bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic profiling and mutation burden of Chinese prostate patients with microsatellite instability.
Authors: Zhang Ning , Hong Baoan , Zhao Xiaochen , Bai Yuezong
Published: May 2020

e17531

Background: Prostate cancer with microsatellite instability-high (MSI-H) is identified as a distinct genotype that potentially benefit from immune checkpoint inhibitors. But the incidence and genomic profiling of microsatellite instability haven’t been well characterized in Chinese prostate cancer patients. Methods: Tumor tissue and matched blood sample from 241 Chinese prostate cancer patients were analyzed with targeted next-generation sequencing covering whole exon of 381 or 90 genes and 100 microsatellite loci. Tumor mutation burden (TMB), defined by non-silent somatic mutation counts in coding region per megabase (Mb), was calculated in tumors sequenced by 381-gene panel with coding region of 1.12Mb. Results: 7 patients (2.90%) were identified as MSI-H in overall population. Somatic or germline alterations of mismatch repair genes were detected in 5 of the 7 patients, including 2 MSH2 germline mutations, 2 MSH6 somatic mutations, 1 MSH2 somatic mutation, 1 PMS2 somatic mutation and 1 MLH3 somatic mutation. In MSI-H tumors, alterations in KMT2C (6/7), EGFR (5/7), KMT2D (5/7), JAK1 (5/7), PTEN (4/7), TP53 (3/7), ZFHX3 (3/7) and SPOP (3/7) were common. AR ligand binding domain was mutated in 3 of 7 patients, while no AR amplification was detected in MSI-H tumors. In 121 tumors sequenced by 381-gene panel, median TMB was 3.23 mutations/Mb. Median TMB was significantly higher in MSI-H tumors compared with MSS tumors (median TMB, 13.71 mutations/Mb versus 2.93 mutations/Mb, P < 0.001). Median counts of single nucleotide variants (SNVs) and insertion-deletions (Indels) were 13 and 10 in MSI-H tumors that were also higher than that of MSS tumors with median SNVs and Indels of 2 (P = 0.004) and 1 (P < 0.001), respectively. Conclusions: 2.9% patients were identified as MSI-H in Chinese prostate patients. MSI-H was associated with higher TMB, SNVs and Indels. Targeted next-generation sequencing is a practical tool for prostate cancer genotyping and treatment decision-making.
Combined 18F-naf and fluciclovine administration for PET imaging of prostate cancer.
Authors: Huang Franklin W. , Trinh Brian , Wang Sunny , Hope Thomas A.
Published: May 2020

e17533

Background: 18F-fluciclovine is FDA approved for the detection of recurrent and metastatic prostate cancer. At our institution, 18F-fluciclovine PET had replaced 18F-NaF PET, but fluciclovine has mild to no uptake in dense sclerotic bony lesions. F18-NaF offers increased sensitivity and specificity in detection of osseous metastases and therefore we converted to using a combination of 18F-NaF and 18F-fluciclovine in patients with biochemical recurrence. In this study, we assessed the feasibility of performing a combined F18- fluciclovine and F18-NaF study, and evaluated the biodistribution of the combined radiotracers in patients with prostate cancer. Methods: We retrospectively reviewed 16 consecutive patients over a period of 3 months. 5 mCi of F18-NaF was injected, followed 45 minutes later by a 10 mCi injection of F18-fluciclovine. Patients were asked to hydrate after NaF injection and empty their bladder immediately prior to scanning. A non-diagnostic CT for attenuation correction and an emission PET scan were acquired on a time of flight Discovery 690 PET/CT (GE Healthcare) within 5 minutes of fluciclovine injection. We characterized the extent of soft tissue and osseous disease, as well as assessed the image quality, taking note for F18-NaF excretion in the bladder and the potential scatter artifact limiting evaluation of the prostate bed. Results: On average patients received 5.5 +/- 0.5 mCi of F18-NaF and 10.4 +/- 0.8 mCi of F18-fluciclovine. All 16 patients had diagnostic quality scans. None had limited evaluation of the prostate bed secondary to artifacts from bladder scatter. 10 patients (62.5%) had residual or recurrent prostate cancer within the prostate bed, of which 3 (18.8%) had distant nodal disease in the perirectal, pelvis, retroperitoneal, or periaortic lymph node regions. 7 patients (43.8%) demonstrated osseous metastatic lesions within the clavicle, sternum, iliac wing, vertebra, coccyx, or sacrum. Conclusions: Combined 18F-NaF and 18F-fluciclovine scans in patients with prostate cancer is a feasible method for detecting soft tissue recurrence and osseous disease. Bladder excretion from F18-NaF does not obscure the prostate bed nor degrades the diagnostic quality of the exam. The combined use of 18F-fluciclovine and F18-NaF in one PET/CT acquisition has the potential to increase the sensitivity for detecting prostate cancer and limit the time and radiation dose delivered compared to the conventional, separate acquisitions of the two radiotracers.
An artificial intelligence-enabled analysis of ECG changes after androgen deprivation therapy (ADT) for prostate cancer.
Authors: Breen William , Carter Rickey , Johnson Patrick , Routman David M. , Noseworthy Peter , Herrmann Joerg , Friedman Paul , Lopez-Jimenez Francisco , Attia Zachi Itzhak , Stish Brad J. , Kapa Suraj
Published: May 2020

e17535

Background: Androgen Deprivation Therapy (ADT) is commonly used to treat prostate cancer (PC), but has been associated with cardiac morbidity and mortality. The exact mechanisms of this association are unclear. We sought to use an artificial intelligence (AI) enabled algorithm to identify ECG changes in PC patients who received ADT compared to PC patients who did not receive ADT. Methods: From 1,000,000 ECGs performed on 210,414 patients between 1993 and 2017 at our institution, a convolutional neural network was developed to detect predictive signatures for cardiac pathologies. During this process, the ability to predict “estimated sex” of the patient was developed, with output values ranging from 0 (female) to 1 (male). We applied this algorithm to 8,619 ECGs performed on 1,057 men age 75 or younger treated with radiation for high-risk or recurrent PC at our institution, and compared estimated sex after receiving ADT (n = 1,065) to ADT-naive ECGs (n = 7,554). We correlated ECG-identified estimated sex with serum testosterone levels using Spearman rank correlation. Results: Patients who had received ADT had a mean (SD) estimated sex value of 0.81 (0.26) compared to 0.92 (0.17) for those who did not (p < 0.001). Difference between estimated sex in post-ADT ECGs and ADT-naive ECGs remained significant across age groups (Table). Decreased serum total testosterone correlated with decreased estimated sex values in men receiving ADT (R = .57, p < 0.001). Conclusions: ADT for prostate cancer is associated with changes in AI-identified ECG parameters, including lower estimated male sex after receiving ADT. Lower ECG male sex estimate was associated with decreased serum testosterone. In this study, we provide preliminary proof of concept for a potential non-invasive means of monitoring treatment effect and physiologic change using ECGs. [Table: see text]
Role of nitric oxide-based immunotherapy in augmenting prostate cancer progression by targeting androgen receptor heterogeneity.
Authors: Arora Himanshu , Vedenko Anastasia , Van Booven Derek J. , Narasimman Manish
Published: May 2020

e17537

Background: A significant proportion of men with Prostate Cancer (PCa) develop castration resistant prostate cancer (CRPC) and do not respond to hormonal agents that decrease androgens. In trying to understand the causes of androgen resistance that develop in CRPC, it is considered most relevant to study the role of Androgen receptor (AR) in the development and progression of PCa from androgen dependent to androgen independent state. Recent studies have highlighted the significance of tumor microenvironment (TME) in regulation of PCa progression in addition to AR. A key molecule in the regulation of TME interactions is nitric oxide (NO). We have shown in our recent study, the critical association of NO with the TME in CRPC. However, the effects of NO to modulate the progression of PCa to CRPC with respect to AR still remains largely unexplored. Methods: 22RV1, LNCaP, LNCaPAPIPC(cells expressing no AR), and LNCaPshAR/pATK (cells expressing low AR), cells were used for the study. Cell proliferation was first assessed by MTT assay. The castrated SCID mice were grafted with 22RV1 cells and were treated with GSNO at the dosage of 10mg/kg/day IP. After treatment, animals were humanely sacrificing. Tumor RNA and proteins were analysed for markers that are important for PCa progression using qPCR, western blot and cytokine antibody array. Animal experiments were carried out in compliance with the IACUC of University of Miami. GraphPad Prism (GraphPad Software) was used for statistical analysis. Results: In addition to reducing the tumor burden, the expression of anti-inflammatory (M2) macrophages (CD206 and Arginase1) is decreased and that of the pro-inflammatory (M1) macrophage (iNOS) is increased in mice which received increased NO levels. Furthermore, to study the effects of NO on progression of PCa from androgen dependent to androgen independent stage, we characterized the LNCAP cell models with differential extent of AR knockdown (LNCaP, LNCaPshAR/pATK and LNCaPAPIPC) for the effects of increased NO levels. Results showed that NO had significant impact on cell proliferation on androgen dependent PCa cells however the effects were negligible in cells expressing low or no AR, suggesting that effects of NO on PCa cell proliferation are AR dependent. Conclusions: Our results suggest that during PCa progression, NO suppresses TAMs to target the TME in an AR dependent manner. Further studies are undergoing to establish the impacts of NO in PCa progression.
Dissecting the immune infiltrate induced by ADT and PD-1 blockade in men with metastatic hormone-sensitive prostate cancer using single-cell RNA-sequencing.
Authors: Hawley Jessica , Obradovic Aleksandar , Guo Xinzheng Victor , Chaimowitz Matthew , Easterlin Clara A , Dallos Matthew , Lim Emerson A. , Drake Charles G. , Stein Mark N.
Published: May 2020

e17548

Background: Overall survival of men with de novo metastatic, hormone-sensitive prostate cancer (mHSPC) is improved by treatment intensification with docetaxel and hormone therapy compared to androgen deprivation therapy (ADT) alone. However, castration-resistant prostate cancer (CRPC) invariably develops. We and others have shown that ADT induces a robust and complex immune infiltrate in localized prostate cancer, in both animal models and humans. We are conducting a clinical trial (NCT03951831) to test the hypothesis that the ADT-induced immune infiltrate can be further augmented with chemotherapy and an anti-PD-1 inhibitor in men with mHSPC. Here, we present single-cell RNA-sequencing analysis of paired metastatic tumor biopsies at baseline and on-treatment. Methods: In our phase 2, open-label, single-center trial, eligible patients with mHSPC are treated with phased administration of ADT, cemiplimab (anti-PD-1 inhibitor), and docetaxel. All patients undergo baseline metastatic tumor biopsies as well as on-treatment biopsies after either ADT alone or ADT in combination with cemiplimab. Biopsies are dissociated by gentleMACS protocol, and single cells are sequenced using the 10X Chromium platform. Cells are Quality-control filtered to those with over 1000 Unique Molecular Identifiers and less than 25% mitochondrial RNA, then clustered on global gene expression and on inferred protein activity by unsupervised Louvain algorithm with silhouette score selection of optimal clustering resolution. Cell types are assigned by the singleR algorithm and tumor cell identity is verified by inference of Copy Number Variations (InferCNV). Differential gene expression across sub-clusters is performed, and baselines will be compared to their paired on-treatment sample (N = 3). Results: Preliminary results showed a significant increase in the normalized fold-change of CD8+ T cells in on-treatment samples relative to baseline samples (P < 0.001). There was also a dramatic increase in other immune cell subtypes with treatment. In addition, we found a shift in transcriptional state of tumor cells and that tumor cells expressing KLK2/KLK3 significantly dissipate with treatment (normalized fold-change 0.56, P < 0.001). Conclusions: Taken together these show the feasibility of SS-RNA-seq on PC metastatic lesions and provide initial support for the hypothesis that ADT induces complex immunological changes in the tumor microenvironment (TME) in metastatic prostate tumors.
PRINT: Prostate cancer intensive, non-cross reactive therapy for CRPC—Early observations of efficacy.
Authors: Liaw Bobby Chi-Hung , Tsao Che-Kai , Galsky Matt D. , Bakst Richard Lorne , Stewart Robert , Stock Richard , Oh William K.
Published: May 2020

e17575

Background: Optimal sequencing of therapeutic agents in mCRPC remains debated, but the standard approach is to treat with one agent until resistance is met before switching. PRINT explores the efficacy of treating mCRPC with a rapidly-cycling, non-cross reactive regimen as a way to more effectively treat intrinsic heterogeneity, delay or prevent drug resistance, and minimize treatment toxicity. Methods: Patients received treatment with 3 consecutive treatment modules, each lasting 12 weeks: 1. abiraterone acetate 1000 mg PO daily + prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV + carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily + radium-223 50 kBq/kg IV q4 weeks (in those with bone metastases). Upon completion of the 9-month regimen, patients are followed on ADT alone. Primary endpoint for the study is PSA or radiographic time to progression (TTP). Results: From 3/2017 to 1/2020, 38 of 40 planned men with mCRPC were enrolled, 28 patients have completed the 9-month study regimen and evaluable for TTP analysis. With median follow up of 54+ weeks, median time to PSA progression after therapy completion is 14.7+ weeks (95%CI; 5.5-23.9+ weeks). PSA response rates showed successive improvements with each sequential treatment module (Table). Eight patients (21.1%) continue on post-study surveillance with ADT alone, two of which have remained off any mCRPC agents for over a year (82+ weeks, 79+ weeks). In patients needing to restart therapy, experience with efficacy and tolerability of each agent while on the study, has helped inform subsequent mCRPC drug selection. The study regimen is well-tolerated, with few grade 3/4 AE’s: hyperglycemia (15.8%), diarrhea (5.3%), anemia (2.6%), fatigue (2.6%), neutropenia (2.6%), and thrombocytopenia (2.6%). Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross reactive regimen demonstrates significant antitumor benefits, with potential for long-term suppression of disease. Further longitudinal follow up will determine if PRINT delays progression compared with standard approaches. Clinical trial information: NCT02903160 . [Table: see text]
The prognostic biomarkers of the patients treated with platinum-based chemotherapy in treatment emergent or related neuroendocrine prostate cancer.
Authors: Kosaka Takeo , Hongo Hiroshi , Yasumizu Yota , Matshumoto Kazuhiro , Mizuno Ryuichi , Oya Mototsugu
Published: May 2020

e17576

Background: Treatment emergent or related neuroendocrine prostate cancer (tNEPC) is an aggressive subtype of prostate cancer in patients previously treated with androgen receptor pathway inhibitor (ARPI) as a mechanism of resistance. These patients are typically treated platinum-based chemotherapy using small cell lung cancer (SCLC). The clinical features of tNEPC are poorly defined. The aim of the present study was to investigate the prognostic biomarkers of the patients treated with platinum-based chemotherapy in tNEPC. Methods: We reviewed baseline, treatment and outcome data of 41 patients with tNEPC. Clinicopathological factors and laboratory data before administering the first cycle of platinum-based chemotherapy were collected to assess the prognostic factors for overall survival (OS). Definition of tNEPC were based on NEPC morphology on the basis of any current or prior tissue sample, development of liver metastases in the absent of PSA progression, or elevated serum neuron specific enolase (NSE). Results: Median PSA and NSE were 119.8 ng/ml and 18.2 ng/ml, respectively. Twenty-four patients had pathologic features of NEPC. NSE were elevated above the 32 patients. The median OS from the start of platinum-based chemotherapy treatment was 10 months. Univariate analysis revealed that LDH (p = 0.003), absolute monocyte count < 280 (p = 0.022), visceral metastasis (p = 0.014) prior to platinum-based chemotherapy were significantly associated with shorter OS. Multivariate analysis revealed that LDH (p = 0.047), absolute monocyte count < 280, (p = 0.012), visceral metastasis (p = 0.005) prior to platinum-based chemotherapy treatment were independent prognostic indicators for OS. Based on the relative risk of death, NEPC patients before platinum-based chemotherapy were divided into 3 risk groups: low, intermediate and high ( p< 0.001). Conclusions: Our findings provide new insights into the practical implication of NEPC. Our results might be to tailor the management of NEPC treated with platinum-based chemotherapy.
Phase 1b study of BXCL701, a novel small molecule inhibitor of dipeptidyl peptidases (DPP), combined with pembrolizumab (pembro), in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Aggarwal Rahul Raj , Costin Dan , O'Neill Vincent J. , Corsi-Travali Stefani , Adurthi Sreenivas , Adedoyin Adedayo , Healey Diane I. , De Bono Johann S. , Monk Paul , Zhang Jingsong , Small Eric Jay
Published: May 2020

e17581

Background: BXCL701 (talabostat previously PT100) is an oral small molecule inhibitor of DPP4, DPP8 and DPP9, which trigger macrophage cell death via pyroptosis resulting in proinflammatory stimulation of the innate immunity pathway. Expression of PD-L1 correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor responses were observed when BXCL701 was used with checkpoint inhibition. In a prior clinical study, BXCL701 at a total daily dose of 0.6mg (as 0.3mg BID) demonstrated single agent activity in 2 pts with Stage IV melanoma (unpublished). Methods: In this multi-center study, eligible patients (pts) had progressing mCRPC (PCWG3), at least 1 line of systemic therapy and ≤ 2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anti-cancer therapy, and an ECOG PS of ≤ 2. Pts received fixed dose pembro (200mg IV q21 days) with escalating doses of BXCL701 (0.4mg and 0.6mg PO QD days 1-14 of 21-day cycles) using a 3X3 design. The key endpoints were safety and identification of the recommended phase 2 dose (RP2D) for the combination. Composite response (RECIST, PSA, CTC), plasma drug concentration and change in relevant immune effector cytokines were also evaluated. Results: Six pts were treated at 2 BXCL701 dose levels of 0.4mg qd (n = 3) and 0.6mg qd (n = 3), with 5 pts having adeno, 1 pt having mixed adeno and SC-NEPC. Prior tx included ADT (n = 6), 2nd generation androgen signaling inhibitors (n = 4), chemo (n = 4), RT (n = 5). Among 3 pts at the BXCL701 dose level of 0.6mg, 1 pt had a DLT of Grade 3 syncope (C1D6) and 1 pt had fatal acidosis (C3D8). A dose-dependent increase in pts with low-grade on-target clinical effects was observed. In the 0.4mg qd cohort 1 pt had lower extremity (LE) edema. Whereas in the 0.6mg qd cohort, all pts had events consistent with cytokine release: 3 had hypotension and 2 pts each had dizziness and LE edema. The 0.6mg/day dose level was expanded using a split dose strategy to improve tolerability while maintaining the daily dose previously associated with objective responses. BXCL701 was quantifiable in plasma. Conclusions: BXCL701 0.4 mg QD on days 1 to 14 of 21-day cycle plus pembrolizumab 200 mg IV on day 1 every 21 days was well tolerated in pts with mCRPC. A dose-dependent increase in on-target clinical effects expected with cytokine upregulation was seen. The final dose expansion using the split dose for the RP2D, plasma drug concentrations and relevant biomarkers will be presented. Clinical trial information: NCT03910660 .
Phase II study of pembrolizumab in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer (mCRPC): Updated follow-up of cohorts (C) one to three from KEYNOTE-199.
Authors: Goh Jeffrey C. , Piulats Rodriguez Jose Maria M. , Gross-Goupil Marine , Vaishampayan Ulka N. , De Wit Ronald , Alanko Tuomo , Fukasawa Satoshi , Tabata Kenichi , Feyerabend Susan , Berger Raanan , Wu Haiyan , Kim Jeri , Schloss Charles , De Bono Johann S. , Antonarakis Emmanuel S.
Published: May 2020

e17584

Background: Pembrolizumab monotherapy has shown antitumor activity and acceptable safety in patients with mCRPC previously treated with a next-generation hormone agent (NHA) and docetaxel. Presented herein are updated results from KEYNOTE-199 (NCT02787005), a multicohort phase 2 study, in patients with RECIST-measurable PD-L1+ disease (C1), RECIST-measurable, PD-L1− disease (C2), and bone-predominant disease, irrespective of PD-L1 (C3). Methods: Patients who previously received ≥1 NHA and 1 or 2 chemotherapies, including docetaxel, received pembrolizumab 200 mg Q3W for 35 cycles or until progression/toxicity. The primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR). Key secondary end points were DCR, PSA response rate (≥50% decrease from baseline), time to PSA progression, rPFS, OS, DOR, and safety. rPFS and OS were evaluated using the Kaplan-Meier method. Results: Of 258 treated patients (C1, 133; C2, 67; C3, 58), 6 completed therapy (C1, 4; C3, 2) and 252 discontinued (C1, 129; C2, 67; C3, 56), primarily due to progression (C1, 106; C2, 61; C3, 45). Median (range) time from enrollment to data cutoff was 31.3 mo (26.7-34.7) in C1, 30.6 mo (28.0-34.1) in C2, and 32.6 mo (27.4-34.4) in C3. Efficacy results are displayed in the table. ORR (95% CI) for patients with measurable disease was 6% (2.6-11.5) in C1 and 3% (0.4-10.4) in C2. Of 10 responders, 6 had a DOR ≥18 mo. Median time to PSA progression was 4 mo across cohorts. Any grade treatment-related AEs (TRAEs) occurred in 57-60% of patients across C1-3. Grade ≥3 TRAEs occurred in 16% of patients in C1, 15% in C2, and 17% in C3; 1 patient in each cohort died of a TRAE (C1, sepsis; C2, unknown; C3, immune-related pneumonitis). Conclusions: Pembrolizumab monotherapy was well tolerated and showed durable, antitumor activity and disease control with survival up to 24 mo in 3 cohorts of docetaxel and NHA-pretreated patients with RECIST-measurable or bone-predominant mCRPC. Clinical trial information: NCT02787005 . [Table: see text]
The impact of genetic mutations on response to radium-223 treatment for castration-resistant prostate cancer with bone metastases.
Authors: Liu Alex John , Kosiorek Heidi E. , Ueberroth Benjamin Edward , Kendi Ayse T. , Tzou Katherine S. , Quevedo Fernando , Choo Richard , Moore Cassandra N. , Ho Thai Huu , Singh Parminder , Keole Sameer R. , Wong William , Bryce Alan Haruo
Published: May 2020

e17587

Background: Radium (Ra)-223 has become the cornerstone treatment in patients with metastatic castrate-resistant prostate cancer (mCRPC) with bone metastases. Ra-223 has been shown to suppress abnormal bone formation by inducing DNA double-strand breaks in tumor cells. This can reduce skeletal-related events, as well as improve survival and quality of life. Studies have indicated mutations that regulate DNA damage response in prostate cancer as susceptible to PARP inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. Methods: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics, genetic mutations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. Results: 239 mCRPC patients treated with Ra-223 were identified. Germline and/or somatic genetic sequencing was available in 50 patients, who had a median age of 61 years at time of diagnosis and 68 years at time of Ra-223 treatment. Median Gleason score at time of diagnosis was 8.0. 100% of patients received prior androgen deprivation therapy. 72% received prior docetaxel, and 18% received prior cabazitaxel. Notable mutations included TP53 (45.2%), TMPRSS2-ERG (28.6%), PTEN (26.2%), BRCA1/2 (14.3%), ATM (9.3%), CDK12 (7.1%), and Rb (4.9%). TMPRSS2-ERG was the second most commonly found mutation, with median OS 12.7 mo versus 15.4 mo in patients without TMPRSS2-ERG mutations (p = 0.099). In patients with CDK12 mutations (2 of 28 tested positive), PFS was 10.4 mo versus 5.6 mo in patients without CDK12 mutations (p = 0.157). The assessment of ALP and PSA response to radium treatment stratified by genetic mutation did not reach statistical significance. Conclusions: Among mCRPC patients treated with Ra-223 at Mayo Clinic, TMPRSS2-ERG was the second most commonly found genetic mutation and had observed worse survival outcomes that approached statistical significance. Prospective studies and increased sample sizes are needed to determine the impact of genetic mutations in response to Ra-223.
Impact of flu vaccine on survival after immunotherapy for metastatic castration resistant prostate cancer (mCRPC): Analysis of Medicare claims data.
Authors: Pachynski Russell Kent , McKay Rana R. , Hafron Jason , Fitch Kate , Flanders Scott , Vogelzang Nicholas J.
Published: May 2020

e17591

Background: Sipuleucel-T (sip-T) is a cellular immunotherapy that activates a patient’s own immune system to target prostate cancer cells. Flu vaccine contains inactivated virus that stimulates the immune system to induce a response. Hypothetically, influenza vaccines may impact sip-T effectiveness by affecting the apheresis procedure, ex vivo production of sip-T, and/or CD 54+ upregulation. We explored the effect of receiving the flu vaccine on outcomes in men who received first line treatment with sip-T. Methods: Claims data from the 2013-2017 CMS Fee for Service 100% Medicare Identifiable Database for Parts A, B and D Data were examined. Among men with dates of first sip-T doses in 2014 and 2015 (ie, index dates), we identified whether or not they received flu vaccine 30 days before or after based on healthcare common procedure coding system (HCPCS) codes and National Drug Codes (NDCs). Kaplan-Meier methodology was used to assess survival with Cox proportional hazards regression model used to calculate hazard ratios (HR). Three years of follow-up (F/U) were available for men with 2014 index dates; 2 years were available for men with 2014 and 2015 index dates. Results: Approximately 8% of men received the flu vaccine (102 of 1279 with 2 years of F/U; 50 of 656 with 3 years of F/U). Overall, mean age was 76 years. Most ( > 86%) were white. Receipt of flu vaccine did not impact the overall survival of men who received sip-T (HR [95% CI], 0.93 [0.64, 1.35] at 2 years and 0.90 [0.60, 1.37] at 3 years). The resultant Kaplan-Meier curves overlapped (not shown). Conclusions: Based on these claims analyses, concomitant use of flu vaccine did not appear to impact survival outcomes after sip-T administration in men with mCRPC. These data have practical application for clinicians and patients given limited prospective data evaluating the role of flu vaccination in patients receiving immunotherapy. [Table: see text]
Tumor response to a mastermind inhibitor protein.
Authors: Epenetos Agamemnon A. , Prokopi Marianna , Pitsillides Costas , Kapnisis Konstantinos , Deonarain Mahendra , Kousparou Christina , Anayiotos Andreas
Published: May 2020

e17601

Background: Notch signalling is implicated in tumorigenesis prompting scientists to research and develop anti-Notch therapeutics. Drugging the Notch pathway has been a challenge due to severe G-I toxicity seen by many small-molecule inhibitors. Mastermind is a key nuclear factor that mediates Notch activity. We generated a novel protein drug, Syntana-4, that inhibits the Notch pathway at the Mastermind transcriptional level. Syntana-4 consists of the cell penetrating domain of Antennapedia, fused to a truncated peptide from Mastermind-like (MAML) that behaves in a dominant-negative fashion inhibiting Notch. Syntana-4 translocates into the cell nucleus, suppressing Notch activity and inducing apoptosis in Notch-driven cancer cells. Methods: We have conducted pharmacokinetics (PK), pharmacodynamics (PD) and toxicology studies, in combination with innovative imaging including in vivo flow cytometry and whole-body fluorescence reflectance imaging to define the behaviour of Syntana-4, determine its mode of action and establish a safety and efficacy profile in an orthotopic model of breast cancer in SCID mice based on the implantation of MDA-MB-231 cells into mammary fat pads. Samples of blood and tissues were examined for toxicity, apoptosis and immunogenicity. Results: We found that Syntana-4 was well-tolerated by normal cells and organs and was not immunogenic. Also, it was shown that free, non-internalized drug was rapidly cleared from the circulation. Whole body imaging showed that the drug in tissues was cleared within 24 hrs. Assessment of tumor growth demonstrated a reduction in tumor growth as evidenced by an overall increase of less than 50% in the intensity of fluorescence signal in the treated group compared to a 3-fold increase in signal and thus tumour size in untreated group by day 14. Conclusions: Syntana-4, a Mastermind inhibitor, was found to be well-tolerated and non-immunogenic in healthy animals. This drug targets the oncogenic Notch mechanism and can be applied across tumours with genetic defects in Notch signalling including breast, prostate, etc. We have demonstrated the utility of an innovative molecular imaging system emulating a clinical ‘phase I/II’ study in an orthotopic cancer model in order to measure the biodistribution, PK, PD, mode of action, toxicity and efficacy of a first-in-class biological therapy prior to entering the clinic. This innovative approach could be useful for accurate selection of lead drug candidates prior to entering clinical development.
Efficacy of androgen receptor antagonists in combination with androgen deprivation therapy in nonmetastatic, castration-resistant prostate cancer: A systematic review and meta-analysis of published phase III randomized controlled trials.
Authors: Jahan Nusrat , Rehman Shabnam , Mogollon-Duffo Francis , Ball Somedeb , Wongsaengsak Sariya , Tijani Lukman Aderoju
Published: May 2020

e17606

Background: Nonmetastatic, castration-resistant prostate cancer (nmCRPC) often heralds metastatic disease which is responsible for majority of the morbidity and mortality associated with prostate cancer. Hence, delaying metastasis is an expedient therapeutic goal for the patients with nmCRPC. Three androgen receptor (AR) antagonists — apalutamide, enzalutamide, and darolutamide — have been approved recently for nmCRPC on the basis of prolongation of metastasis-free survival. The purpose of our meta-analysis is to consolidate the efficacy data of AR-antagonists prolonging metastasis-free survival in nmCRPC. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until November 2019. Phase 3 RCTs using AR-antagonists for nmCRPC were included in the final analysis. We used generic inverse variance method and random effects model to calculate the pooled hazard ratio (HR) for distant metastasis or death with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q test. Results: Three phase 3 RCTs (ARAMIS, PROSPER, and SPARTAN) randomizing 2694 patients in the AR-antagonist arms and 1423 patients in the control arms are included in the final analysis. All studies enrolled only patients with prostate specific antigen (PSA) doubling time of 10 months or less. AR-antagonists used in the study arms were — ARAMIS: darolutamide, PROSPER: enzalutamide, and SPARTAN: apalutamide. Placebo was used in the control arms. All patients continued androgen deprivation therapy (ADT). Randomization was 2:1 in all studies. The pooled HR for distant metastasis or death was highly significant at 0.32 (95% CI: 0.25 - 0.41; P < 0.00001, I2 = 79%) in the favor of AR-antagonist arm in overall population. The pooled HR remained significant when patients were stratified according to PSA doubling time. For patients with PSA doubling time > 6months, the pooled HR was 0.34 (95% CI: 0.27 - 0.43; P < 0.00001, I2 = 0%); for patients with PSA doubling time ≤6 months, the pooled HR was 0.32 (95% CI: 0.25 - 0.41; P < 0.00001, I2 = 73%). Conclusions: Our meta-analysis demonstrated addition of AR-antagonists to ADT significantly prolongs the metastasis-free survival in patients with nmCRPC — an exciting new development in the management of prostate cancer.
Dissection of primary prostate cancer to determine the clonal origin of synchronous lymph node metastasis.
Authors: Nallandhighal Srinivas , Tosoian Jeffrey J. , Singhal Udit , Karim Razeen , Mathieu Romain , Plouffe Komal , Rioux-Leclercq Nathalie , Siddiqui Javed , Liu Chia-Jen , Hovelson Daniel H. , Doglioni Claudio , Morgan Todd Matthew , Susani Martin , Luciano Luciano Roberta , Shariat Shahrokh F. , Tomlins Scott A. , Briganti Alberto , Palapattu Ganesh S. , Udager Aaron M. , Salami Simpa Samuel
Published: May 2020

e17614

Background: Primary prostate cancer often consists of multiple, genomically-distinct clones. The clonal source of lymph node metastasis in multifocal disease is unknown. We sought to analyze and determine the histopathologic and molecular characteristics of the tumor sub-clones capable of metastasis in primary prostate cancers with synchronous lymph node metastasis. Methods: We identified patients with primary prostate cancer found to have lymph node (LN) metastasis at the time of radical prostatectomy, including those with multifocal disease. Punch biopsies were obtained from multiple regions of primary tumors and LN metastases. Targeted next generation sequencing to assess somatic DNA mutations, copy number alterations (CNA), and TMPRSS2:ERG fusion status. Bioinformatic analyses were performed using in-house developed pipelines. Phylogenetic evolutionary analyses were performed to delineate the primary cancer clone responsible for LN metastasis. Results: We identified 2 patients with LN cancer regions. In one patient, while all four Grade Group (GG) 5 primary tumor (PT) regions showed concordant TP53 and TPR non-synonymous mutations and broad copy number alterations (CNAs) with two LN foci, only two regions shared high level CNAs with both lymph node foci. In this case, a GG1 tumor focus showed no TP53 somatic mutation or CNA overlap with the high-grade tumor or lymph node samples. Critically, phylogenetic analysis revealed that the GG5 PT with extra-prostatic extension (EPE) showed higher concordance with the LN metastases than regions confined to the prostate. In another patient with four PT, phylogenetic analysis revealed that the PT with EPE closely resembled the LN metastasis; both were TMPRSS2:ERG fusion positive share PTEN copy number loss. Two PT (GG1 and 2) appeared to be independent clones and were TMPRSS2:ERG fusion negative. One of the six circulating tumor cells (isolated pre-prostatectomy) from this patient demonstrated a significant PTEN copy loss consistent with the findings in the region of EPE and the LN metastasis. Conclusions: Our findings confirm molecular heterogeneity of primary prostate cancers and homogeneity of LN metastases supporting the use of shared molecular alterations to infer clonal lineage. Our results highlight the critical role of adverse pathologic features, such as grade and EPE, in prostate cancer with synchronous lymph node metastasis.
Possibilities for improving the diagnosis of clinically significant prostate cancer based on 3D modeling.
Authors: Dimitriadi Sergey N. , Frantsiyants Elena M. , Demchenko Nikolay S. , Iozefi Dmitry Ya. , Vinidchenko Mikhail A. , Kit Oleg I.
Published: May 2020

e17617

Background: The purpose of the study was improving the accuracy of diagnosis of clinically significant prostate cancer, using 3D models based on multiparametric MRI. Methods: We examined a total of 126 patients using a 12-point transrectal biopsy supplemented with an MRI targeted biopsy. The study included patients with a PSA in plasma of 1-20 ng / ml and symptoms of the lower urinary tract. We used a GE Signa HD 1.5T tomograph and an Advantage workstation. The scanning protocol included DWI, T2-FS, T2, 3D-Cube and a multiphase series with contrast. We evalueted focal changes in the structure of the prostate during MRI, using the PiRads v2.0 system, the results were processed at the GEAW 4.7 workstation, the prostate gland, urethra, seminal vesicles and sections were separated in layers. In the final 3D model, the prostate was labeled transparent, the urethra and seminal vesicles were labeled white. This model was saved and used as a visual three-dimensional image of the volume, size and localization of the foci of the prostate gland. When conducting a standard 12-point biopsy of the prostate under ultrasound control, based on a visual analysis of the 3D model, 2 additional injections were made into each part of the prostate, graded according to the PiRads≥ 3 scale. Results: We compared MRI with the histological results of a 12-point biopsy on the main 3D models of the prostate gland Among 126 patients, changes in MRI using the PiRads v2.0 system had 3 points in 48, PiRads 4 points - 32, PiRads 5 in 46 Among patients with PiRads 3 who underwent a standard 12-point biopsy, supplemented by targeted biopsy based on analysis of 3D models after MRI in 4 (8.3%) revealed clinically significant prostate cancer. Among patients with PiRads 4, clinically significant cancer was found in 11 (34.4%). In patients with PiRads 5, clinically significant cancer was found in 33 (71.7%). Conclusions: A transrectal biopsy of the prostate (using 3D modeling based on MRI with focal marking according to PI-RADS v2.0) allows to effectively identify clinically significant prostate cancer. Performing a transrectal biopsy of the prostate based on 3D modeling is the result of the effective application of an interdisciplinary approach to solving the problem of diagnosing clinically significant prostate cancer.
Molecular profiles and immune checkpoint inhibitor-related biomarkers analysis in advanced cervical cancer.
Authors: Xu Qin , Chen Chuanben , Sun Yang , Lin Yibin , Liu Jing , Li Li , Chang Lianpeng , Xu Yaping , Li Lifeng , Huang Bin , Zhu Chenchen
Published: May 2020

e18003

Background: Treatment options for advanced cervical cancer (ACC) are limited and patients experiencing recurrence after first-line chemotherapy and bevacizumab have a poor prognosis. Checkpoint inhibitors targeting the PD-1/PD-L1 are promising treatment option. However, related genomic biomarker study is rare reported in ACC. Methods: We prospectively enrolled 102 pts with ACC. Tumor and plasma samples were obtained to analysis genomic profiles. DNA was sequenced by target-capture deep sequencing with the pan-cancer panel. TMB of tissue (tTMB) and blood (bTMB) analysis interrogated single nucleotide variants, small insertion and deletion. PD-L1 expression was evaluated in tumor specimens by immunohistochemistry (IHC) using a combined-positive-score (CPS) cutoff of ≥1. Results: The median age of enrolled pts was 63 yrs, and most (84.3 %, 86/102 pts) weresquamous carcinoma. A total of 93 tissues and 96 plasma were collected from 102 pts. The most frequently mutated genes were PIK3CA (40.9%, 38/93 pts), KMT2D (35.5%, 33/93 pts), and KMT2C (28.0%, 26/93 pts) in tissues. 80% (77/96 pts) of plasma was detected positive, with PIK3CA (23.4%, 18/77 pts), KMT2D (20.8%, 16/77 pts), KMT2C (20.8%, 17/77 pts) mutant frequently. Among 87 pts with paired samples, at least a tumor-derived mutation was detected in 35 (40.2%)plasma. Median of tTMB was 11.9 mut/Mb, and 45% pts were TMB-H. Significant correlation was found between tTMB and bTMB (Pearson r = 0.39, P = 0.001). Higher tTMB was identified in KMT2D- or KMT2C-mut pts (P = 0.002 or P = 0.01, respectively). tTMB showed no relation with clinic characteristics, including pathological subtype, FIGO stage, and status of distant metastasis. PD-L1 expression (CPS≥1) was identified in 53 pts (93 %, 53/57) and mutually independent with TMB status. Conclusions: Molecular profiles and TMB in plama showed high consistence with that in tissue. Prospective clinical trial is ongoing to determine the genomic biomarkers and the PD-L1 expression as predictive factors for the ICI efficacy in ACC (ChiCTR1900023015).
Identification of risk factors associated with pelvic lymph node metastasis in patients with stage IB1 cervical cancer.
Authors: Jiang Ping , Cai Jing , He Xiaoqi , Wang Hongbo , Dong Weihong , Zhang Yuan , Dunst Juergen , Willborn Kay C , Huang Bangxing , Wang Zehua
Published: May 2020

e18005

Background: Evaluation the distribution of nodal metastases in the stage IB1 cervical cancer and the risk factors associated with pelvic lymph node metastasis (LNM) at each anatomic location. Methods: 728 patients with stage IB1 cervical cancer who underwent radical hysterectomies and systemic pelvic lymphadenectomies from January 2008 to December 2017 were retrospectively studied. All removed pelvic lymph nodes were pathologically examined, and the risk factors for LNM at the obturator, internal iliac, external iliac, and common iliac regions were evaluated by univariate and multivariate logistic regression analyses. Results: 20,134 lymph nodes were analysed with the average number of 27.80 (± SD 9.43) lymph nodes per patient. Nodal metastases were present in 266 (14.6%) patients. The obturator was the most common site for nodal metastasis (42.5%) followed by the internal iliac nodes (20.3%) and the external iliac nodes (19.9%), while the common iliac (9.8%) and parametrial (7.5%) nodes were the least likely to be involved. Tumor size more than 2 cm, histologically proven lymphovascular space involvement (LVSI) and parametrial invasion correlated independently significantly with the higher risk of the lymphatic metastasis. Obesity (BMI≥25) was independently significantly negatively correlated with the risk of lymphatic metastases. All the positive common iliac nodes were found in patients with tumors greater than 2 cm. The multivariate analysis showed that tumor size greater than 3 cm was associated with a 16.6-fold increase in the risk for common iliac LNM. Interestingly, tumor size was not an independent risk factor for pelvic LNM in the lower regions, i.e., the obturator, internal iliac and external iliac areas, where LVSI was the most significant predictor for LNM. In addition, parametrial invasion was related to external and internal iliac LNM; deep stromal invasion and age less than 50 years were associated with obturator LNM. Conclusions: The incidence of lymph node metastasis in patients with stage IB1 cervical cancer is low but prognostically relevant. The data offer the opportunity for tailored individual treatment in selected patients with small tumors and obesity.
Treatment patterns in cervical cancer patients initiating systemic therapy.
Authors: Shah Anuj , Kebede Nehemiah , Shah Ruchit , Corman Shelby , Nwankwo Chizoba
Published: May 2020

e18009

Background: NCCN recommends the use of systemic treatment for advanced cervical cancer patients. However, no study has assessed treatment patterns in this population. This study described real-world treatments patterns among women with cervical cancer newly initiating a systemic therapy. Methods: Cervical cancer patients with ≥2 claims for systemic therapy (i.e., chemo- or immunotherapy) within a 4-week period between June 2014 – October 2018, no claims within 6 months prior to systemic treatment initiation (baseline period), and continuously enrolled within the baseline period and 3 months post therapy initiation were identified from the Optum Clinformatics DataMart database. Patients who had a cervical cancer-related surgery within ±3 months of therapy initiation were excluded to exclude adjuvant use. All claims for the same systemic therapy without a > 90-day gap or new systemic therapy started within 28 days of a previous treatment were considered to be part of the same LOT. Descriptive analysis, stratified for presence of non-cervical cancers during the baseline period, were conducted to identify most common treatments, durations, and use of mono versus combination therapy within each LOT. Results: 1,229 women newly initiated systemic therapy, 357 (29.0%) received LOT2 and 141 (11.5%) had a LOT3. Treatments received within each LOT are described in the table below. The proportion receiving radiation reduced from LOT1 (49.9%) to LOT2 (12.0%). The mean duration of LOT1 and LOT2 were 2.9 and 3.7 months. The proportion of patients receiving monotherapy in LOT1 and LOT2 were 77.8% and 64.1% respectively. Conclusions: The treatment received by patients in this analysis suggested receipt of guideline concordant care. [Table: see text]
Clinicopathological correlation of serum vascular endothelial growth factor and tissue carbonic anhydrase factor IX in stage IA to IIA carcinoma cervix.
Authors: Rajaram Shalini , Khan Musarrat Bahadur , Gupta Bindiya , Arora Vinod Kumar , Ahmed Rafat , Upreti Lalendra
Published: May 2020

e18012

Background: VEGF initiates endothelial cell proliferation and angiogenesis in tumour cells while CA IX has an important role in pH regulation and elimination of hypoxia generated acid load during glycolysis.The present study was designed to identify these biomarkers and their correlation with tissue spread and behavior and eventually could lead to development of novel target therapies. The objective of this study was to correlate serum VEGF levels and tissue CA IX expression with clinicopathological features of carcinoma cervix stage IA to IIA. Methods: This exploratory case-control study included 19 cases with carcinoma cervix FIGO 2009 stage IA to IIA and 19 age matched controls. Out of the 19 cases, 12 underwent surgery and 7 received chemoradiation. Pre-therapy blood samples were collected for serum VEGF estimation from both cases and controls. For CA IX expression estimation, cervical tissue was taken for analysis. For cases, post-operative / post chemoradiation blood samples were taken for VEGF level estimation after 6 weeks. Results: The difference in mean serum VEGF levels between cases 1235.84 pg/ml (SD± 433.67) and controls 153.74 pg/ml (SD± 108.11) was statistically significant (p = 0.001). Mean serum VEGF level between pre and post-operative cases was 1108 pg/ml (SD± 407.62) and 391.42 pg/ml (SD± 270.71) while in pre and post chemoradiation cases it was 1455 pg/ml (SD± 413.38) and 623 pg/ml (SD± 238.41). This decrease was statistically significant (p = 0.00 & p = 0.018). VEGF positively correlated with histopathologic type (p = 0.016), grade (p = 0.012), and lymphovascular space invasion (p = 0.042).CA IX expression was seen in all cases while in controls no expression was seen. CA IX expression had a positive association with lymphnode metastasis (p = 0.041). Conclusions: Elevated pre-therapeutic serum VEGF suggests spread of tumor and can be used as a prognostic marker for cancer cervix. CA IX immunostaining in cervical biopsy samples can be used as a surrogate marker for tumor aggressiveness and distant spread.