic profiling of DDR GAs highlights the clinical and therapeutic implication. Further exploration of the deleterious nature and alterations of unknown significance are required. [Table: see text]
Impact of socioeconomic disparities on upstaging for prostate cancer: A national cancer database analysis.
Authors: Patel Sagar , Worrilow William Mills , Trufan Sally Jeanne , Beano Hamza Mustafa , Kearns James T. , Riggs Stephen Boyd
Published: May 2020

e17526

Background: Recent data suggest that socioeconomic disparities impact the outcome of oncologic disease. This retrospective analysis investigates the role of socioeconomic variables on clinical to pathologic staging of prostate cancer (PC). Methods: 455,773 males with stage 1-3 adenocarcinoma of prostate who underwent surgical intervention (96% radical prostatectomy) were extracted from the National Cancer Database from 2004-2016. Patients were stratified into age groups based on American Urologic Association PSA screening recommendations ( < 40, 40-54, 55-69, > 70 years). Changes from clinical to pathological staging were the primary outcomes. Demographics, income level, education status and distance to treatment facility ( < 12.5, 12.5-49.9, > 50 miles) were analyzed using Chi-square and logistic regression to find upstaging predictors. Results: Rates of stage changes are summarized in Table. Increased distance ( > 50 vs < 12.5 mi) was associated with upstaging in all age groups (40-54: OR 1.10 95%CI 1.05-1.16; 55-69: OR 1.20 95%CI 1.18-1.23; > 70: OR 1.42 95%CI 1.35-1.50) except for < 40 years (OR 1.15, 95%CI 0.60-2.21). Other predictors of upstaging included black or other race compared to white (OR 1.06 95%CI 1.04-1.09 and OR 1.10 95% CI 1.06-1.14, respectively) and in men with government insurance vs private insurance (OR 1.19 95%CI 1.17-1.21). Lower risk of upstaging was seen for those who were not insured vs private insurance (OR 0.70 95%CI 0.67-0.73), lived in areas with the highest vs lowest high school education rate (OR 0.95, 95%CI 0.92-0.98), or lived in the lowest vs highest income areas (OR 0.93, 95%CI 0.90-0.96). Conclusions: Socioeconomic disparities directly impact the outcome for prostate cancer. Our study suggests age, distance from treatment facility, and race are associated with a greater risk for clinical to pathologic upstaging. Investigation should continue to better understand at-risk populations. [Table: see text]
Tumor subtypes associated with prostate cancer (PCa) both as first and second primary tumors: A registry-based analysis.
Authors: Wellen Andrew , Peace David J.
Published: May 2020

e17528

Background: First primary tumors (FPT) generally are associated with decreased survival and, thus, reduced risk of second primary tumors (SPT). A greater than expected incidence of SPT may indicate causal factors shared in common with a particular FPT, especially if the converse also is observed, i.e. if incidence is also greater than expected when tumor sequence is reversed. We analyzed the Surveillance, Epidemiology, and End Results (SEER) cancer registry to identify tumors with higher than expected incidence in relation to PCa, both as FPT and SPT. Methods: We searched the SEER18 cancer database covering 18 geographical regions of the U.S. from 2000 to 2016. SEER*Stat software v.8.3.6 was used to calculate standardized incidence ratios (SIR) of various SPT after defined FPT. SIR compare the incidence of a particular cancer within subsets of the registry population as a ratio to the expected incidence from a comparable matched group derived from the general population. 813,712 men with prostatic FPT (1° PCa) were included in the analysis for SIR of any SPT, while 2,554,835 men with any FPT were included in the analysis for SIR of prostatic SPT (2° PCa). Results were stratified by race and latency. Reciprocal SIR (1° PCa; 2° PCa) for values with p < 0.05 are reported. Results: Aggregate analysis of all tumors demonstrated lower than expected SIR for SPT, both for any SPT after 1° PCa and for 2° PCa after any FPT (0.69; 0.53). By contrast, six tumor subtypes – small intestine (1.17; 1.19), melanoma (1.05; 1.23), bladder (1.14; 2.02), kidney (1.22; 1.36), thyroid (1.27; 1.36), and chronic myelogenous leukemia (1.10; 1.15) – had bidirectionally increased secondary SIR in relation to PCa. The reciprocal increases were detected across racial subgroups for bladder, kidney and thyroid cancers. SIR tended to be highest in the early post-FPT period (2-11 mo.) with significant increases for bladder (1.49; 6.75), kidney (2.66; 1.87), and thyroid (1.61; 1.65) cancers. These three tumor types retained bidirectional increases in relation to PCa over intermediate latencies (12-119 mo.), but not beyond 120 mo. Conclusions: Overall, FPT were associated with lower than expected incidence of SPT, most likely as a result of shortened life expectancy. However, several tumors were identified that 1). occurred with higher than expected incidence after 1° PCa and 2). were associated with higher than expected incidence of 2° PCa. Further examination of the relationship of these tumors with PCa may identify mutual intrinsic or extrinsic factors that contribute to tumor development.
Epidemiological profile of patients diagnosed with prostate cancer at Muriaé Cancer Hospital, Minas Gerais, Brazil.
Authors: Freitas Carla Simone Moreira de , Soares Aleida Nazareth
Published: May 2020

e17530

Background: Prostate cancer (CP) is one of the most common malignant neoplasms among men with high prevalence worldwide. In Brazil, in 2019, 582,000 new cases of cancer were estimated, 282,000 in women and 300,000 in men, 75% are prostate cancer in individuals over 65 years of age (BRASIL, 2019). The occurrence of CP has specific risk factors, such as advanced age (over 65 years), genetic predisposition (patients with a family history of prostate cancer, between 35 and 40 years of age) and ethnicity (mostly blacks). Mortality due to this neoplasm is considered relatively low compared to other types of cancers, which partly reflects a good prognosis.The objective of this study is to describe the epidemiological profile of prostate cancer patients treated in an Muriae Cancer hospital in Minas Gerais - Brazil. Methods: Descriptive cross-sectional study conducted between 1997 and 2019 with 4,395 patients diagnosed with CP, living in the region and adjacencies, 4,175 (95%) assisted by the Unified Health System (SUS). Results: Patients from Minas Gerais-Brazil, cities of microregions and rural areas, the most prevalent age group was between 61-70 years of age with 1769 cases (40.25%), 3476 (79.1%) with low schooling, 3156 (71.82%) with per capita family income less than 0.5 minimum wages, and in regarding profession, the majority 541 (58.05%) is retired and rural workers 148 (15.88%); 1933 (44%) alcohol users, 2021 (46%) smokers and 1626 (37%) with a report of a family history of cancer. As for ethnicity, 1943 (44.23%) were black. Nutritional status 3845 (87.49) were eutrophic. The mean time between diagnosis and treatment was 51 months. PSA levels were 1ng/ml to 10 ng/ml (39%), from 10 ng/ml to 28 ng/ml (21%), from 28 ng/ml to 70 ng/ml (9%) and from 70 ng/ml to 200 ng/ml (6%) and > 200 ng/ml (5%); altered tests 1845 (42%), PSA elevation 1538 (35%), obstructive symptoms 965 (5%), dysuria 579 (3%) and pain 579 (3%). The majority (50.41%) with stage II, stage III (18.10%) and IV (9%), highlighting that in 1997 the percentage of advanced stages (III and IV) was 47% and in 2019 it decreased to 18%, due to earlier diagnoses. Conclusions: The analyzed data allowed to characterize the epidemiological and sociodemographic profile of patients treated in Muriaé Cancer hospital, Brazil, contributing to decision-making regarding the treatment provided to this population.
Early PSA decline as a predictor of progression in patients with metastatic castration-naïve prostate cancer (mCNPC) treated with abiraterone acetate and prednisone (AA/P).
Authors: Barata Pedro C. , Sheng Iris Yeong- Fung , Fallah Jaleh , Gupta Ruby , Li Hong , Allman Kimberly D. , Martin Allison , Ornstein Moshe Chaim , Gilligan Timothy D. , Rini Brian I. , Garcia Jorge A.
Published: May 2020

e17542

Background: Treatment intensification with androgen deprivation therapy (ADT) plus AA/P is a standard of care in patients with metastatic castration naïve prostate cancer (mCNPC). Despite initial responses, nearly all men will eventually progress to castration resistant disease (CRPC). Early changes in PSA while on ADT plus AA/P has significant clinical and therapeutic implications for mCNPC patients, yet limited data is available. We aimed to assess PSA patterns while on therapy with ADT plus AA/P and time to CRPC. Methods: mCNPC patients treated with ADT plus AA/P between June 2017 and February 2019 at the Cleveland Clinic, were included. The primary objective was to describe patterns of PSA change evaluated using a longitudinal mixed model at time 0, 3, 6, 9, and 12 months from AA/P initiation. Other endpoints of interest included PSA progression by PCWG3 and CRPC-free survival at 12 and 18 months. Results: A total of 130 patients, 82% Caucasian, median age 69 years, with 50% with de-novo mCNPC, 47% high-volume (60.8% Gleason score ≥8, 16.2% visceral disease, and 53.8%had ≥3 bony lesions) were included. Half of the patients achieved undetectable PSA ( < 0.03) while on therapy. The median time to PSA < 0.03 was 13.1 months (95%CI, 7.6-NE). The greatest PSA reduction occurred at the first 3 months (80%, p < 0.0001), changes after 3 months were small, (4% from 3 to 6 months, p < 0.0001; 3% from 6 to 9 months, p < 0.0001) and not significant from 9 to 12 months. The 12 and 18-months mCRPC-free survival after initiation of ADT plus AA/P was 88.1% and 81.3%, respectively. A PSA > 0.2 at 3 months was associated with a shorter time to mCRPC (p = 0.002). Similarly, a PSA reduction < 98% at 3 months was associated with worse outcomes (12 mo CRPC survival 68.0% vs. 94.9%, respectively; p < 0.001). Conclusions: In this data set, timing and depth of serologic response predicted the early development of CRPC in patients receiving ADT plus AA/P. Further validation is ongoing using data from large randomized clinical trials.
Serum testosterone level and overall survival in first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer patients.
Authors: Vilbert Maysa Tamara Silveira , Cesca Marcelle Goldner , Pandolfi Natasha Carvalho , Calsavara Vinicius Fernando , Uchôa Bruno Cezar de Mendonça , de Andrade Poliana , Coelho Ricardo Lima , Corassa Marcelo , Rinck Jose A. , Dettino Aldo A. , Oliveira Thiago Bueno
Published: May 2020

e17545

Background: Androgen receptor-targeted agents Abiraterone and Enzalutamide (Abi/Ez) prolonged overall survival in metastatic castration resistant prostate cancer (mCRPC). Patients with very-low serum testosterone levels seem to have less benefit from these therapies as well as more aggressive prostate cancer. Methods: A retrospective observational cohort study was conducted to evaluate whether a serum testosterone measured at time of start first-line therapy with Abi/Ez is related to overall survival (OS) and time-to-treatment failure (TTF) in mCRPC patients. Kaplan-Meier survival estimates and Cox-regression models were used for time-to-event analyses. The best cut-off for testosterone was defined using Log-rank statistics (Lausen and Schumacher). X² test and Mann-Whitney U-test were applied to compare categorical and continuous variables, respectively. Logistic regression was used to assess characteristics related to serum testosterone levels. Statistical significance was fixed at 0.05. Results: From May 2012 to February 2017, 100 patients were assessed. Median follow-up was 27.8 months (range 2.23 to 68.26). Pts with a high testosterone level ( > 28.2; n = 20) achieved a significantly higher OS (median 66.0 vs 31.9 mo, testosterone > 28.2 HR: 0.206, 95% CI 0.074 to 0.571, p = 0.002) and TTF (median 30.6 vs 11.8 mo, testosterone > 28.2 HR: 0.408, 95%CI 0.219 to 0.762, p = 0.005) than pts with a low serum testosterone level ( < 28.2; n = 80), regardless of receiving therapy with either Abi (n = 69) or Ez (n = 31). Pts with a higher testosterone level were younger (median 67.7 vs 73.6 years; p = 0.026), had a higher body mass index (BMI) (28.5 vs 25.9, p = 0.023) and a lower PSA at start Abi/Ez (12 vs 26, p = 0.031) than pts with lower values. Age (OR 0.93, 95%CI 0.8 to 0.9, p = 0.021), BMI (OR 1.21, 95%CI 1.1 to 1.4, p = 0.006) and baseline PSA (OR 1.2, 95%CI 1.03 to 1.4, p = 0.020) were significantly associated with testosterone > 28.2. After 4 months of Abi/Ez treatment, PSA decrease > 50% of baseline was seen more frequently in high testosterone levels group than in low testosterone levels pts (90% vs 57.5% of pts, respectively, p = 0.007). Conclusions: Pts with high levels of testosterone ( > 28.2) achieved a better OS and TTF when treated with Abi/Ez in first-line mCRPC than those with low levels. Testosterone can be considered a prognostic and predictive biomarker in this scenario, and could be used in treatment decision for this population.
Retzius-sparing robotic-assisted laparoscopic radical prostatectomy: Racial considerations for 250 consecutive cases.
Authors: Madi Rabii , Sayyid Rashid K. , Sherwood Dalton , Klaassen Zachary William Abraham
Published: May 2020

e17546

Background: To report the functional and oncologic outcomes of a cohort of 250 consecutive prostate cancer patients undergoing a Retzius-sparing approach and to assess for racial differences in continence outcomes. Methods: This was a prospective, single-center, case series of 250 consecutive prostate cancer patients who underwent a Retzius-sparing robotic assisted laparoscopic radical prostatectomy by a single surgeon between May 2015 and April 2019.Our primary objective was to describe post-operative continence outcomes of patients undergoing this technique. Results: Median follow up was 24.0 months [Interquartile range (IQR) 18.0-30.0 months]. Median age and body mass index were 62.0 years (IQR 57.0-67.0) and 29.0 kg/m 2 (IQR 26.0-33.0), respectively. Median PSA was 8.22 ng/ml (IQR 5.74-13.31). 84.8% of patients were intermediate or high-risk pre-operatively. 96.0% had Gleason Score 7 or worse disease on final pathologic analysis. Positive margin incidence was 18.1% and 44.4% in patients with pT2 and pT3 disease, respectively. Immediate continence (i.e. continence achieved within one moth post-operatively) was achieved in 45.0% of patients. One-year continence rate was 92.0%. Caucasian patients experienced earlier return of continence (77% versus 65% at 3 months) compared to African American patients. IPSS scores gradually improved from 8.0 pre-operatively to 4.0 one year later. Median PSA level was 0.01 ng/ml (IQR 0.01-9.01) post-operatively. Conclusions: Retzius-sparing robotic assisted laparoscopic radical prostatectomy is an oncologically safe surgical technique with excellent short and long-term continence outcomes.
Radium 223 treatment in metastatic prostate cancer: Exploring use of clinical factors for prognostication in routine practice.
Authors: Vengalil Salil , Bee Paula , Beetham Dawn , Bhana Rajanee , Joseph Shibu , Dainty Stephen , Seedhouse Ian , El-Helw Loaie
Published: May 2020

e17550

Background: Skeletal metastases are seen in over 90% of metastatic castrate resistant prostate cancer (mCRPC) patients during the course of their disease and is a major cause for significant morbidity and mortality in them. Radium 223 (Ra-223) is a bone seeking calcium mimetic alpha emitter that has demonstrated significant improvement in survival and reduction in skeletal related events (ALSYMPCA trial). Ra-223 treatment was well tolerated and showed benefit before or after chemotherapy. In this study we aimed to assess efficacy of Ra-223 in mCRPC patients treated in our centre and their survival in relation to some common clinical variables that may assist patient selection in routine clinical practice. Methods: We conducted a retrospective audit of mCRPC patients treated with Ra-223 from June 2015 – December 2019. We analysed treatment outcomes and use of Haemoglobin (Hb), Albumin (Alb) and Alkaline Phosphatase (ALP) as potential prognostic factors. Results: There were 46 patients in total with a median age of 76 years (range; 56-90) and 26% were ≥80 years of age. The median follow-up was 10 months (range; 2-38 months). Median baseline PSA was 103.7 (range; 7.2 - 2534) and median baseline ALP was 188 U/L (range; 51 - 2262). Ra-223 was given as 1st or 2nd line treatment in 65% of our patients. Median number of cycles of Ra-223 administered was 4 and 41% of patients completed 6 cycles of treatment. Biochemical response (drop in PSA > 50%) was only seen in 11% of patients but good response in ALP levels (drop in ALP > 50%) was seen in 35%. Median overall survival (OS) was 10 months. Median OS for patients who received Ra-223 as 1st or 2nd line vs subsequent line was 13 and 8.5 months respectively. Median OS for patients with Haemoglobin (Hb) ≥12gm/dl) and lower Hb were 11 and 7 months respectively. Patients with normal albumin at baseline had median OS of 15 months compared to 6 months for those with low albumin. Favourable prognostic group patients (Normal Hb, Normal albumin at baseline and normal ALP after treatment) had a median OS of 31 months compared to 9 months for those in less favourable group. Patients who completed at least 5 cycles had a better survival (13 vs 8.5 months). Fractures were reported in 3 patients (6.5%). Conclusions: Ra-223 treated patients in our centre had a reasonable survival despite having a larger proportion of elderly population compared to the registration trial. Ra-223 treatment seems to be more effective when given at earlier lines in mCRPC setting. Pre-treatment Albumin lower than normal seems to be a predictor for poor overall survival.