ORCID Profile
0000-0002-1411-0417
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Publisher: Springer Science and Business Media LLC
Date: 14-06-2008
DOI: 10.1007/S00280-007-0524-6
Abstract: Fluoropyrimidine based therapy has modest activity in patients with metastatic renal carcinoma and inhibition of ribonucleotide reductase is synergistic in model systems. GTI-2040 is a 20-mer phosphorothioate oligonucleotide complimentary to the R2 component of ribonucleotide reductase that has activity in renal cancer models. Metastatic renal carcinoma patients without prior fluoropyrimidine therapy and normal organ function were treated with oral capecitabine 880 mg/m(2) twice daily along with continuous infusion GTI-2040 starting at 148 mg/m(2)/day for 21 days, for each 28-day cycle. After completion of the phase I portion, the phase II study portion sought to rule out a null hypothesized 10% response rate versus an alternative 25% response rate utilizing alpha and beta errors of 0.05 and 0.2, respectively. GTI-2040 pharmacokinetics and effects on ribonucleotide reductase expression in peripheral mononuclear cells were evaluated in a subset of patients. Based on one dose limiting toxicity in nine patients in the phase I portion, the phase II portion was conducted using the previously recommended 185 mg/m(2)/day dose of GTI-2040. Twenty-six patients were enrolled in the phase II portion to obtain 18 fully evaluable for response. Only one patient, treated at a GTI 2040 dose of 185 mg/m(2)/day in the phase I portion of the protocol, responded. Toxicities and GTI-2040 pharmacokinetics were consistent with previously reported results. R2 expression in peripheral mononuclear cells was too variable for accurate interpretation. Further study of GTI-2040 and capecitabine in metastatic renal cancer at this dose and schedule is not indicated. Further study is necessary to determine whether lack of activity is due to inadequate target inhibition or inadequate effect of appropriate targeting.
Publisher: Massachusetts Medical Society
Date: 03-2001
Publisher: Springer Science and Business Media LLC
Date: 2006
DOI: 10.1007/S10637-005-4542-0
Abstract: The objective of this phase I study was to determine the maximal tolerated dose (MTD) of the combination of weekly docetaxel and exisulind in patients with advanced solid tumors. Patients with advanced or refractory solid tumors were treated with intravenous weekly docetaxel with daily oral exisulind. The following dose levels (docetaxel/exisulind) were explored: 30-mg/m2/200 mg po bid, 35/200, 35/250 and 40/250. Docetaxel was administered weekly for 6 weeks followed by 2 weeks off, and exisulind was taken twice daily. Each cycle was 8 weeks. Eighteen patients were enrolled in the study. All of them had received prior systemic therapy. Most patients had either melanoma or carcinomas of the upper gastrointestinal tract. A total of 31 cycles of therapy were administered. DLTs were grade 3 diarrhea, anorexia and fatigue and grade 3 cutaneous toxicity at dose level 4 (40/250). Myelosuppression was mild. Fatigue and gastrointestinal toxicity (anorexia, dyspepsia, nausea, abdominal pain and diarrhea) represented the most common toxicities. However, grade 3 and grade 4 toxicities were uncommon. There were no treatment related deaths. No objective responses were observed and five patients achieved stable disease. The recommended dose for phase II studies is weekly docetaxel 35 mg/m2 for 6 weeks followed by 2 weeks off in combination with oral exisulind 250 mg po bid. This combination is feasible and well-tolerated at these doses.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Wiley
Date: 06-05-2014
DOI: 10.1002/CNCR.28767
Publisher: Society of Nuclear Medicine
Date: 06-01-2014
Publisher: Elsevier BV
Date: 07-2013
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275153.V1
Abstract: Supplementary TablesSupplementary Table 1: Patient and tumor s le informationSupplementary Table 2: Tumor mutation burdenSupplementary Table 3: Unfiltered whole exome sequencing mutation analysisSupplementary Table 4: Filtered whole exome sequencing mutation analysisSupplementary Table 5: Immunohistochemistry scores of tumorsSupplementary Table 6: FACS panel for PBMC analysisSupplementary Table 7: Geometric mean fluorescence intensity (GMFI) from PBMC FACSSupplementary Table 8: Representativeness of Study Participants
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.EJCA.2014.10.013
Abstract: Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib-a broad-targeted inhibitor of tyrosine kinases, including FGFR3-were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations. Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3(MUT) n=12), wild-type (FGFR3(WT) n=31), or unknown (n=1) FGFR3 status. Patients received 500 mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). Most of the patients were men (75%) and over half of the patients were aged ⩾65 years (61%). All patients had received ⩾1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3(MUT) (0% 95% confidence interval [CI], 0.0-26.5) and FGFR3(WT) (3.2% 95% CI, 0.1-16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. clinicaltrials.gov NCT00790426.
Publisher: Informa UK Limited
Date: 10-2005
Abstract: Although pure testicular seminoma is most often confined to the testis, it can present with advanced-stage bulky retroperitoneal metastases in nearly a quarter of cases. While highly treatable with cisplatin-based chemotherapy, up to 80% of patients with advanced disease are found to have a radiographically detectable residual mass after chemotherapy. The management of these postchemotherapy residual masses remains controversial. Surgical resection is technically challenging due to a desmoplastic reaction resulting from seminoma treatment and regression. In addition, these residual masses often demonstrate a protracted period of regression that can span several months to years. Surveillance protocols, therefore, may be appropriate for most patients. Several retrospective studies have supported surgical resection only for discrete, well-delineated masses over 3 cm in size. Despite the highly radiosensitive nature of seminoma, radiation therapy in this setting has not been shown to provide significant benefit, and may limit the tolerability of subsequent salvage chemotherapy. The incorporation of noninvasive imaging modalities, such as positron emission tomography, into the management algorithm may better delineate the presence of viable residual tumor and thus allow better risk stratification.
Publisher: American Association for Cancer Research (AACR)
Date: 03-03-2022
DOI: 10.1158/1078-0432.CCR-21-3089
Abstract: In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell–inflamed gene expression profile (TcellinfGEP), and stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC). Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS nominal P values were calculated without multiplicity adjustment (one-sided, pembrolizumab two-sided, chemotherapy). Significance was prespecified at α = 0.05. In KEYNOTE-052, PD-L1, TMB, and TcellinfGEP were significantly associated with improved outcomes stromal signature was significantly associated with worse outcomes. In KEYNOTE-045, although findings for TMB and TcellinfGEP with pembrolizumab were consistent with those of KEYNOTE-052, PD-L1 was not significantly associated with improved outcomes, nor was stromal signature associated with worse outcomes with pembrolizumab chemotherapy was not associated with outcomes in a consistent manner for any of the biomarkers. Hazard ratio (HR) estimates at prespecified cutoffs showed an advantage for pembrolizumab versus chemotherapy regardless of PD-L1 or TMB, with a trend toward lower HRs in the combined positive score ≥10 and the TMB ≥175 mutation/exome subgroup. For TcellinfGEP, PFS and OS HRs were lower in the TcellinfGEP-nonlow subgroup regardless of treatment. Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC, and potential clinical utility of these biomarkers may be context-dependent.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
Publisher: American Association for Cancer Research (AACR)
Date: 26-05-2023
DOI: 10.1158/1078-0432.23223078.V1
Abstract: Supplementary Data for Antonarakis et al
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626885.V1
Abstract: Supplementary Data for Antonarakis et al
Publisher: Wiley
Date: 22-08-2017
DOI: 10.1002/CNCR.30942
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478562
Abstract: Supplementary Data
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.MATURITAS.2011.04.012
Abstract: As the most common malignancy among North American males, prostate cancer causes more than 30,000 deaths each year. After local and hormonal treatments, a great number of patients ultimately progressed to castrate-resistant prostate cancer (CRPC), in which chemotherapy provides a small survival advantage, but with significant toxicities. In the past decade, prostate cancer has become a target for several immunotherapeutic approaches. Sipuleucel-T (Provenge®, or APC8015) is a novel cancer vaccine developed from autologous dendritic cells (DC) loaded with engineered fusion protein of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Phase I and Phase II trials show that the vaccine is safe and effective in creating immune responses toward the fusion-protein target antigen, PAP-GM-CSF also call PA2024. Recent Phase III studies also demonstrated sipuleucel-T's efficacy in prolonging median survival in patients with CRPC, despite little or no effect on clinical disease progression or surrogates such as serum PSA kinetics. Subsequently, the United States Food and Drug Administration approved sipuleucel-T for the treatment of asymptomatic or minimally symptomatic CRPC in April 2010. Filings are projected with international regulatory agencies in 2011. While the development of sipuleucel-T provides an option for patients with early CRPC, it also introduces physicians and researchers to new unanswered questions regarding its optimal clinical use and questions about mechanism of action and combination and sequencing with other agents.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-07-2012
Abstract: Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m 2 on days 1 and 8 every 21 days, cisplatin 75 mg/m 2 every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression. One hundred fifteen patients were enrolled at 11 sites 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater. The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM.
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.EURURO.2012.08.010
Abstract: We present a summary of the Second International Consultation on Bladder Cancer recommendations on chemotherapy for the treatment of bladder cancer using an evidence-based strategy. To review the data regarding chemotherapy in patients with clinically localized and metastatic bladder cancer with a focus on its use for patients in the neoadjuvant and adjuvant settings. Medline databases were searched for original articles published prior to April 1, 2012, using the following search terms: bladder cancer, urothelial cancer, metastatic, advanced, neoadjuvant, and adjuvant therapy. Proceedings of major conferences from the last 5 yr also were searched. Novel and promising drugs currently in clinical trials were included. The major findings are addressed in an evidence-based manner. Prospective trials and important cohort data were analyzed. Cisplatin-based combination chemotherapy for advanced and metastatic bladder cancer is an established standard, improving overall survival. In the advanced setting, cisplatin-ineligible patients may benefit from gemcitabine and carboplatin. Meta-analyses undertaken for neoadjuvant cisplatin-based combination chemotherapy show a 5% benefit in overall survival. Pathologic complete remission may be an intermediate surrogate for survival, but requires further validation. Use of neoadjuvant chemotherapy is low, and is attributable to patient and physician choice because of limited benefit, advanced age, and comorbidities including renal and/or cardiac dysfunction. Sufficient data to support adjuvant chemotherapy are lacking.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626879.V1
Abstract: Supplementary Fig 2. Analysis of survival by baseline median alkaline phosphatase across the two studies using the study-specific median.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275156
Abstract: Supplementary Figure 9: CD8 infiltration in tumor is associated with survival.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275153
Abstract: Supplementary TablesSupplementary Table 1: Patient and tumor s le informationSupplementary Table 2: Tumor mutation burdenSupplementary Table 3: Unfiltered whole exome sequencing mutation analysisSupplementary Table 4: Filtered whole exome sequencing mutation analysisSupplementary Table 5: Immunohistochemistry scores of tumorsSupplementary Table 6: FACS panel for PBMC analysisSupplementary Table 7: Geometric mean fluorescence intensity (GMFI) from PBMC FACSSupplementary Table 8: Representativeness of Study Participants
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275165.V1
Abstract: Supplementary Figure 6: Gene Set Enrichment Analysis reveals immune-related pathways discriminate PD and SD tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2005
DOI: 10.1158/0008-5472.CAN-04-2667
Abstract: Prostate cancer is the most common cancer in men. Advanced prostate cancer spreading beyond the gland is incurable. Identifying factors that regulate the spread of tumor into the regional nodes and distant sites would guide the development of novel diagnostic, prognostic, and therapeutic targets. The aim of our study was to examine the expression and biological role of EphB4 in prostate cancer. EphB4 mRNA is expressed in 64 of 72 (89%) prostate tumor tissues assessed. EphB4 protein expression is found in the majority (41 of 62, 66%) of tumors, and 3 of 20 (15%) normal prostate tissues. Little or no expression was observed in benign prostate epithelial cell line, but EphB4 was expressed in all prostate cancer cell lines to varying degrees. EphB4 protein levels are high in the PC3 prostate cancer cell line and several folds higher in a metastatic clone of PC3 (PC3M) where overexpression was accompanied by EphB4 gene lification. EphB4 expression is induced by loss of PTEN, p53, and induced by epidermal growth factor/epidermal growth factor receptor and insulin-like growth factor-I/insulin-like growth factor-IR. Knockdown of the EphB4 protein using EphB4 short interfering RNA or antisense oligodeoxynucleotide significantly inhibits cell growth/viability, migration, and invasion, and induces apoptosis in prostate cancer cell lines. Antisense oligodeoxynucleotide targeting EphB4 in vivo showed antitumor activity in murine human tumor xenograft model. These data show a role for EphB4 in prostate cancer and provide a rationale to study EphB4 for diagnostic, prognostic, and therapeutic applications.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487295.V1
Abstract: Supplementary Data from Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2006
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275159.V1
Abstract: Supplementary Figure 8: PD-L1 levels in tumor or tumor microenvironment does not associate with tumor progression or control.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275165
Abstract: Supplementary Figure 6: Gene Set Enrichment Analysis reveals immune-related pathways discriminate PD and SD tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275168
Abstract: Supplementary Figure 5: Overall tumor mutation burden and frequency of mutations in cancer-associated genes in UC tumors.
Publisher: Wiley
Date: 21-11-2008
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.UROLONC.2012.07.005
Abstract: We evaluated pathologic and survival outcomes of GC (gemcitabine/cisplatin) and methotrexate/vinblastine/doxorubicin/cisplatin (M-VAC) neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). A retrospective analysis of prospectively collected data on 116 patients who received NAC (GC: n = 58 M-VAC: n = 58) before radical cystectomy and superextended pelvic lymph node dissection for clinical stage T2-4N0M0 bladder cancer was performed. The outcomes were complete response rate (CRR pT0N0), partial response rate (PRR pT0N0, pTaN0, pT1N0, or pTisN0), overall mortality (OM), and recurrence. The Kaplan-Meier method and multivariable Cox regression analysis were used to analyze OM. The cumulative incidence method and Fine and Gray's competing risk regression analysis were used to analyze recurrence. The median follow-up duration was 2.1 years for the GC group and 7.4 years for the M-VAC group (P < 0.001). There were no statistically significant differences between the GC and M-VAC groups with regard to CRR (27.3% vs. 17.1%, P = 0.419) or PRR (45.5% vs. 37.1%, P = 0.498). The predicted 5-year freedom from OM rate (P = 0.634) and cumulative incidence of recurrence rate (P = 0.891) did not differ between the GC and M-VAC groups. Multivariable analysis showed that there was no independent association between type of NAC and OM (P = 0.721) or recurrence (P = 0.065). Pathologic and survival outcomes did not differ in patients who received GC and M-VAC NAC. These data support the use of the GC regimen in the neoadjuvant setting.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2020
DOI: 10.1200/CCI.20.00023
Abstract: Unplanned health care encounters (UHEs) such as emergency room visits can occur commonly during cancer chemotherapy treatments. Patients at an increased risk of UHEs are typically identified by clinicians using performance status (PS) assessments based on a descriptive scale, such as the Eastern Cooperative Oncology Group (ECOG) scale. Such assessments can be bias prone, resulting in PS score disagreements between assessors. We therefore propose to evaluate PS using physical activity measurements (eg, energy expenditure) from wearable activity trackers. Specifically, we examined the feasibility of using a wristband (band) and a smartphone app for PS assessments. We conducted an observational study on a cohort of patients with solid tumor receiving highly emetogenic chemotherapy. Patients were instructed to wear the band for a 60-day activity-tracking period. During clinic visits, we obtained ECOG scores assessed by physicians, coordinators, and patients themselves. UHEs occurring during the activity-tracking period plus a 90-day follow-up period were later compiled. We defined our primary outcome as the percentage of patients adherent to band-wear ≥ 80% of 10 am to 8 pm for ≥ 80% of the activity-tracking period. In an exploratory analysis, we computed hourly metabolic equivalent of task (MET) and counted 10 am to 8 pm hours with 1.5 METs as nonsedentary physical activity hours. Forty-one patients completed the study (56.1% female 61.0% age 40-60 years) 68% were adherent to band-wear. ECOG score disagreement between assessors ranged from 35.3% to 50.0%. In our exploratory analysis, lower average METs and nonsedentary hours, but not higher ECOG scores, were associated with higher 150-day UHEs. The use of a wearable activity tracker is generally feasible in a similar population of patients with cancer. A larger randomized controlled trial should be conducted to confirm the association between lower nonsedentary hours and higher UHEs.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275162
Abstract: Supplementary Figure 7: Representative IHC staining of additional PD and SD tumors in pre-treatment and post-treatment timepoint from additional patients.
Publisher: Oxford University Press
Date: 2010
Publisher: Wiley
Date: 09-10-2008
Publisher: BMJ
Date: 27-01-2014
Publisher: Springer Science and Business Media LLC
Date: 04-09-2003
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2004
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/1078-0432.CCR-22-3832
Abstract: We present long-term outcomes from 2 randomized studies [STAMP (with abiraterone, NCT01487863) and STRIDE (with enzalutamide, NCT01981122)] that were performed to study the impact of sequential or concurrent administration of androgen receptor–targeting agents (ARTAs) on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan–Meier methodology was used to analyze survival. Updated data reduced patient censoring in each study compared with the original analyses the 95% confidence intervals (CIs) for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1–40.7) months for STAMP and 32.5 (26.0–45.1) months for STRIDE. There was no notable impact on median OS [HR, 0.727 (0.458–1.155) P = 0.177, reference = STRIDE]. OS with sequential administration was similar to concurrent administration [NDI update: HR, 0.963 (0.639–1.453) P = 0.845, reference = concurrent arm]. Sipuleucel-T potency, measured as antigen-presenting cell (APC) activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated versus baseline. No new safety signals were observed. Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.
Publisher: American Association for Cancer Research (AACR)
Date: 26-05-2023
DOI: 10.1158/1078-0432.23223072.V1
Abstract: Supplementary Fig 2. Analysis of survival by baseline median alkaline phosphatase across the two studies using the study-specific median.
Publisher: Informa UK Limited
Date: 02-12-2014
DOI: 10.1586/17512433.2014.862496
Abstract: Although targeted therapy against VEGF and mTOR have revolutionized the treatment of advanced renal cell carcinoma (RCC), additional agents are required due to toxicity and resistance to currently available drugs. Some next-generation tyrosine kinase inhibitors have focused on VEGF, narrowing the spectrum of receptors which are inhibited and enhancing binding affinity. However, targeting novel receptors with tyrosine kinase inhibition of additional receptor targets has also emerged as an important future therapeutic strategy for RCC, both clear cell and variant histology. New pathways being targeted include FGF, angiopoietin and MET. In this review, we highlight five novel tyrosine kinase inhibitors in development for RCC: tivozanib dovitinib regorafenib cabozantinib and tivantinib.
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2014
DOI: 10.1158/1078-0432.CCR-14-0489
Abstract: Purpose: AEZS-108, formerly AN-152, is a cytotoxic hybrid molecule consisting of a luteinizing hormone-releasing hormone (LHRH) agonist moiety covalently coupled to doxorubicin, allowing it to deliver doxorubicin selectively to cells expressing LHRH receptors. LHRH receptors are expressed on the cell membrane of many tumors, including prostate cancer. This phase I study determined the maximum tolerated dose (MTD) of AEZS-108 in men with taxane- and castration-resistant prostate cancer (CRPC) while providing additional information on the safety profile and efficacy of this agent. Experimental Design: AEZS-108 was administered as an intravenous infusion every 21 days until progression or unacceptable toxicity in cohorts of 3 or 6 patients until the MTD was reached. Blood was collected for capture of circulating tumor cells (CTC) to visualize internalization of AEZS-108, an autofluorescent molecule. Results: The MTD of AEZS-108 in this cohort was 210 mg/m2, which was lower than that seen in a phase I study conducted in women with endometrial or ovarian cancers. The dose-limiting toxicity was persistent neutropenia. Three patients had a PSA response with an additional 10 patients maintaining PSA stable disease. Of the 10 patients evaluable by RECIST criteria, 9 achieved stable disease. AEZS-108 internalization in CTCs was routinely visualized using its autofluorescence. Conclusion: These findings show that AEZS-108 has an acceptable safety profile and a signal of efficacy, lowering PSA in heavily pretreated patients with prostate cancer, and that internalization of AEZS-108 in prostate cancer CTCs may be a viable pharmacodynamic marker. A phase II study in men with prostate cancer is ongoing. Clin Cancer Res 20(24) 6277–83. ©2014 AACR.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2013
DOI: 10.1007/S10637-013-9934-Y
Abstract: Tivantinib is a selective, small-molecule inhibitor of the MET receptor tyrosine kinase. Preclinical and phase 1 data suggested a possible role for MET in the pathophysiology of germ cell tumors (GCTs) and a potential clinical benefit from tivantinib in patients with these tumors. Men (≥ 16 years) with relapsed or refractory, histologically confirmed, non-central nervous system GCTs received oral tivantinib 360 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate in the first 4 cycles, with study termination for <2 responses among the first 21 patients. Secondary endpoints included 12-week progression-free survival (PFS), overall survival (OS), and safety. Twenty-seven patients were enrolled in 9 months (median age, 32 years). Most patients had tumors with nonseminoma histology (n = 25), and primary tumor sites were testis (n = 24) and mediastinum (n = 3). Among 25 evaluable patients, no objective responses were observed accrual was halted when the 21st patient became evaluable. Best response was stable disease (n = 5). Median PFS was 1 month, the 12-week PFS rate was 21 %, and median OS was 6 months. Grade 3 or 4 adverse events considered related to study drug included grade 3 pneumonia and grade 3 syncope (n = 1, each). Tivantinib was well tolerated but did not demonstrate single-agent activity in patients with relapsed/refractory GCTs. Rapid accrual to this phase 2 trial was achieved in this rare patient population through multicenter collaboration.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275171.V1
Abstract: Supplementary Figure 4: Weak correlation of TE expression induction with DNA methylation change and viral mimicry activation.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487295
Abstract: Supplementary Data from Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials
Publisher: Elsevier BV
Date: 08-2014
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275159
Abstract: Supplementary Figure 8: PD-L1 levels in tumor or tumor microenvironment does not associate with tumor progression or control.
Publisher: Springer Science and Business Media LLC
Date: 04-11-2022
DOI: 10.1038/S41467-022-33980-9
Abstract: Urothelial Cancer - Genomic Analysis to Improve Patient Outcomes and Research (NCT02643043), UC-GENOME, is a genomic analysis and biospecimen repository study in 218 patients with metastatic urothelial carcinoma. Here we report on the primary outcome of the UC-GENOME—the proportion of subjects who received next generation sequencing (NGS) with treatment options—and present the initial genomic analyses and clinical correlates. 69.3% of subjects had potential treatment options, however only 5.0% received therapy based on NGS. We found an increased frequency of TP53 E285K mutations as compared to non-metastatic cohorts and identified features associated with benefit to chemotherapy and immune checkpoint inhibition, including: Ba/Sq and Stroma-rich subtypes, APOBEC mutational signature (SBS13), and inflamed tumor immune phenotype. Finally, we derive a computational model incorporating both genomic and clinical features predictive of immune checkpoint inhibitor response. Future work will utilize the biospecimens alongside these foundational analyses toward a better understanding of urothelial carcinoma biology.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-01-2023
DOI: 10.1200/JCO.21.02303
Abstract: Rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR1-4) inhibitor, showed promising phase I efficacy and safety in patients with advanced urothelial carcinoma (UC) with FGFR1-3 mRNA overexpression. We assessed rogaratinib efficacy and safety versus chemotherapy in patients with FGFR mRNA-positive advanced/metastatic UC previously treated with platinum chemotherapy. FORT-1 (ClinicalTrials.gov identifier: NCT03410693 ) was a phase II/III, randomized, open-label trial. Patients with FGFR1/ 3 mRNA-positive locally advanced or metastatic UC with ≥ 1 prior platinum-containing regimen were randomly assigned (1:1) to rogaratinib (800 mg orally twice daily, 3-week cycles n = 87) or chemotherapy (docetaxel 75 mg/m 2 , paclitaxel 175 mg/m 2 , or vinflunine 320 mg/m 2 intravenously once every 3 weeks n = 88). The primary end point was overall survival, with objective response rate (ORR) analysis planned following phase II accrual. Because of comparable efficacy between treatments, enrollment was stopped before progression to phase III a full interim analysis of phase II was completed. ORRs were 20.7% (rogaratinib, 18/87 95% CI, 12.7 to 30.7) and 19.3% (chemotherapy, 17/88 95% CI, 11.7 to 29.1). Median overall survival was 8.3 months (95% CI, 6.5 to not estimable) and 9.8 months (95% CI, 6.8 to not estimable hazard ratio, 1.11 95% CI, 0.71 to 1.72 P = .67). Grade 3/4 events occurred in 37 (43.0%)/4 (4.7%) patients and 32 (39.0%)/15 (18.3%), respectively. No rogaratinib-related deaths occurred. Exploratory analysis of patients with FGFR3 DNA alterations showed ORRs of 52.4% (11/21 95% CI, 29.8 to 74.3) for rogaratinib and 26.7% (4/15 95% CI, 7.8 to 55.1) for chemotherapy. To our knowledge, these are the first data to compare FGFR-directed therapy with chemotherapy in patients with FGFR-altered UC, showing comparable efficacy and manageable safety. Exploratory testing suggested FGFR3 DNA alterations in association with FGFR1/ 3 mRNA overexpression may be better predictors of rogaratinib response.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587060.V1
Abstract: Supplementary Figure 2: Modest treatment-induced DNA methylation changes in UC tumors.
Publisher: Informa UK Limited
Date: 2014
DOI: 10.1586/14737140.2014.848065
Abstract: Immunotherapies such as sipuleucel-T present new and unique challenges for the optimal timing and sequencing of therapies for metastatic castration-resistant prostate cancer (mCRPC). Key considerations for the sequencing of sipuleucel-T are its unique proposed mechanism of action, the time required to generate a clinically relevant immune response, and the observed efficacy in Phase III trials in 'early' or asymptomatic or minimally symptomatic mCRPC. There are three broad timing and sequencing options for sipuleucel-T in patients with rising prostate-specific antigen and radiologic evidence of disease: immediately after androgen-deprivation therapy failure, after failure of secondary hormonal maneuvers, or after chemotherapy. There are several other agents in Phase III development in mCRPC and any future approvals will impact on the current treatment algorithm, and raise further questions regarding how to optimize sequencing and timing of therapies for better clinical outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2018
DOI: 10.1158/2159-8290.CD-18-0229
Abstract: BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a erse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted. Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov 8(7) 812–21. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 781
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587045.V1
Abstract: Supplementary Figure 7: Representative IHC staining of additional PD and SD tumors in pre-treatment and post-treatment timepoint from additional patients.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587048.V1
Abstract: Supplementary Figure 6: Gene Set Enrichment Analysis reveals immune-related pathways discriminate PD and SD tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275186.V1
Abstract: Supplementary Figure 10: Peripheral immune cell dynamics induced by combination therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.C.6666732
Abstract: AbstractPurpose: We present long-term outcomes from 2 randomized studies [STAMP (with abiraterone, NCT01487863) and STRIDE (with enzalutamide, NCT01981122)] that were performed to study the impact of sequential or concurrent administration of androgen receptor–targeting agents (ARTAs) on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan–Meier methodology was used to analyze survival. Results: Updated data reduced patient censoring in each study compared with the original analyses the 95% confidence intervals (CIs) for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1–40.7) months for STAMP and 32.5 (26.0–45.1) months for STRIDE. There was no notable impact on median OS [HR, 0.727 (0.458–1.155) i P /i = 0.177, reference = STRIDE]. OS with sequential administration was similar to concurrent administration [NDI update: HR, 0.963 (0.639–1.453) i P /i = 0.845, reference = concurrent arm]. Sipuleucel-T potency, measured as antigen-presenting cell (APC) activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated versus baseline. No new safety signals were observed. Conclusions: Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2010
DOI: 10.1158/1078-0432.CCR-09-3122
Abstract: Purpose: Interleukin-6 (IL-6) facilitates cancer cell survival via pleotrophic effects. We conducted a multicenter phase II study of CNTO328 (siltuximab) as second-line therapy for men with castration-resistant prostate cancer. Experimental Design: Eligible men had castration-resistant prostate cancer treated with one prior chemotherapy. Subjects were treated with 6 mg/kg CNTO328 i.v. every 2 weeks for 12 cycles. Response was assessed after every three cycles. Primary end point was prostate-specific antigen (PSA) response rate defined as a 50% reduction. Accrual was planned in two stages, with 20 eligible patients in the first stage and 40 overall. Plasma cytokines and growth factors were measured by Luminex. Results: Fifty-three eligible subjects had all received prior taxane therapy. Two (3.8% 95% CI, 0.5-13.0%) had PSA response. None of the 31 patients with measurable disease had a RECIST (Response Evaluation Criteria in Solid Tumors) response but 7 (23%) had stable disease. With median follow-up of 14.8 months, median progression-free survival was 1.6 months (95% CI, 1.6-1.7) and median overall survival was 11.6 months (95% CI, 7.5-19.0). Grade 3/4 toxicities included disseminated intravascular coagulation (1), central nervous system ischemia (1), elevated aspartate aminotransferase (1), gastritis/esophagitis (2), thrombocytopenia (2), pain (2), leukopenia (1), and neuropathy (2). Median baseline IL-6 levels were 12.5 pg/mL (interquartile range, 2.5-41.5). Patients with IL-6 & .5 pg/mL had worse survival than those with levels & .5 pg/mL (53% versus 94% P = 0.02). After treatment, IL-6 levels were & -fold higher. Thirty-two of 38 patients had a decline in C-reactive protein plasma levels at 6 weeks. Conclusions: CNTO328 resulted in a PSA response rate of 3.8% and a RECIST stable disease rate of 23%. Declining C-reactive protein levels during treatment may reflect biological activity. Despite evidence of CNTO-mediated IL-6 inhibition, elevated baseline IL-6 levels portended a poor prognosis. Clin Cancer Res 16(11) 3028–34. ©2010 AACR.
Publisher: Springer Science and Business Media LLC
Date: 06-11-2014
DOI: 10.1007/S00280-014-2600-Z
Abstract: To determine the maximal tolerated dose (MTD) of the combination of weekly temsirolimus and every other week vinorelbine in patients with advanced or refractory solid tumors. Patients were treated with intravenous temsirolimus on days 1, 8, 15, and 22 and intravenous vinorelbine on days 1 and 15. Cycles were repeated every 28 days. Nineteen patients were enrolled in the study. Tumor types included lung (5), prostate (2), neuroendocrine of pancreas (1), bladder (2), uterus (3), cervix (4), and vagina (2). All patients had received prior chemotherapy. Four patients were enrolled to dose level I, nine to dose level II, and six to dose level III. Six patients were inevaluable and replaced. Fifty-seven total cycles were administered. There was 1 dose-limiting toxicity at level II (grade 3 anorexia/dehydration) and 2 at level III (grade 3 hypokalemia grade 4 neutropenia). Two patients died at dose level III one was study-related with grade 4 neutropenia. Grade 3/4 toxicities observed during the first cycle included neutropenia (2), anemia (1), anorexia (1), dehydration (1), hyperglycemia (1), hypertriglyceridemia (1), and hypokalemia (1). Best response included two patients (prostate and non-small cell lung cancer) with partial response and eight patients with stable disease with median duration of best response of 3.2 months. Temsirolimus 25 mg given days 1, 8, 15, and 22 in combination with vinorelbine 20 mg/m(2) given days 1 and 15 every 4 weeks was found to be the MTD. This dose combination is considered feasible in phase II trials.
Publisher: Springer Science and Business Media LLC
Date: 20-11-2009
DOI: 10.1007/S00345-008-0342-4
Abstract: To describe the tolerability of two chemotherapy regimens, gemcitabine and cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) for adjuvant treatment of patients with locally advanced urothelial cancer after radical cystectomy. The USC Department of Urology bladder cancer database was searched for subjects who received adjuvant chemotherapy following cystectomy for transitional cell carcinoma with extravesical and/or lymph node involvement, yielding 187 cases. Clinical details regarding toxicity, number of cycles administered, and cancer outcome were analyzed. The majority of subjects had lymph node involvement (70%). Sixty-eight percent of subjects received MVAC and 32% received GC, the latter regimen was predominant after 2000. Fifty-six percent of subjects received all four planned cycles (51% GC and 58% MVAC). With a median follow-up of 11.2 years (range 1.9-19.6), 96 patients (51%) have suffered a relapse, with no significant difference between chemotherapy regimens. Median time to recurrence for the population was 3.7 years and median overall survival is 4.6 years (3.0-9.3). The median time from recurrence to death was 6.7 months and was not significantly different between MVAC and GC. Both MVAC and GC are tolerated after cystectomy for advanced urothelial carcinoma. A significant proportion of high-risk patients survive, free of disease, beyond 10 years. At recurrence, patients previously treated with adjuvant chemotherapy have a survival that appears much shorter than patients who develop metastases in the absence of this exposure, suggesting resistance to salvage chemotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587054.V1
Abstract: Supplementary Figure 4: Weak correlation of TE expression induction with DNA methylation change and viral mimicry activation.
Publisher: Public Library of Science (PLoS)
Date: 22-08-2014
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587039.V1
Abstract: Supplementary Figure 9: CD8 infiltration in tumor is associated with survival.
Publisher: Elsevier BV
Date: 05-2005
DOI: 10.1016/J.UCL.2005.03.002
Abstract: Urothelial transitional cell cancer has a high rate of response to combination cytotoxic therapy. Approximately 50% of patients with high-grade bladder cancer and deep muscle invasion ultimately die of disseminated disease. Translating the high response seen in locally advanced disease into long-term survival in the metastatic setting and to improved survival in the advanced setting has proved difficult. This article reviews the use of adjuvant chemotherapy in localized or locally advanced transitional cell cancer. The chemotherapy of urological malignancies, including bladder cancer, has recently been reviewed in detail this article does not contain an extensive review of the drugs used.
Publisher: Elsevier BV
Date: 04-2012
Abstract: YM155, a small-molecule survivin suppressor, showed modest single-agent activity in a phase I study of heavily pretreated patients. This study was conducted to determine the activity of YM155 in patients with castration-resistant prostate cancer (CRPC) who received prior taxane therapy. Patients received 4.8 mg/m(2)/day of YM155 over 168-h continuous i.v. infusion every 3 weeks. Study end points included prostate-specific antigen (PSA) response, objective tumor response, safety, progression-free survival (PFS) and overall survival (OS). Thirty-five patients were enrolled. Two of 32 (6.2%) assessable patients had a PSA response and 2 additional patients had PSA decrements >50% but not confirmed. One of 16 (6.2%) patients also had a partial response per RECIST V1. Median PFS and OS were 3.1 and 11.2 months, respectively. The most common adverse events were fatigue (63%), nausea (40%), anorexia (31%), constipation (31%), fever (26%) and vomiting (26%). YM155 has modest activity in taxane-pretreated CRPC with 25% of patients having prolonged stable disease (≥18 weeks). The regimen appears to be well tolerated. Based on the mechanism of action and preclinical evidence of synergy with docetaxel (Taxotere), YM155 combined with docetaxel is being evaluated in patients with CRPC.
Publisher: Wiley
Date: 04-08-2011
Publisher: Wiley
Date: 02-06-2004
DOI: 10.1002/CNCR.20300
Abstract: The current study evaluated factors influencing survival in patients diagnosed with human immunodeficiency virus (HIV)-related primary central nervous system lymphoma (PCNSL), with a focus on the effects of therapeutic radiotherapy (RT) and highly active antiretroviral therapy (HAART). A retrospective chart review of patients with a diagnosis of HIV-related PCNSL at one of five university hospitals between 1987 and 1998 was performed. Clinical details including antiretroviral agent use, brain imaging scan results, RT use, and survival outcomes were recorded. One hundred eleven patients with HIV-related PCNSL were identified. The annual incidence decreased significantly between 1992 and 1995 and between 1996 and 1998 (P = 0.04). The median survival period was 50 days (mean, 109 days range, 4-991 days), with improved survival for patients diagnosed after 1993. Patients treated with two or more antiretroviral agents had improved survival (P = 0.01), as did patients who received RT (P or = 30 Gray (Gy) independently predicted a more favorable outcome. RT used in conjunction with antiretroviral therapy involving two or more agents had an additive positive effect on survival. For patients who did not receive RT, poor performance status and encephalopathy predicted a shorter survival duration. The results of the current study suggest that HAART and treatment with RT to > or = 30 Gy improve survival for patients with HIV-related PCNSL. This combination of therapies may provide a standard of care as the basis for further trials of chemotherapy, novel adjunctive treatment, and quality of life assessment.
Publisher: Springer Science and Business Media LLC
Date: 18-03-2008
Publisher: American Association for Cancer Research (AACR)
Date: 26-05-2023
DOI: 10.1158/1078-0432.23223069
Abstract: Supplementary Fig 3 In vivo cellular and humoral responses through 52 weeks are illustrated here.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2008
Publisher: American Society of Clinical Oncology (ASCO)
Date: 08-2002
Abstract: PURPOSE: We evaluated the predictive accuracy of a recently published preoperative nomogram for prostate cancer that predicts 5-year freedom from recurrence. We applied this nomogram to patients from seven different institutions spanning three continents. METHODS: Clinical data of 6,754 patients were supplied for validation, and 6,232 complete records were used. Nomogram-predicted probabilities of 60-month freedom from recurrence were compared with actual follow-up in two ways. First, areas under the receiver operating characteristic curves (AUCs) were determined for the entire data set according to several variables, including the institution where treatment was delivered. Second, nomogram classification–based risk quadrants were compared with actual Kaplan-Meier plots. RESULTS: The AUC for all institutions combined was 0.75, with in idual institution AUCs ranging from 0.67 to 0.83. Nomogram predictions for each risk quadrant were similar to actual freedom from recurrence rates: predicted probabilities of 87% (low-risk group), 64% (intermediate-low–risk group), 39% (intermediate-high–risk group), and 14% (high-risk group) corresponded to actual rates of 86%, 64%, 42%, and 17%, respectively. The use of neoadjuvant therapy, variation in the prostate-specific antigen recurrence definitions between institutions, and minor differences in the way the Gleason grade was reported did not substantially affect the predictive accuracy of the nomogram. CONCLUSION: The nomogram is accurate when applied at international treatment institutions with similar patient selection and management strategies. Despite the potential for heterogeneity in patient selection and management, most predictions demonstrated high concordance with actual observations. Our results demonstrate that accurate predictions may be expected across different patient populations.
Publisher: Elsevier BV
Date: 10-2010
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478562.V1
Abstract: Supplementary Data
Publisher: American Association for Cancer Research (AACR)
Date: 03-2021
DOI: 10.1158/1078-0432.CCR-20-2891
Abstract: Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of in idual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy. Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test. From December 2016 to January 2019, 183 s les from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline (P = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9–2.3 vs. 28.2 months P & 0.0001–0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS (P = 0.045). PD-L1+ CTCs on-therapy were associated with worse OS (P & 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category. Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1+ CTCs, and low %CD4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.CLGC.2013.07.011
Abstract: Although new androgen-targeted therapies offer prolonged survival in metastatic castration-resistant prostate cancer (CRPC), most men still face progressive disease and require additional therapy. Oxaliplatin and pemetrexed have each shown modest activity in the treatment of CRPC. Given their favorable nonoverlapping toxicity profiles, we studied them in combination. Men with CRPC whose disease had progressed on 1 or 2 previous chemotherapy regimens, including a taxane, were eligible. All participants received oxaliplatin 120 mg/m(2) and pemetrexed 500 mg/m(2) intravenously every 21 days. The primary end point was response rate objective responses were determined using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, criteria and the Prostate Cancer Working Group (1999) criteria. Secondary end points included progression-free survival and OS. Forty-seven men received a median of 6 cycles (range, 1-21). The overall response rate was 30% (95% confidence interval [CI], 18%-45%), including 10 men with RECIST responses of the 40 who had measurable disease (25%). Overall, 64% had a prostate-specific antigen (PSA) decline and 74% of men had clinical disease control (partial response or stable disease as their best response). Median progression-free survival was 5.8 months (95% CI, 3.8-7.6), with a median OS of 11.9 months. Six of 15 evaluable patients (40%) experienced a pain response. Nineteen patients (40%) experienced a grade 3 or 4 hematologic toxicity, and 16 (34%) experienced a grade 3 nonhematologic toxicity. One patient died while participating in the study. Combination oxaliplatin and pemetrexed (PemOx) is an effective and tolerable second- or third-line treatment for men with CRPC.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2018
DOI: 10.1158/1078-0432.CCR-18-0638
Abstract: Purpose: Sipuleucel-T is FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) based on the IMPACT trial showing a 4.1-month benefit in median overall survival (OS) for patients receiving sipuleucel-T versus control. Although efficacy of sipuleucel-T is well established, its mechanism remains incompletely understood. Patients and Methods: Patient s les from three sipuleucel-T trials were assessed for peripheral cellular immune responses to the immunogen PA2024 and the target antigen prostatic acid phosphatase (PAP). PAP- and PA2024-specific proliferative and cytolytic responses were characterized to delineate sipuleucel-T–induced immune responses. To quantify potential cytotoxic T lymphocyte (CTL) activity, cell-surface CD107a expression on PAP- or PA2024-specific CD8+ T cells was measured in sipuleucel-T–treated patient and healthy volunteer s les. Results: Increased PA2024-specific CD4+ (P = 0.030) and CD8+ (P = 0.052) T-cell proliferation from baseline to week 6 was observed (N = 14) post–sipuleucel-T, with greater magnitude of PA2024-specific responses compared with PAP. PAP- and PA2024-CTL activity (CD107a positivity) significantly increased at weeks 6 and 26 after sipuleucel-T treatment (P & 0.0001 N = 22). At 26 weeks post–sipuleucel-T, OS correlated with the magnitude of PAP (Pearson R, 0.52 P = 0.013) or PA2024 (Pearson R, 0.67 P = 0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis (P = 0.0005 N = 22), with PA2024 responses correlating with PAP responses at week 26 (R = 0.90 P = 1.53E−08). Conclusions: This study is the first to report PAP-specific CD8+ T-cell responses elicited by sipuleucel-T treatment. Increased and persistent potential PA2024-specific CTL activity correlated with PAP-specific CTL activity and associated with improved OS following sipuleucel-T treatment. Clin Cancer Res 24(19) 4662–71. ©2018 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626876.V1
Abstract: Supplementary Fig 3 In vivo cellular and humoral responses through 52 weeks are illustrated here.
Publisher: Wiley
Date: 15-04-2003
DOI: 10.1002/CNCR.11263
Abstract: Predicting outcome for men with clinically localized prostate carcinoma treated with curative intent remains imprecise and further evaluation of accepted and potential predictive factors is needed. The authors studied 696 men with localized prostate carcinoma diagnosed on transrectal biopsy and treated with radical prostatectomy at one institution between 1986 and 1999 to determine the relation between putative pretreatment prognostic factors and disease-free survival. Clinical stage, Gleason score, perineural invasion, number of biopsies containing tumor, and serum prostate specific antigen (PSA) were evaluated as predictors of extracapsular extension, seminal vesicle involvement, lymph node metastases, and surgical margin involvement as well as outcome after surgery. Kaplan-Meier method and Cox regression analyses were used to evaluate the contribution of different factors to adverse pathologic features and relapse. At mean follow-up of 56.9 months (range, 1.0-177.9 months median, 54.9 months), 26.1% (182 of 696 patients) of patients had developed a disease recurrence. Pretreatment serum PSA concentration, biopsy Gleason score, and clinical stage as well as number of biopsies involved with tumor as a percentage of the total number obtained were found to be independent predictors of outcome. In patients with PSA > 10 ng/mL, biopsy perineural invasion and percentage of biopsies containing tumor were found to independently predicted disease recurrent. Increased number of biopsies involved with tumor independently predicted extracapsular extension, margin involvement, seminal vesicle, and lymph node involvement. This study demonstrated that the proportion of prostate biopsy cores containing tumor is an independent predictor of outcome after subsequent radical prostatectomy and suggested that perineural invasion has a predictive role in patients with a preoperative PSA > 10 ng/ml.
Publisher: Informa UK Limited
Date: 06-2013
DOI: 10.2147/BTT.S32958
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626882.V1
Abstract: Supplementary Fig 1 Analysis of Survival by Baseline Median PSA across the two studies using the study-specific median and quartiles.
Publisher: Proceedings of the National Academy of Sciences
Date: 06-03-2003
Abstract: Genetic alterations in tumor cells often lead to the emergence of growth-stimulatory autocrine and paracrine signals, involving overexpression of secreted peptide growth factors, cytokines, and hormones. Increased levels of these soluble proteins may be exploited for cancer diagnosis and management or as points of therapeutic intervention. Here, we combined the use of controlled vocabulary terms and sequence-based algorithms to predict genes encoding secreted proteins from among ≈12,500 sequences represented on oligonucleotide microarrays. Expression of these genes was queried in 150 carcinomas from 10 anatomic sites of origin and compared with 46 normal tissues derived from the corresponding sites of tumor origin and other body tissues and organs. Of 74 different genes identified as overexpressed in cancer tissues, several encode proteins with demonstrated clinical diagnostic application, such as α-fetoprotein in liver carcinoma, and kallikreins 6 and 10 in ovarian cancer, or therapeutic utility, such as gastrin-releasing peptide/bombesin in lung carcinomas. We show that several of the other candidate genes encode proteins with high levels of tumor-associated expression by immunohistochemistry on tissue microarrays and further demonstrate significantly elevated levels of another novel candidate protein, macrophage inhibitory cytokine 1, a distant member of the tranforming growth factor-β superfamily, in the serum of patients with metastatic prostate, breast, and colorectal carcinomas. Our results suggest that the combination of annotation rotein sequence analysis, transcript profiling, immunohistochemistry, and immunoassay is a powerful approach for delineating candidate biomarkers with potential clinical significance and may be broadly applicable to other human diseases.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587066.V1
Abstract: Supplementary Figure 11: Peripheral immune cells are activated mid-treatment cycle.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587072
Abstract: Supplementary Figure 1: Patient recruitment and s le collection overview.
Publisher: MDPI AG
Date: 18-04-2012
Publisher: Elsevier BV
Date: 02-2013
Publisher: American Association for Cancer Research (AACR)
Date: 15-06-2005
DOI: 10.1158/1078-0432.CCR-04-2109
Abstract: Purpose: Mesothelioma is a rare malignancy that is incurable and carries a short survival despite surgery, radiation, or chemotherapy. This study was designed to identify novel targets for diagnostic, prognostic, and therapeutic approaches. Experimental Design: The expression and functional significance of the receptor tyrosine kinase EphB4 was studied in vitro and in a murine model of mesothelioma. Results: EphB4 was highly expressed in mesothelioma cell lines and primary tumor tissues but not in normal mesothelium. Knockdown of EphB4 using small interfering RNA and antisense oligodeoxynucleotide showed reduction in cell survival, migration, and invasion. EphB4 knockdown initiated a caspase-8-mediated apoptosis and down-regulation of the antiapoptotic protein bcl-xl. EphB4 knockdown also resulted in reduced phosphorylation of Akt and down-regulation of matrix metalloproteinase-2 transcription. In addition, murine tumor xenograft studies using EphB4 oligodeoxynucleotides showed a marked reduction in tumor growth accompanied by a specific decline in EphB4 protein levels, reduced cell ision, apoptosis in tumor tissue, and decreased microvascular density. Conclusions: EphB4 is expressed in mesothelioma, provides a survival advantage to tumor cells, and is therefore a potential novel therapeutic target.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-2022
DOI: 10.1200/JCO.21.02517
Abstract: Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 1:1 to ADT with orteronel (300 mg oral twice daily experimental arm) or ADT with bicalutamide (50 mg oral once daily control arm). The primary objective was the comparison of overall survival (OS), targeting a 33% improvement in median survival. A stratified log-rank test with a one-sided P ≤ .022 would indicate statistical significance. Secondary end points were progression-free survival (PFS), prostate-specific antigen (PSA) level at 7 months (≤ 0.2 v 0.2 to ≤ 4 v 4 ng/mL), and adverse event profile. Among 1,279 patients included in the analysis, 638 were randomly assigned to the ADT plus orteronel arm and 641 to the control arm. The median age was 68 years 49% had extensive disease. After a median follow-up of 4.9 years, there was a significant improvement in PFS (median 47.6 v 23.0 months, hazard ratio 0.58 95% CI, 0.51 to 0.67 P .0001) and PSA response at 7 months ( P .0001), but not in OS (median 81.1 v 70.2 months, hazard ratio 0.86 95% CI, 0.72 to 1.02 P = .040, one-sided). More grade 3/4 adverse events occurred in the experimental versus the control arms (43% v 14%). Postprotocol life-prolonging therapy was received by 77.4% of patients in the control arm and 61.3% of patients in the orteronel arm. The study did not meet the primary end point of improved OS with orteronel. The lack of correlation of PFS and PSA response with OS raises concerns over assumption of their consistent surrogacy for OS in the context of extensive postprotocol therapy in this setting.
Publisher: Elsevier BV
Date: 11-2013
Publisher: Elsevier BV
Date: 07-2014
Publisher: American Society of Clinical Oncology (ASCO)
Date: 2013
Abstract: A MESSAGE FROM ASCO'S PRESIDENT I am delighted to present you with “Clinical Cancer Advances 2012: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.” The American Society of Clinical Oncology (ASCO) uses this opportunity each year to share the steady progress occurring in our understanding and treatment of cancer. For 2012, we offer again an inspiring perspective on clinical cancer advances over the past year, but with a cautionary note: if current threats to federal funding materialize, future progress in cancer research will be seriously undermined. Continued progress against cancer. As you read the following pages of this report, I hope you will share my unabashed enthusiasm—and pride—in how far we have come. To appreciate what this progress has meant to the millions of people who receive a cancer diagnosis each year, consider the following: (1) two of three people in the United States live at least 5 years after a cancer diagnosis (up from roughly one of two in the 1970s) (2) the nation's cancer death rate has dropped 18% since the early 1990s, reversing decades of increases and (3) in iduals with cancer are increasingly able to live active, fulfilling lives because of better management of symptoms and treatments with fewer adverse effects. Importance of clinical cancer trials. These dramatic trends—and the advances highlighted in this report—would have been unthinkable without the engine that drives life-saving cancer treatment: clinical cancer research. Advances in technology and in our knowledge of how patient-specific molecular characteristics of the tumor and its environment fuel the growth of cancer have brought new hope to patients. Clinical trials are the key to translating cutting-edge laboratory discoveries into treatments that extend and improve the lives of those with cancer. But progress is only part of the story. Cancer remains a challenge, with many cancers undetected until their latest stages and others resisting most attempts at treatment. Tragically, cancer still kills more than 500,000 people in the United States every year, and its global burden is growing rapidly. Bridges to better care. To conquer cancer, we need to build bridges to the future—bridges that will get scientific advances to the patient's bedside quicker, bridges that will enable us to share information and learn what works in real time, and bridges that will improve care for all patients around the world. At ASCO, we recognize the unique role that oncologists must play. ASCO's “Accelerating Progress Against Cancer: Blueprint for Transforming Clinical and Translational Cancer Research,” 1 published last year, presents our vision and recommendations to make cancer research and patient care vastly more targeted, more efficient, and more effective. We have also launched a groundbreaking initiative, CancerLinQ, that aims to improve cancer care and speed research by drawing insights from the vast pool of data on patients in real-world settings. Renewing a national commitment to cancer research. We are on the threshold of major advances in cancer prevention, detection, and treatment—but only if, as a nation, we remain committed to this critical endeavor. The federally funded cancer research system is currently under threat by larger federal budget concerns. Clearly, Congress faces a complex budget environment, but now is not the time to retreat from our nation's commitment to conquering a disease that affects nearly all of us. Bold action must be taken to ensure that we can take full advantage of today's scientific and technologic opportunities. Please join me in celebrating our nation's progress against cancer and in recommitting ourselves to supporting cancer research. Millions of lives depend on it. Sandra M. Swain, MD President American Society of Clinical Oncology
Publisher: American Association for Cancer Research (AACR)
Date: 26-05-2023
DOI: 10.1158/1078-0432.C.6666732.V1
Abstract: AbstractPurpose: We present long-term outcomes from 2 randomized studies [STAMP (with abiraterone, NCT01487863) and STRIDE (with enzalutamide, NCT01981122)] that were performed to study the impact of sequential or concurrent administration of androgen receptor–targeting agents (ARTAs) on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC). Experimental design: Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan–Meier methodology was used to analyze survival. Results: Updated data reduced patient censoring in each study compared with the original analyses the 95% confidence intervals (CIs) for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1–40.7) months for STAMP and 32.5 (26.0–45.1) months for STRIDE. There was no notable impact on median OS [HR, 0.727 (0.458–1.155) i P /i = 0.177, reference = STRIDE]. OS with sequential administration was similar to concurrent administration [NDI update: HR, 0.963 (0.639–1.453) i P /i = 0.845, reference = concurrent arm]. Sipuleucel-T potency, measured as antigen-presenting cell (APC) activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated versus baseline. No new safety signals were observed. Conclusions: Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs. /
Publisher: Wiley
Date: 03-11-2009
DOI: 10.1002/CNCR.24569
Publisher: Springer Science and Business Media LLC
Date: 03-10-2005
Abstract: We sought to evaluate the biological function of the receptor tyrosine kinase EphB4 in bladder cancer. All of the nine bladder cancer cell lines examined express EphB4 and the receptor could be phosphorylated following stimulation with its cognate ligand, EphrinB2. Out of the 15 fresh bladder cancer specimens examined, 14 expressed EphB4 with a mean sevenfold higher level of expression compared to adjacent normal urothelium. EphB4 expression was regulated by several mechanisms: EPHB4 gene locus was lified in 27% tumor specimens and 33% cell lines studied inhibition of EGFR signaling downregulated EphB4 levels and forced expression of wild-type p53 reduced EphB4 expression. EphB4 knockdown using specific siRNA and antisense oligodeoxynucleotides molecules led to a profound inhibition in cell viability associated with apoptosis via activation of caspase-8 pathway and downregulation of antiapoptotic factor, bcl-xl. Furthermore, EphB4 knockdown significantly inhibited tumor cell migration and invasion. EphB4 knockdown in an in vivo murine tumor xenograft model led to a nearly 80% reduction in tumor volume associated with reduced tumor proliferation, increased apoptosis and reduced tumor microvasculature. EphB4 is thus a potential candidate as a predictor of disease outcome in bladder cancer and as target for novel therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587063
Abstract: Supplementary Figure 12: HLA-DR and NKG2D abundance on peripheral lymphocytes associate with longer progression free survival.
Publisher: Elsevier BV
Date: 12-2007
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587066
Abstract: Supplementary Figure 11: Peripheral immune cells are activated mid-treatment cycle.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532491.V1
Abstract: AbstractPurpose: In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell–inflamed gene expression profile (Tcell sub inf /sub GEP), and stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC). Patients and Methods: Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS nominal i P /i values were calculated without multiplicity adjustment (one-sided, pembrolizumab two-sided, chemotherapy). Significance was prespecified at i α /i = 0.05. Results: In KEYNOTE-052, PD-L1, TMB, and Tcell sub inf /sub GEP were significantly associated with improved outcomes stromal signature was significantly associated with worse outcomes. In KEYNOTE-045, although findings for TMB and Tcell sub inf /sub GEP with pembrolizumab were consistent with those of KEYNOTE-052, PD-L1 was not significantly associated with improved outcomes, nor was stromal signature associated with worse outcomes with pembrolizumab chemotherapy was not associated with outcomes in a consistent manner for any of the biomarkers. Hazard ratio (HR) estimates at prespecified cutoffs showed an advantage for pembrolizumab versus chemotherapy regardless of PD-L1 or TMB, with a trend toward lower HRs in the combined positive score ≥10 and the TMB ≥175 mutation/exome subgroup. For Tcell sub inf /sub GEP, PFS and OS HRs were lower in the Tcell sub inf /sub GEP-nonlow subgroup regardless of treatment. Conclusions: Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC, and potential clinical utility of these biomarkers may be context-dependent. /
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2015
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587060
Abstract: Supplementary Figure 2: Modest treatment-induced DNA methylation changes in UC tumors.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2021
DOI: 10.1007/S10637-020-01038-6
Abstract: Until the advent of T cell check point inhibitors standard second-line therapy for patients with metastatic urothelial cancer (mUC) was undefined. Histone deacetylase inhibitors (HDACi) have anti-cancer activity in a variety of tumor models including modulation of apoptosis in bladder cancer cell lines. We evaluated the efficacy and toxicity of the HDACi vorinostat in patients with mUC failing first-line platinum-based therapy either in the adjuvant/neoadjuvant setting or for recurrent/advanced disease. Vorinostat was given orally 200 mg twice daily continuously until progression or unacceptable toxicity. The primary end point was RECIST response rate (RR) a RR > 20% was deemed interesting in a 2-stage design requiring one response in the first 12 patients to proceed to 2nd stage for a total of 37 subjects. CT or MRI scan imaging occurred every 6 weeks. Fourteen patients were accrued characterized by: median age 66 years (43-84) Caucasian (79%) males (86%) and Karnofsky performance status ≥90 (50%). Accrual was terminated in the first stage as no responses were observed. Best response was stable disease (3 patients). Progression was observed in 8 patients. Two patients came off therapy prior to re-imaging and a 3rd patient died while on treatment and was not assessed for response. Median number of cycles was 2 (range 1-11). Median disease-free survival and overall survival times were 1.1 (0.8, 2.1) & 3.2 (2.1, 14.5) months, respectively. Toxicities were predominantly cytopenias and thrombocytopenic bleeding. Two pts. had grade 5 toxicity unlikely related to treatment. Two pts. had grade 4 and 6 had grade 3 toxicities observed. Two patients with stable disease remained on therapy for 6+ cycles. Vorinostat on this dose-schedule had limited efficacy and significant toxicity resulting in a unfavorable risk:benefit ratio in patients with mUC. NCT00363883.
Publisher: Wiley
Date: 08-10-2015
DOI: 10.1002/IJC.29212
Publisher: Elsevier BV
Date: 2009
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587069
Abstract: Supplementary Figure 10: Peripheral immune cell dynamics induced by combination therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587072.V1
Abstract: Supplementary Figure 1: Patient recruitment and s le collection overview.
Publisher: American Association for Cancer Research (AACR)
Date: 11-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529986.V1
Abstract: AbstractPurpose: Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of in idual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy. Experimental Design: Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test. Results: From December 2016 to January 2019, 183 s les from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline ( i P /i = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9–2.3 vs. 28.2 months i P /i 0.0001–0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS ( i P /i = 0.045). PD-L1 sup + /sup CTCs on-therapy were associated with worse OS ( i P /i 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category. Conclusions: Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1 sup + /sup CTCs, and low �4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies. /
Publisher: Oxford University Press (OUP)
Date: 10-03-2014
DOI: 10.1093/JNCI/DJU013
Publisher: Springer Science and Business Media LLC
Date: 06-2003
Publisher: Wiley
Date: 13-04-2007
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.UROLOGY.2013.08.074
Abstract: To describe 3 cases of advanced refractory penile cancer treated with targeted therapy against the epidermal growth factor receptor (EGFR). We identified 3 patients with advanced penile cancer who had disease progression after platinum chemotherapy refractory and who subsequently received EGFR-targeted therapy. Their tumor tissue was evaluated for expression of EGFR by immunohistochemistry and messenger ribonucleic acid quantitation and was also tested for the presence of human papillomavirus deoxyribonucleic acid by line hybridization. K-ras mutation was evaluated by polymerase chain reaction for 6 mutations in codon 12 and 1 mutation in codon 13. One patient responded to cetuximab and remains disease-free 42 months after presentation. One patient responded to panitumumab, then suffered relapse. One other progressed through EGFR-targeted therapy. EGFR expression by immunohistochemistry was 1-2+ in all cases, and messenger ribonucleic acid expression ranged from 4.08 to 7.33. No K-ras mutations or human papillomavirus deoxyribonucleic acid was detected. We report 3 cases in which EGFR-targeted therapy was used to treat platinum-refractory penile cancer patients. Because 2 of the 3 had clinical benefit, future prospective trials of EGFR-targeted therapy in penile cancer are warranted.
Publisher: Springer Science and Business Media LLC
Date: 2009
DOI: 10.2165/00003088-200948030-00006
Abstract: Bortezomib, an antineoplastic for the treatment of relapsed multiple myeloma and mantle cell lymphoma, undergoes metabolism through oxidative deboronation by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2C19. Omeprazole, a proton-pump inhibitor, is primarily metabolized by and demonstrates high affinity for CYP2C19. This study investigated whether coadministration of omeprazole affected the pharmacokinetics, pharmacodynamics and safety profile of bortezomib in patients with advanced cancer. The variability of bortezomib pharmacokinetics with CYP enzyme polymorphism was also investigated. This open-label, crossover, pharmacokinetic drug-drug interaction study was conducted at seven institutions in the US and Europe between January 2005 and August 2006. Patients who had advanced solid tumours, non-Hodgkin's lymphoma or multiple myeloma, were aged >/=18 years, weighed >/=50 kg and had a life expectancy of >/=3 months were eligible. Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 for two 21-day cycles, plus omeprazole 40 mg in the morning of days 6-10 and in the evening of day 8 in either cycle 1 (sequence 1) or cycle 2 (sequence 2). On day 21 of cycle 2, patients benefiting from therapy could continue to receive bortezomib for six additional cycles. Blood s les for pharmacokinetic harmacodynamic evaluation were collected prior to and at various timepoints after bortezomib administration on day 8 of cycles 1 and 2. Blood s les for pharmacogenomics were also collected. Pharmacokinetic parameters were calculated by noncompartmental analysis of plasma concentration-time data for bortezomib administration on day 8 of cycles 1 and 2, using WinNonlin version 4.0.1.a software. The pharmacodynamic profile was assessed using a whole-blood 20S proteasome inhibition assay. Twenty-seven patients (median age 64 years) were enrolled, 12 in sequence 1 and 15 in sequence 2, including eight and nine pharmacokinetic-evaluable patients, respectively. Bortezomib pharmacokinetic parameters were similar when bortezomib was administered alone or with omeprazole (maximum plasma concentration 120 vs 123 ng/mL area under the plasma concentration-time curve from 0 to 72 hours 129 vs 135 ng . h/mL). The pharmacodynamic parameters were also similar (maximum effect 85.8% vs 93.7% area under the percent inhibition-time curve over 72 hours 4052 vs 3910 % x h) the differences were not statistically significant. Pharmacogenomic analysis revealed no meaningful relationships between CYP enzyme polymorphisms and pharmacokinetic harmacodynamic parameters. Toxicities were generally similar between patients in sequence 1 and sequence 2, and between cycle 1 and cycle 2 in both treatment sequences. Among 26 evaluable patients, 13 (50%) were assessed as benefiting from bortezomib at the end of cycle 2 and continued to receive treatment. No impact on the pharmacokinetics, pharmacodynamics and safety profile of bortezomib was seen with coadministration of omeprazole. Concomitant administration of bortezomib and omeprazole is unlikely to cause clinically significant drug-drug interactions and is unlikely to have an impact on the efficacy or safety of bortezomib.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587054
Abstract: Supplementary Figure 4: Weak correlation of TE expression induction with DNA methylation change and viral mimicry activation.
Publisher: American Association for Cancer Research (AACR)
Date: 26-05-2023
DOI: 10.1158/1078-0432.23223075.V1
Abstract: Supplementary Fig 1 Analysis of Survival by Baseline Median PSA across the two studies using the study-specific median and quartiles.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587051
Abstract: Supplementary Figure 5: Overall tumor mutation burden and frequency of mutations in cancer-associated genes in UC tumors.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2014
DOI: 10.1038/PCAN.2014.37
Publisher: Society of Nuclear Medicine
Date: 19-06-2013
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587057
Abstract: Supplementary Figure 3: Copy number variation detected by SeSAMe from DNA methylation data.
Publisher: Elsevier BV
Date: 04-2015
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.C.6571947
Abstract: AbstractPurpose: On the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab [anti–programmed cell death ligand 1 (PD-L1)] together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy. Patients and Methods: We designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors. Results: Safety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8–11 months) and survival ( months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients’ plasma was associated with short survival. Conclusions: No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival. /
Publisher: Springer Science and Business Media LLC
Date: 23-03-2011
DOI: 10.1007/S10147-011-0212-8
Abstract: This study was conducted to evaluate the efficacy of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib with pegylated-IFNα (PEG-IFNα) in patients with advanced renal cell carcinoma. Progression-free survival (PFS) rate at 6 months >50% was considered promising for further evaluation. Patients with unresectable or metastatic disease, unlimited prior therapies, and adequate performance status and end-organ function were eligible. PEG-IFNα was dosed subcutaneously once weekly (initially 6 μg/kg/week, later reduced to 4 μg/kg/week) for 12 weeks. Gefitinib was given 250 mg orally once daily until progression or intolerance. Twenty-one patients were accrued. Fourteen patients had a prior nephrectomy, and twelve had prior systemic therapy. The 6-month PFS was 29% (95%CI 15-56%). Best responses by RECIST criteria: complete, partial (1, plus 3 unconfirmed) stable (Uhlman et al. Clin Cancer Res 1:913-920, 1995), and progression (Sirotnak et al. Clin Cancer Res 6:4885-4892, 2000). Response duration: complete response (35+ months) and partial response (2, 3, 3, 37 months). Median PFS and overall survival were 5.3 (95%CI 3-10.1) and 13.6 (95%CI 10.3-NA) months, respectively. Most common toxicities included myelosuppression, rash, and nausea. Although generally well tolerated, gefitinib plus PEG-IFNα did not meet the pre-specified 6-month PFS rate >50%. Further evaluation of similar regimens would require appropriate molecular selection of subjects most likely to benefit. Thus, preclinical studies to determine candidate predictive markers for this combination are warranted.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275162.V1
Abstract: Supplementary Figure 7: Representative IHC staining of additional PD and SD tumors in pre-treatment and post-treatment timepoint from additional patients.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587042
Abstract: Supplementary Figure 8: PD-L1 levels in tumor or tumor microenvironment does not associate with tumor progression or control.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-05-2015
Abstract: Cixutumumab, formerly IMC-A12, is a recombinant human monoclonal immunoglobulin G 1 antibody that targets insulin-like growth factor I receptor (IGF-IR). Cixutumumab was synergistic with castration in a hormone-sensitive prostate cancer xenograft model. Patients with new metastatic prostate cancer were randomly assigned within 30 days of initiating androgen deprivation (AD) to cixutumumab added to a luteinizing hormone–releasing hormone agonist with bicalutamide versus AD alone. With 180 patients and one-sided alpha of 0.10, there would be 90% power to detect an absolute 20% difference in undetectable prostate-specific antigen (PSA ≤ 0.2 ng/mL) rate at 28 weeks (relative risk, 1.44) this end point was previously strongly correlated with survival. Secondary end points included the proportion of patients with PSA 4.0 ng/mL, safety and tolerability, circulating tumor cell (CTC) levels, and seven plasma IGF-IR biomarkers. Fisher's exact test was used for the primary end point, and extended Mantel-Haenszel χ 2 test was used for three PSA response categories. The trial accrued 210 eligible patients (105 randomly assigned to each arm). Patient characteristics were similar in both arms. Undetectable PSA rate was 42 (40.0%) of 105 for cixutumumab plus AD and 34 (32.3%) of 105 for AD alone (relative risk, 1.24 one-sided P = .16). Lower baseline CTCs (0 v 1 to 4 v ≥ 5/7.5 mL whole blood) were associated with higher rate of PSA response (three categories P = .036) in 39 evaluable patients. IGF-IR biomarkers were not correlated with PSA outcome, and cixutumumab did not significantly change these biomarker levels. Cixutumumab plus AD did not significantly increase the undetectable PSA rate in men with new metastatic hormone-sensitive prostate cancer. CTCs at baseline may carry prognostic value.
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/290160
Abstract: Recent phase III trial data clearly demonstrate that adjuvant therapy can reduce recurrence and increase survival after prostatectomy for prostate cancer. There is great interest in being able to accurately predict who is at risk of failure to avoid treating those who may not benefit. The standard markers consisting of prostate specific antigen (PSA), Gleason score, and pathological stage are not very specific, so there is an unmet need for other markers to aid in prognostic stratification. Numerous studies have been conducted with various markers and more recently gene signatures, but it is unclear whether any of them are really useful. We conducted a comprehensive review of the literature to determine the current status of molecular markers in predicting outcome after radical prostatectomy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2011
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275156.V1
Abstract: Supplementary Figure 9: CD8 infiltration in tumor is associated with survival.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587045
Abstract: Supplementary Figure 7: Representative IHC staining of additional PD and SD tumors in pre-treatment and post-treatment timepoint from additional patients.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1053/J.SEMINONCOL.2012.08.009
Abstract: Small cell bladder cancer (SCBC) is a rare and aggressive form of bladder cancer. It exhibits similar biological behavior to small cell lung carcinoma. Untreated, it is associated with a very poor prognosis. Appropriate oncologic surgery remains the mainstay of treatment of this disease but is not curative alone in the majority of the cases. Adding systemic therapy to the treatment regimen has been shown to improve survival. The most common chemotherapy regimens used in published series include a platinum complex plus etoposide, although doxorubicin-based regimens and standard urothelial cancer regimens also have been associated with response. Despite robust chemotherapy responses, metastatic disease is associated with relapse and a median overall survival of 18 months or less. Better understanding of the molecular alterations driving SCBC may facilitate the development of new therapeutic strategies and improved outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587048
Abstract: Supplementary Figure 6: Gene Set Enrichment Analysis reveals immune-related pathways discriminate PD and SD tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2005
DOI: 10.1158/1535-7163.MCT-04-0288
Abstract: We discovered a series of salicylhydrazide class of compounds with remarkable anticancer activity against a panel of hormone receptor–positive and -negative cell lines. In the present study, we evaluated the in vitro activity of SC21 and SC23 against a range of human tumor cell types and the in vivo efficacy of compound SC21 in a PC3 human prostate cancer xenograft model in mice. We also determined the effects of SC21 on cell cycle regulation and apoptosis. Our in vitro results show that salicylhydrazides are highly potent compounds effective in both hormone receptor–positive and -negative cancer cells. SC21 induced apoptosis and blocked the cell cycle in G0/G1 or S phase, depending on the cell lines used and irrespective of p53, p21, pRb, and p16 status. SC21 effectively reduced the tumor growth in mice without apparent toxicity. Although the mechanism of action of SC21 is not completely elucidated, the effect on cell cycle, the induction of apoptosis and the activity against a panel of tumor cell lines of different origins prompted us to carry out an in-depth preclinical evaluation of SC21.
Publisher: SAGE Publications
Date: 18-08-2009
Abstract: The major goals of the Southwest oncology genitourinary (SWOG-GU) committee in the area of advanced prostate cancer are to improve the survival and quality of life (QOL) of patients with advanced prostate cancer. SWOG trials have examined the role of combined androgen blockade, intermittent androgen deprivation, and the early application of chemotherapy in castration-naïve disease. In addition, they have contributed to advancing the current chemotherapy standard of docetaxel plus prednisone, and ongoing trials seek to improve upon that standard. Finally, surrogate endpoints have been identified and markers of treatment response or resistance with novel technology are under active investigation. This review highlights findings from recent SWOG clinical trials for advanced prostate cancer, emphasizing the clinical impact and future applications of the data.
Publisher: American Association for Cancer Research (AACR)
Date: 26-05-2023
DOI: 10.1158/1078-0432.23223072
Abstract: Supplementary Fig 2. Analysis of survival by baseline median alkaline phosphatase across the two studies using the study-specific median.
Publisher: American Association for Cancer Research (AACR)
Date: 26-05-2023
DOI: 10.1158/1078-0432.23223075
Abstract: Supplementary Fig 1 Analysis of Survival by Baseline Median PSA across the two studies using the study-specific median and quartiles.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275174.V1
Abstract: Supplementary Figure 3: Copy number variation detected by SeSAMe from DNA methylation data.
Publisher: Research Square Platform LLC
Date: 11-05-2022
DOI: 10.21203/RS.3.RS-1576467/V1
Abstract: HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2 -mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (NCT01953926). The primary objective of the BTC cohort was objective response rate (ORR). Among 25 treatment-refractory patients (11 cholangiocarcinoma, 10 gallbladder, 4 ullary cancers), the ORR was 16%. The most common HER2 mutations were S310F (n = 11 48%) and V777L (n = 4 17%). Outcomes appeared worse for ullary tumours or those with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of lified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations were identified at progression in one responder. Neratinib demonstrated anti-tumour activity in patients with refractory BTC harbouring HER2 mutations. Future studies of rational combinations are warranted.
Publisher: Massachusetts Medical Society
Date: 04-04-2013
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275168.V1
Abstract: Supplementary Figure 5: Overall tumor mutation burden and frequency of mutations in cancer-associated genes in UC tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275180.V1
Abstract: Supplementary Figure 12: HLA-DR and NKG2D abundance on peripheral lymphocytes associate with longer progression free survival.
Publisher: Springer Science and Business Media LLC
Date: 06-02-2023
DOI: 10.1038/S41467-023-36399-Y
Abstract: HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2 -mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (ClinicalTrials.gov: NCT01953926). The primary objective of the BTC cohort, which is now complete, is first objective response rate (ORR) to neratinib 240 mg orally daily. Secondary objectives include confirmed ORR, clinical benefit rate, progression-free survival, duration of response, overall survival, safety and tolerability. Genomic analyses were exploratory. Among 25 treatment-refractory patients (11 cholangiocarcinoma, 10 gallbladder, 4 ullary cancers), the ORR is 16% (95% CI 4.5–36.1%). The most common HER2 mutations are S310F (n = 11 48%) and V777L (n = 4 17%). Outcomes appear worse for ullary tumours or those with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of lified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations are identified at progression in one responder. Diarrhoea is the most common adverse event, with any-grade diarrhoea in 14 patients (56%). Although neratinib demonstrates antitumour activity in patients with refractory BTC harbouring HER2 mutations, the primary endpoint was not met and combinations may be explored.
Publisher: American Association for Cancer Research (AACR)
Date: 26-05-2023
DOI: 10.1158/1078-0432.23223078
Abstract: Supplementary Data for Antonarakis et al
Publisher: Springer Science and Business Media LLC
Date: 17-05-2007
DOI: 10.1007/S00432-007-0200-6
Abstract: Oblimersen is an 18-base oligodeoxynucleotide encoding antisense to the gene for bcl-2, an anti-apoptotic protein that is upregulated in renal and other cancers. This study was designed to evaluate the combination of oblimersen with alpha-Interferon in advanced renal cancer. Trial endpoints were antitumor efficacy and toxicity, pharmacokinetics, and evidence of apoptosis in peripheral blood mononuclear cells. Patients with measurable advanced renal cancer and 0-1 prior therapy were eligible. Treatment consisted of oblimersen, 7 mg/kg/day, as a continuous intravenous infusion 7 days of every 14 day cycle, plus alpha-IFN, 5 million units/m(2) subcutaneously, days 4 and 6 of the first oblimersen infusion, then thrice weekly. Blood for laboratory correlates was collected before treatment, during oblimersen, and during therapy with both agents. Twenty-three patients were enrolled, five of whom had prior systemic therapy (three with prior high-dose interleukin-2). The median number of treatment cycles was 4 (range 1-12). One patient had a partial response lasting 2.5 months. The Grade 3-4 toxicities were fatigue, fever, myelosuppression, hepatic enzyme and metabolic abnormalities. Laboratory analyses of CD3+ lymphocyte apoptotic markers demonstrated no change between pre-treatment and on-treatment levels of bcl-2 or Annexin/PI positivity by flow cytometry. Mean oblimersen steady-state plasma concentration and clearance was 2.3 +/- 0.9 microg/ml and 0.15 +/- 0.07 l/h/kg, respectively. Oblimersen given in this dose and schedule with alpha-IFN does not appear sufficiently active to warrant further study in advanced renal cancer. Combinations with newer targeted agents may show greater promise.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587039
Abstract: Supplementary Figure 9: CD8 infiltration in tumor is associated with survival.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587036
Abstract: Supplementary TablesSupplementary Table 1: Patient and tumor s le informationSupplementary Table 2: Tumor mutation burdenSupplementary Table 3: Unfiltered whole exome sequencing mutation analysisSupplementary Table 4: Filtered whole exome sequencing mutation analysisSupplementary Table 5: Immunohistochemistry scores of tumorsSupplementary Table 6: FACS panel for PBMC analysisSupplementary Table 7: Geometric mean fluorescence intensity (GMFI) from PBMC FACSSupplementary Table 8: Representativeness of Study Participants
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.UROLONC.2014.10.009
Abstract: The approval of sipuleucel-T in conjunction with data from other immunotherapeutic trials for prostate cancer and other solid tumors demonstrates the potential of harnessing the patients' immune system for long-term survival. Thus, a range of therapeutic approaches are under evaluation. This review describes the rationale for immunotherapy for prostate cancer, summarizes the approaches under evaluation, and discusses sequencing options for immunotherapy in the current treatment paradigm. References for this review were identified through searches of PubMed with the search terms "prostate cancer," "immune system," "vaccine," "immunotherapy," and "T cells." Articles were also identified through searches of the authors' own files. The final reference list was generated based on originality and relevance. The immune system can recognize and respond to prostate tumor antigens, effected through tumor-associated antigens and tumor infiltration of immune effector cells. However, evidence also suggests that prostate tumors are adept at escaping immunological recognition, thus hypothesizing multiple therapeutic strategies. Therapeutic approaches could include vaccination and modulation of T-cell function via the blockade of checkpoint receptors such as cytotoxic T-lymphocyte antigen-4 and programmed death 1. In phase III trials, sipuleucel-T improved overall survival for an M1 patient population with castration-resistant prostate cancer and ipilimumab also did so when given after radiotherapy in a subset of better risk patients. In randomized phase II trials, prostate-specific antigen-TRICOM improved overall survival and tasquinimod improved progression-free survival. Although immunotherapy has the potential to affect advanced prostate cancer, additional research is needed to (1) identify predictive or surrogate markers of activity, (2) understand which agents are clinically effective alone or in combination with other therapies, and (3) define the optimal timing for an immunotherapy to achieve maximal benefit.
Publisher: Wiley
Date: 12-1995
DOI: 10.1111/J.1445-5994.1995.TB02851.X
Abstract: The hexaploid spring wheat cultivar, Carberry, was registered in Canada in 2009, and has since been grown over an extensive area on the Canadian Prairies. Carberry has maintained a very high level of leaf rust (
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-04-2014
Abstract: Circulating tumor cell (CTC) enumeration has not been prospectively validated in standard first-line docetaxel treatment for metastatic castration-resistant prostate cancer. We assessed the prognostic value of CTCs for overall survival (OS) and disease response in S0421, a phase III trial of docetaxel plus prednisone with or without atrasentan. CTCs were enumerated at baseline (day 0) and before cycle two (day 21) using CellSearch. Baseline counts and changes in counts from day 0 to 21 were evaluated for association with OS, prostate-specific antigen (PSA), and RECIST response using Cox regression as well as receiver operator characteristic (ROC) curves, integrated discrimination improvement (IDI) analysis, and regression trees. Median day-0 CTC count was five cells per 7.5 mL, and CTCs versus ≥ five per 7.5 mL were significantly associated with baseline PSA, bone pain, liver disease, hemoglobin, alkaline phosphatase, and subsequent PSA and RECIST response. Median OS was 26 months for five versus 13 months for ≥ five CTCs per 7.5 mL at day 0 (hazard ratio [HR], 2.74 [adjusting for covariates]). ROC curves had higher areas under the curve for day-0 CTCs than for PSA, and IDI analysis showed that adding day-0 CTCs to baseline PSA and other covariates increased predictive accuracy for survival by 8% to 10%. Regression trees yielded new prognostic subgroups, and rising CTC count from day 0 to 21 was associated with shorter OS (HR, 2.55). These data validate the prognostic utility of CTC enumeration in a large docetaxel-based prospective cohort. Baseline CTC counts were prognostic, and rising CTCs at 3 weeks heralded significantly worse OS, potentially serving as an early metric to help redirect and optimize therapy in this clinical setting.
Publisher: Oxford University Press (OUP)
Date: 04-10-2006
DOI: 10.1093/JNCI/DJJ378
Abstract: The risk of metastatic progression for prostate cancer patients who undergo radical prostatectomy is best estimated presently based on prostate-specific antigen (PSA) doubling time (PSADT). However, additional markers of risk are needed to identify patients who may benefit from aggressive salvage treatment. A decrease in zinc-alpha2-glycoprotein (AZGP1) mRNA levels in malignant prostate epithelium was previously shown to predict biochemical recurrence, as defined by rising levels of serum PSA after radical prostatectomy. We assessed the reliability with which AZPG1 expression could predict clinical recurrence and metastatic progression. Using immunohistochemical methods, we analyzed AZPG1 expression in malignant prostate epithelium in prostatectomy specimens from 228 prostate cancer patients. Low (i.e., absent or weak) AZGP1 expression was associated with clinical recurrence (defined as confirmed localized recurrence, metastasis, or death from prostate cancer hazard ratio [HR] = 4.8, 95% confidence interval [CI] = 2.2 to 10.7, P<.001) and with bony metastases or death from prostate cancer (HR = 8.0, 95% CI = 2.6 to 24.3, P<.001). Among the 17 patients in the cohort in whom clinical recurrence was associated with short PSADT, absent or weak AZGP1 expression was observed in 13 patients. If these preliminary findings are validated in independent cohorts, the measurement of AZGP1 levels in radical prostatectomy specimens may permit an accurate and timely assessment of risk of metastatic progression after radical prostatectomy.
Publisher: Springer Science and Business Media LLC
Date: 05-03-2014
Publisher: Wiley
Date: 11-1998
DOI: 10.1111/J.1479-828X.1998.TB03112.X
Abstract: The aim of this review was to determine the factors that impact upon oestradiol levels in patients receiving oestradiol implants and to assess the relationship between symptom scores and oestradiol levels. In addition we sought to determine the incidence of tachyphylaxis (menopausal symptoms in spite of high oestradiol levels) among our patients, and to assess the degree of menstrual cycle control in the nonhysterectomized women receiving implant treatment. We undertook an audit of the medical records of 118 women who received 673 oestradiol implants (50 or 100 mg) over an 8-year period in the menopause clinics at Royal North Shore Hospital. Data on patient age, clinical diagnosis, symptom score, previous or subsequent hysterectomy, oestradiol implant dosage (50 mg or 100 mg), number of doses, oestradiol levels and concurrent testosterone implant insertion were recorded. We found that implant dosage (p<0.001) and implant number (p<0.001) were the factors that significantly impact upon oestradiol levels. Concomitant testosterone implant usage (p=0.74), patient age (p=0.14) and hysterectomy (p=0.57) did not have a statistically significant effect upon oestradiol levels. The incidence of tachyphylaxis was 1.7% (2 patients). There was no relationship between oestradiol levels and symptom scores (p=0.69). Oestradiol implant treatment, when administered on the basis of return of symptoms, without a strict target oestradiol level, results in a steady increase in baseline oestradiol levels. The dosage used and the number of implants received are important factors influencing oestradiol levels. The incidence of tachyphylaxis is low when patients are counselled regarding the lack of agreement between symptom scores and oestradiol levels.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2013
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.CRITREVONC.2010.03.006
Abstract: Sorafenib was the first multikinase inhibitor to be approved for use in renal cell cancer (RCC) in the US (2005) and in Europe (2006). In the Treatment Approaches in Renal Cell Cancer Global Evaluation Trial (TARGET), sorafenib showed a significant progression-free survival advantage over placebo in patients with advanced RCC. Incidence rates of adverse events were significantly higher with sorafenib than with placebo. Management of adverse events is an essential component of care to prevent negative impact on patient quality of life and dose modification of sorafenib therapy. This report, based on an expert panel discussion held in February 2009, presents recommendations for the management of skin rash, hand-foot skin reaction, diarrhea, and hypertension, and strategies to help lessen the frequency and severity of these events. In addition, general recommendations for dose modifications are discussed. The goal of these management recommendations is to optimize sorafenib therapy for advanced RCC.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529986
Abstract: AbstractPurpose: Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of in idual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy. Experimental Design: Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test. Results: From December 2016 to January 2019, 183 s les from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline ( i P /i = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9–2.3 vs. 28.2 months i P /i 0.0001–0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS ( i P /i = 0.045). PD-L1 sup + /sup CTCs on-therapy were associated with worse OS ( i P /i 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category. Conclusions: Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1 sup + /sup CTCs, and low �4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies. /
Publisher: American Association for Cancer Research (AACR)
Date: 26-05-2023
DOI: 10.1158/1078-0432.23223069.V1
Abstract: Supplementary Fig 3 In vivo cellular and humoral responses through 52 weeks are illustrated here.
Publisher: Informa UK Limited
Date: 06-2010
DOI: 10.1586/ERA.10.68
Abstract: The incidence of renal cell carcinoma is increasing globally. Targeted agents offer treatment options that were not available less than a decade ago. However, it is important to carefully select therapy for each in idual patient, weighing both the drug efficacy and tolerability profile and patient-related factors, such as adherence, age and comorbidities. Based on our clinical experience in treating patients with renal cell carcinoma, this article offers our opinions on factors that characterize patients for whom sorafenib may serve as a viable first-line therapeutic option.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587051.V1
Abstract: Supplementary Figure 5: Overall tumor mutation burden and frequency of mutations in cancer-associated genes in UC tumors.
Publisher: Springer Science and Business Media LLC
Date: 11-1997
DOI: 10.2165/00003088-199733050-00003
Abstract: Many clinicians are confronted by the use of illicit drugs on a daily basis. The unsanctioned use of opioids, psychostimulants, benzodiazepines, alcohol and nicotine is a major cause of morbidity and mortality. Multiple factors have inhibited the scientific study of these agents including prohibition, public denial and lack of commercial interests. In dealing with problems related to these drugs, clinicians need a scientific understanding of their pharmacology, quantifiable effects and potential adverse effects. Illicit drug users select drugs with particular pharmacokinetic parameters and pharmacodynamic properties. Generally, rapid absorption, rapid entry into the central nervous system, high bioavailability, short half-life, small volume of distribution and high free drug clearance are pharmacokinetic characteristics which predict a high potential for harmful use because these factors increase positive reinforcement. Drug users adapt the method and route of drug administration to optimise the delivery of the drug to the brain while attempting to maximise the bioavailability of the drug. Inhalation and smoking are the routes of administration which allow the most rapid delivery of drug to the brain, while intravenous injection maximises the bioavailability of an administered drug. Each route of administration results in attendant complications related to mucosal damage, carcinogenesis and risk of infection. Negative reinforcement or withdrawal is a major drive to recurrent use. Many illicit drugs have pharmacological features that promote dependence, including long half-life, low free drug clearance and sufficient drug exposure to allow development of tolerance. The preventive or reductive pharmacotherapeutics of illicit drug use makes use of several subsets of agents: those which act on the same receptor or system as the illicit drug (such as methadone), those which produce an adverse reaction on consumption of the illicit drug (such as disulfiram) and those which symptomatically attenuate illicit drug withdrawal symptoms (such as clonidine). Many new agents are being trialled as potential preventive or reductive agents. It is important to consider pharmacotherapy as only one potential part of the treatment of illicit drug users. The complications of illicit drug use present many therapeutic challenges. As with all patients consuming multiple drugs, illicit drug users are prone to developing drug interactions. The most common interactions seen in practice are pharmacodynamic in nature, most often due to the additive effects of different drugs on the central nervous system. However, alcohol, cocaine, disulfiram, methadone and tricyclic antidepressants may be involved in important pharmacokinetic interactions. Of these the effect of long term alcohol consumption in increasing the hepatotoxicity of paracetamol and of cytochrome P450 3A microsomal enzyme stimulating drugs in diminishing the efficacy of methadone are the most commonly encountered.
Publisher: Wiley
Date: 10-05-2006
DOI: 10.1002/CNCR.21925
Abstract: To the authors' knowledge, no satisfactory therapy is available for patients with refractory germ cell neoplasms. The activity and safety of arsenic trioxide in refractory germ cell tumors was assessed. Twenty patients were treated with arsenic trioxide at a dose of 0.25 mg/kg/day and administered intravenously over 1 to 2 hours on Days 1-5 and repeated every 28 days. There were no complete or partial responses. The median progression-free survival was 1 month and the median overall survival was 2 months. Three patients died as a result of adverse events believed to be possibly related to treatment: ventricular arrhythmia, adult respiratory distress syndrome, and pneumonitis. In the current study, arsenic trioxide in the dose regimen and schedule employed was found to have no activity in men with refractory germ cell malignancies. Treatment was associated with severe toxicity. Dismal overall survival reflects the poor outcome in this patient group and highlights the acute need for new agents with activity in refractory germ cell neoplasms.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275177
Abstract: Supplementary Figure 2: Modest treatment-induced DNA methylation changes in UC tumors.
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1016/S0959-8049(03)00300-9
Abstract: The optimal management of bladder cancer depends on the accurate assessment of the tumour's biological potential. Advances in molecular biology and cytogenetics have spurred intense research in identifying and characterising prognostic markers for patients with transitional cell carcinoma (TCC) of the bladder. The molecular changes that occur can be categorised into (1) chromosomal alterations leading to carcinogenesis, (2) cellular proliferation as a result of dysregulation of cell cycle control, and (3) growth control processes such as angiogenesis leading to metastasis. The accumulation of these changes ultimately determines a tumour's clinical behaviour and response to therapy. As the understanding of bladder cancer evolves, novel molecular markers for prognostication will make their way from the research laboratory to the clinical setting with the promise to improve patient care and outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275174
Abstract: Supplementary Figure 3: Copy number variation detected by SeSAMe from DNA methylation data.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2009
Abstract: Patients with advanced papillary renal cell cancer (pRCC) have poor survival after systemic therapy the reported median survival time is 7 to 17 months. In this trial, we evaluated the efficacy of erlotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in patients with advanced pRCC, a tumor type associated with wild-type von Hippel Lindau gene. Patients with histologically confirmed, advanced, or metastatic pRCC were treated with erlotinib 150 mg orally once daily. A RECIST (Response Evaluation Criteria in Solid Tumors) response rate (RR) of ≥ 20% was considered a promising outcome. Secondary end points included overall survival and 6-month probability of treatment failure. Of 52 patients registered, 45 were evaluable. The overall RR was 11% (five of 45 patients 95% CI, 3% to 24%), and the disease control rate was 64% (ie five partial response and 24 stable disease). The median overall survival time was 27 months (95% CI, 13 to 36 months). Probability of freedom from treatment failure at 6 months was 29% (95% CI, 17% to 42%). There was one grade 5 adverse event (AE) of pneumonitis, one grade 4 thrombosis, and nine other grade 3 AEs. Although the RECIST RR of 11% did not exceed prespecified estimates for additional study, single-agent erlotinib yielded disease control and survival outcomes of interest with an expected toxicity profile. The design of future trials of the EGFR axis in pRCC should be based on preclinical or molecular data that define appropriate patient subgroups, new drug combinations, or potentially more active alternative schedules.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2005
DOI: 10.1097/01.JU.0000176799.63184.99
Abstract: Symptomatic, hormone refractory prostate cancer (HRCAP) is a major cause of morbidity with a median survival of less than 12 months and a 2-year survival of only up to 10% in most series. Mitoxantrone has been approved by the Food and Drug Administration for HRCAP. Preliminary data suggest that DPPE (N,N-diethyl-2-[4-(phenylmethyl) phenoxy]-ethanamine) or tesmilifene modulates cytotoxics to enhance the anticancer effect. In this phase II trial we assessed whether there is sufficient evidence of enhanced efficacy of DPPE and mitoxantrone to lead to a phase III clinical trial. A total of 29 patients with a median age of 73 years, of whom 10% were older than 80 years, with progressive HRCAP received 5.3 mg/kg DPPE intravenously every 3 weeks, 12 mg/m mitoxantrone intravenously every weeks and 5 mg prednisone orally twice daily. All patients had pain at presentation, while 97% had bone metastases, 10% had liver metastases and 17% had lung metastases. Median prostate specific antigen (PSA) was 210 ng/ml (IQR 77 to 430). Of the patients 75% had some pain improvement, 66% had decreased analgesia, 59% had a PSA decrease of 50% or greater and 45% had a PSA decrease of 75% or greater. Actual (not actuarial) 2-year survival was 21%. Despite major limitations of historical comparison the PSA decrease and decreased symptoms with DPPE-mitoxantrone-prednisone compare favorably to those of mitoxantrone-prednisone and docetaxel-estramustine in the literature. The 2-year survival rate of 21% mandates further assessment. This will be tested in a phase III Southwest Oncology Group trial.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275171
Abstract: Supplementary Figure 4: Weak correlation of TE expression induction with DNA methylation change and viral mimicry activation.
Publisher: Elsevier BV
Date: 03-2011
Publisher: Elsevier BV
Date: 06-2002
DOI: 10.1016/S0960-7404(02)00007-5
Abstract: Invasive bladder cancer has a predilection for early, occult metastasis. Despite effective local control from radiotherapy or cystectomy, approximately 50% of the patients with clinically localized, invasive bladder cancer ultimately die of their disease. Over the past 25 years, systemic chemotherapy has been combined with definitive local treatment in an attempt to improve cure rates. Non-randomized phase I-II trials have shown promising results, with significant tumor down-staging. However, many randomized trials have failed to show a statistically significant survival benefit from adjunctive systemic chemotherapy. Recently, two intergroup randomized trials have shown a survival benefit from neoadjuvant combination chemotherapy, although the differences between the arms have not been dramatic. Adjuvant chemotherapy trials to date have failed to show statistically improved survival, although most published studies have been methodologically flawed. This review analyzes the results of published data and constructs a practical paradigm for patient management.
Publisher: Elsevier BV
Date: 10-2010
Publisher: Springer Science and Business Media LLC
Date: 29-05-2020
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626876
Abstract: Supplementary Fig 3 In vivo cellular and humoral responses through 52 weeks are illustrated here.
Publisher: Springer Science and Business Media LLC
Date: 06-1995
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.UROLONC.2013.08.007
Abstract: The oncological basis behind the observation that females experience worse outcomes following radical cystectomy for urothelial carcinoma of the bladder (UCB) is unclear. This study was aimed at examining the sole effect of gender on postcystectomy UCB outcomes and identifying potential factors that may explain the poor prognosis in females using a balanced case-control approach. A review of 2,567 patients with UCB who underwent radical cystectomy identified 414 females ("cases") who were matched 1:1 for demographic, tumor, and treatment characteristics with 414 male counterparts ("controls"). Cases were also compared with an independent male UCB cohort (n = 1,166). Differences between females vs. matched control and independent male patients with UCB were analyzed. Recurrence-free survival, cancer-specific survival, and overall survival were compared by univariable and multivariable Cox regression models. Median follow-up for cases, controls, and independent control cohort was 12.2, 8.6, and 13.5 years, respectively. Females were matched to male controls for tumor and nodal stages (P = 1.00), lymphovascular invasion and surgical margin status, age, prior intravesical treatment, and neoadjuvant and adjuvant chemotherapy administration (P = 0.61-1.00). Cases were also balanced with controls for grade, p53 status, nodal yield, American Society of Anesthesiologists score, presence of hydronephrosis, and times to diagnosis and cystectomy (P ≥ 0.14). When thus matched, outcomes between females and males were not different (P ≥ 0.34). However, when compared with an independent unmatched male control cohort, females had significantly poorer outcomes (P ≤ 0.006). In this comparison, females presented with higher tumor (P<0.001) and nodal (P = 0.049) stages and a lesser proportion received precystectomy intravesical therapy (P = 0.032). Females have similar UCB outcomes to males when matched for demographic, clinicopathologic, and management characteristics. However, they present with more advanced tumors, thus explaining the observation of poor outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626879
Abstract: Supplementary Fig 2. Analysis of survival by baseline median alkaline phosphatase across the two studies using the study-specific median.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2011
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-04-2006
Abstract: Vascular endothelial growth factor antisense (VEGF-AS) is an antisense oligonucleotide that targets VEGF, inhibiting angiogenesis and tumor cell proliferation. This study established the safety, biologic effects, and pharmacokinetics of VEGF-AS in 51 patients with advanced malignancies. VEGF-AS was administered as a 2-hour infusion daily for 5 consecutive days for only one cycle on the first four dose levels, and then administered daily for 5 days every other week for up to 4 months on subsequent levels. Pharmacokinetics, tumor response, and the effect on plasma VEGF levels were determined. The maximum-tolerated dose was 200 mg/m 2 . Dose-limiting toxicities included grade 4 fever, and pulmonary embolism in one patient each at 250 mg/m 2 . Mild anemia, fever, fatigue, and gastrointestinal complaints were the most common adverse events. VEGF-AS t 1/2β (beta-phase terminal half-life of drug concentration) was 2.25 hours (range, 1.97 to 2.95 hours). Mean plasma VEGF-A (P = .002) and VEGF-C (P = .01) levels decreased 24 hours postinfusion, with a trend towards greater decreases at higher dose levels. At the maximum-tolerated dose, five of six patients demonstrated reductions in plasma VEGF. Clinical responses included complete remission in one patient with AIDS-Kaposi's sarcoma, a mixed but dramatic response in one patient with cutaneous T-cell lymphoma, and prolongation of progression-free survival compared with that obtained on the immediate prior regimen in six patients (12%) with renal cell, bronchoalveolar, small cell lung, thyroid, and ovarian carcinomas, and chondrosarcoma, respectively. VEGF-AS was well tolerated, with biologic effects and preliminary evidence of clinical efficacy.
Publisher: Wiley
Date: 24-03-2005
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275177.V1
Abstract: Supplementary Figure 2: Modest treatment-induced DNA methylation changes in UC tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275189
Abstract: Supplementary Figure 1: Patient recruitment and s le collection overview.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275183
Abstract: Supplementary Figure 11: Peripheral immune cells are activated mid-treatment cycle.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275186
Abstract: Supplementary Figure 10: Peripheral immune cell dynamics induced by combination therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275180
Abstract: Supplementary Figure 12: HLA-DR and NKG2D abundance on peripheral lymphocytes associate with longer progression free survival.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587042.V1
Abstract: Supplementary Figure 8: PD-L1 levels in tumor or tumor microenvironment does not associate with tumor progression or control.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275183.V1
Abstract: Supplementary Figure 11: Peripheral immune cells are activated mid-treatment cycle.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587063.V1
Abstract: Supplementary Figure 12: HLA-DR and NKG2D abundance on peripheral lymphocytes associate with longer progression free survival.
Publisher: Mary Ann Liebert Inc
Date: 06-2015
Publisher: American Association for Cancer Research (AACR)
Date: 03-2006
DOI: 10.1158/1078-0432.CCR-05-2074
Abstract: Background: BMS-275291 is a selective matrix metalloproteinase inhibitor (MMPI) that does not inhibit sheddases implicated in the dose-limiting arthritis of older MMPIs. We conducted a randomized phase II trial of two doses of BMS-275291 (1,200 versus 2,400 mg) in hormone-refractory prostate cancer (HRPC) patients with bone metastases to probe for a dose-response relationship and to assess differential toxicities. Serial serum and urine specimens were collected to assess for markers of bone metabolism. Methods: The primary end point was 4-month progression-free survival (PFS). Eligibility criteria included documentation of androgen-independent disease (including anti-androgen withdrawal), skeletal metastasis, adequate end-organ function and performance status, and no more than one prior chemotherapy regimen. Patients were randomized to 1,200 mg orally once daily (arm A) or 1,200 mg orally twice daily (arm B). Response was assessed every 56 days. Results: Eighty patients were enrolled: 39 in arm A and 41 in arm B. There were no responders by prostate-specific antigen or measurable disease to treatment. Stable disease was noted at 8 weeks in 39% of patients in arm A and in 17% of patients in arm B. Progression of disease at 8 weeks was seen in 61% of patients in arm A versus 83% of patients in arm B. Median survival time was 21.6 months (95% confidence interval, 17.5 not reached), whereas median PFS time was 1.8 months (95% confidence interval 1.74 2) for all patients. Patients in arm A had a median survival time that was not reached, whereas patients on arm B has a median survival time of 21 months (P = 0.2). PFS at 4 months favored arm A: 22% versus 10% (log-rank, P = 0.008). Grade 3 toxicities occurred in 5 (13%) patients in arm A and in 9 (22%) patients in arm B. Grade 4 toxicities were uncommon (only 4% of patients): one each of thrombosis, fatigue, and motor neuropathy was seen in the arm B. Bone marker studies showed that baseline serum levels of N-telopeptide, osteocalcin, procollagen I NH2-terminal propeptide, and PICP had prognostic significance for PFS and/or overall survival. Conclusions: Regardless of dose schedule, BMS-275291 was well tolerated in HRPC patients and had no dose-limiting arthritis. Toxicities differed modestly according to the dose schedule employed. As overall survival and PFS favored the once daily schedule, this dose schedule is recommended for future studies. Baseline markers of bone metabolism may have prognostic value in HRPC patients with bone metastases.
Publisher: Elsevier BV
Date: 10-2012
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.EJCA.2004.12.035
Abstract: Molecular markers have the potential to serve not only as prognostic factors but may be targets for new therapeutic strategies and predictors of response in a range of cancers. Prostate cancer development and progression is predicated on a series of genetic and epigenetic events within the prostate cell and its milieu. Within this review, we identify candidate molecules involved in erse processes such as cell proliferation, death and apoptosis, signal transduction, androgen receptor (AR) signalling, cellular adhesion and angiogenesis that are linked to outcome in prostate cancer. Current markers with potential prognostic value include p53, Bcl-2, p16INK4A, p27Kip1, c-Myc, AR, E-cadherin and vascular endothelial growth factor. Evolving technology permits the identification of an increasing number of molecular markers with prognosis and predictive potential. We also review the use of gene microarray analysis in gene discovery as a means of identifying and cosegregating novel markers of prostate cancer outcome. By integrating selected markers into prospective clinical trials, there is potential for us to provide specific targeted therapy tailored for an increasing number of patients.
Publisher: Wiley
Date: 20-08-2003
DOI: 10.1002/CNCR.11569
Abstract: The current TNM classification for bladder carcinoma stratifies extravesical extension into microscopic (pT3a) and macroscopic (pT3b) tumor involvement. The authors evaluated the outcomes of patients with pT3a and pT3b disease after radical cystectomy. Patients (n = 129) with transitional cell carcinoma of the bladder treated with radical cystectomy alone demonstrated pathologic extravesical tumor extension: 37 (29%) had pT3a disease and 92 (71%) had pT3b disease. No patient received any adjuvant therapy. With a median follow-up of 13.6 years, the presence of lymph node involvement, margin positivity, local (pelvic) and distant disease recurrence, and clinical outcomes were determined. Of the 129 patients, 43 (33%) had lymph node tumor involvement: 13 of 37 patients with pT3a disease (35%) and 30 of 92 patients with pT3b disease (33%). The 10-year recurrence-free and overall survival for the entire group was 54% and 20%, respectively. No statistical difference between pT3a and pT3b disease was observed with regard to recurrence-free (P = 0.54) and overall (P = 0.66) survival. Lymph node involvement was predictive of a significantly worse 10-year recurrence-free survival (32%) compared with lymph node-negative disease (60% P = 0.003). Local disease recurrence was reported to occur in 12 patients (9%), whereas 37 patients (29%) were reported to develop distant metastases. Among those who had disease recurrence, the type of disease recurrence (local or distant) was not found to be associated with tumor stage (pT3a vs, pT3b, P = 0.47). This cohort of surgically managed patients provided insight into the long-term natural history of pathologically confirmed extravesical bladder carcinoma after radical cystectomy. There was no important difference in the incidence of lymph node involvement, survival rates, and disease recurrence rates between patients with microscopic and macroscopic extravesical extension. Adjuvant protocols should be undertaken for these high-risk patients to further improve on these clinical outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 26-01-2021
DOI: 10.1158/1078-0432.CCR-20-3587
Abstract: In metastatic castrate-sensitive prostate cancer (mCSPC), combined androgen axis inhibition is a standard of care. Noninvasive biomarkers that guide initial therapy decisions are needed. We hypothesized that CellSearch circulating tumor cell (CTC) count, an FDA-cleared assay in metastatic castrate-resistant prostate cancer (mCRPC), is a relevant biomarker in mCSPC. SWOG S1216 is a phase III prospective randomized trial of androgen deprivation therapy (ADT) combined with orteronel or bicalutamide for mCSPC. CellSearch CTC count was measured at registration (baseline). Prespecified CTC cut-off points of 0, 1–4, and ≥5 were correlated with baseline patient characteristics and, in a stratified subs le, were also correlated with two prespecified trial secondary endpoints: 7-month PSA ≤0.2 ng/mL versus 0.2–4.0 versus & .0 (intermediate endpoint for overall survival) and progression-free survival (PFS) ≤ versus & years. A total of 523 patients submitted baseline s les, and CTCs were detected (median 3) in 33%. Adjusting for two trial stratification factors (disease burden and timing of ADT initiation), men with undetectable CTCs had nearly nine times the odds of attaining 7-month PSA ≤ 0.2 versus & 4.0 [OR 8.8, 95% confidence interval (CI), 2.7–28.6, P & 0.001, N = 264] and four times the odds of achieving & 2 years PFS (OR 4.0, 95% CI, 1.9–8.5, P & 0.001, N = 336) compared with men with baseline CTCs ≥5. Baseline CTC count in mCSPC is highly prognostic of 7-month PSA and 2-year PFS after adjusting for disease burden and discriminates men who are likely to experience poor survival outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587036.V1
Abstract: Supplementary TablesSupplementary Table 1: Patient and tumor s le informationSupplementary Table 2: Tumor mutation burdenSupplementary Table 3: Unfiltered whole exome sequencing mutation analysisSupplementary Table 4: Filtered whole exome sequencing mutation analysisSupplementary Table 5: Immunohistochemistry scores of tumorsSupplementary Table 6: FACS panel for PBMC analysisSupplementary Table 7: Geometric mean fluorescence intensity (GMFI) from PBMC FACSSupplementary Table 8: Representativeness of Study Participants
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587057.V1
Abstract: Supplementary Figure 3: Copy number variation detected by SeSAMe from DNA methylation data.
Publisher: Elsevier BV
Date: 05-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2012
Publisher: SAGE Publications
Date: 11-2009
Abstract: Renal cell cancer (RCC) has an increasing incidence internationally and is a disease for which there have been limited therapeutic options until recently. The last decade has seen a vastly improved understanding of the biological and clinical factors that predict the outcome of this disease. We now understand some of the different molecular underpinnings of renal clear cell carcinoma by mutation or silencing of the von Hippel Lindau (VHL) gene and subsequent deregulated proliferation and angiogenesis. Survival in advanced disease is predicted by factors (performance status, anemia, hypercalcemia, and serum lactate dehydrogenase, time from diagnosis to recurrence) incorporated into the Memorial Sloan Kettering Cancer Center (MSKCC) criteria (also referred to as ‘Motzer’ criteria). These criteria allow classification of patients with RCC into good, intermediate and poor risk categories with median overall survivals of 22 months, 12 months and 5.4 months, respectively. Predicated upon these advances, six new targeted drugs (sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab and pazopanib) have been tested in well-designed phase III trials, selected or stratified for MSKCC risk criteria, with positive results. All of these new drugs act at least in part through vascular endothelial growth factor (VEGF) mediated pathways with other potential therapeutic impact on platelet-derived growth factor (PDGF), raf kinase and mammalian target of rapamycin (mTOR) pathways. Importantly, data from each of these trials show a consistent doubling of progression-free survival (PFS) over prior standard of care treatments. In addition, sorafenib, sunitinib and temsirolimus, have demonstrated significant overall survival (OS) benefits as well further follow-up is required to determine whether the disease control exhibited by everolimus and pazopanib will translate into a survival advantage. These drugs are generally well tolerated, as demonstrated by quality-of-life improvement in clinical trials, and result in clinical benefit for in excess of 70% of patients treated. They have challenged the traditional outcomes of clinical trial design by achieving their benefits with relatively few radiographic responses, but high rates of disease stability. The unique side-effect profile coupled with the chronicity of therapy requires increased vigilance to maximize exposure to the drugs while maintaining quality of life and minimizing toxicity. This review focuses on the background, clinical development and practical use of these new drugs in RCC.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532491
Abstract: AbstractPurpose: In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell–inflamed gene expression profile (Tcell sub inf /sub GEP), and stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC). Patients and Methods: Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS nominal i P /i values were calculated without multiplicity adjustment (one-sided, pembrolizumab two-sided, chemotherapy). Significance was prespecified at i α /i = 0.05. Results: In KEYNOTE-052, PD-L1, TMB, and Tcell sub inf /sub GEP were significantly associated with improved outcomes stromal signature was significantly associated with worse outcomes. In KEYNOTE-045, although findings for TMB and Tcell sub inf /sub GEP with pembrolizumab were consistent with those of KEYNOTE-052, PD-L1 was not significantly associated with improved outcomes, nor was stromal signature associated with worse outcomes with pembrolizumab chemotherapy was not associated with outcomes in a consistent manner for any of the biomarkers. Hazard ratio (HR) estimates at prespecified cutoffs showed an advantage for pembrolizumab versus chemotherapy regardless of PD-L1 or TMB, with a trend toward lower HRs in the combined positive score ≥10 and the TMB ≥175 mutation/exome subgroup. For Tcell sub inf /sub GEP, PFS and OS HRs were lower in the Tcell sub inf /sub GEP-nonlow subgroup regardless of treatment. Conclusions: Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC, and potential clinical utility of these biomarkers may be context-dependent. /
Publisher: Informa UK Limited
Date: 16-04-2012
DOI: 10.4161/HV.19188
Abstract: Immune therapy has traditionally had a limited role in the treatment of solid malignancies, outside of renal cancer and melanoma. However, early evidence of the ability to provoke an effective anti-tumor immune response in prostate cancer has led to interest in developing a variety of immune activating strategies in this disease. The first immune therapy to attain success in prolonging survival for metastatic prostate cancer patients is Sipuleucel-T. Rather than utilizing a typical vaccine approach in which antigens and immune activators are injected into the cancer host, sipuleucel-T was developed to stimulate autologous dendritic cells ex vivo, in order to evade the immune suppressive environment created by the cancer. We review the components of the immune system which may be harnessed in the development of immunotherapy in the setting of the recent success with sipuleucel-T.
Publisher: Elsevier BV
Date: 12-2014
Publisher: American Association for Cancer Research (AACR)
Date: 16-03-2023
DOI: 10.1158/1078-0432.CCR-22-3642
Abstract: On the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab [anti–programmed cell death ligand 1 (PD-L1)] together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy. We designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors. Safety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8–11 months) and survival (& months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients’ plasma was associated with short survival. No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.C.6571947.V2
Abstract: AbstractPurpose: On the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab [anti–programmed cell death ligand 1 (PD-L1)] together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy. Patients and Methods: We designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors. Results: Safety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8–11 months) and survival ( months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients’ plasma was associated with short survival. Conclusions: No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival. /
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.C.6571947.V1
Abstract: AbstractPurpose: On the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab [anti–programmed cell death ligand 1 (PD-L1)] together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy. Patients and Methods: We designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors. Results: Safety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8–11 months) and survival ( months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients’ plasma was associated with short survival. Conclusions: No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival. /
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-09-2008
Abstract: To determine the effectiveness of the Alleviating Depression Among Patients With Cancer (ADAPt-C) collaborative care management for major depression or dysthymia. Study patients included 472 low-income, predominantly female Hispanic patients with cancer age ≥ 18 years with major depression (49%), dysthymia (5%), or both (46%). Patients were randomly assigned to intervention (n = 242) or enhanced usual care (EUC n = 230). Intervention patients had access for up to 12 months to a depression clinical specialist (supervised by a psychiatrist) who offered education, structured psychotherapy, and maintenance/relapse prevention support. The psychiatrist prescribed antidepressant medications for patients preferring or assessed to require medication. At 12 months, 63% of intervention patients had a 50% or greater reduction in depressive symptoms from baseline as assessed by the Patient Health Questionnaire-9 (PHQ-9) depression scale compared with 50% of EUC patients (odds ratio [OR] = 1.98 95% CI, 1.16 to 3.38 P = .01). Improvement was also found for 5-point decrease in PHQ-9 score among 72.2% of intervention patients compared with 59.7% of EUC patients (OR = 1.99 95% CI, 1.14 to 3.50 P = .02). Intervention patients also experienced greater rates of depression treatment (72.3% v 10.4% of EUC patients P .0001) and significantly better quality-of-life outcomes, including social/family (adjusted mean difference between groups, 2.7 95% CI, 1.22 to 4.17 P .001), emotional (adjusted mean difference, 1.29 95% CI, 0.26 to 2.22 P = .01), functional (adjusted mean difference, 1.34 95% CI, 0.08 to 2.59 P = .04), and physical well-being (adjusted mean difference, 2.79 95% CI, 0.49 to 5.1 P = .02). ADAPt-C collaborative care is feasible and results in significant reduction in depressive symptoms, improvement in quality of life, and lower pain levels compared with EUC for patients with depressive disorders in a low-income, predominantly Hispanic population in public sector oncology clinics.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2012
DOI: 10.1158/1535-7163.MCT-11-0806
Abstract: With six agents approved for metastatic renal cell carcinoma (mRCC) within the past 5 years, there has undoubtedly been progress in treating this disease. However, the goal of cure remains elusive, and the agents nearest approval (i.e., axitinib and tivozanib) abide by the same paradigm as existing drugs (i.e., inhibition of VEGF or mTOR signaling). The current review will focus on investigational agents that erge from this paradigm. Specifically, novel immunotherapeutic strategies will be discussed, including vaccine therapy, cytotoxic T-lymphocyte antigen 4 (CTLA4) blockade, and programmed death-1 (PD-1) inhibition, as well as novel approaches to angiogenesis inhibition, such as abrogation of Ang/Tie-2 signaling. Pharmacologic strategies to block other potentially relevant signaling pathways, such as fibroblast growth factor receptor or MET inhibition, are also in various stages of development. Although VEGF and mTOR inhibition have dramatically improved outcomes for patients with mRCCs, a surge above the current plateau with these agents will likely require exploring new avenues. Mol Cancer Ther 11(3) 526–37. ©2012 AACR.
Publisher: Massachusetts Medical Society
Date: 19-08-2021
Publisher: S. Karger AG
Date: 2023
DOI: 10.1159/000530719
Abstract: b i Introduction: /i /b This study investigates how quantitative texture analysis can be used to non-invasively identify novel radiogenomic correlations with clear cell renal cell carcinoma (ccRCC) biomarkers. b i Methods: /i /b The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma open-source database was used to identify 190 sets of patient genomic data that had corresponding multiphase contrast-enhanced CT images in The Cancer Imaging Archive. 2,824 radiomic features spanning fifteen texture families were extracted from CT images using a custom-built MATLAB software package. Robust radiomic features with strong inter-scanner reproducibility were selected. Random forest, AdaBoost, and elastic net machine learning (ML) algorithms evaluated the ability of the selected radiomic features to predict the presence of 12 clinically relevant molecular biomarkers identified from the literature. ML analysis was repeated with cases stratified by stage (I/II vs. III/IV) and grade (1/2 vs. 3/4). 10-fold cross validation was used to evaluate model performance. b i Results: /i /b Before stratification by tumor grade and stage, radiomics predicted the presence of several biomarkers with weak discrimination (AUC 0.60–0.68). Once stratified, radiomics predicted KDM5C, SETD2, PBRM1, and mTOR mutation status with acceptable to excellent predictive discrimination (AUC ranges from 0.70 to 0.86). b i Conclusions: /i /b Radiomic texture analysis can potentially identify a variety of clinically relevant biomarkers in patients with ccRCC and may have a prognostic implication.
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/1078-0432.22587069.V1
Abstract: Supplementary Figure 10: Peripheral immune cell dynamics induced by combination therapy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2004
Publisher: American Association for Cancer Research (AACR)
Date: 06-2023
DOI: 10.1158/1078-0432.23275189.V1
Abstract: Supplementary Figure 1: Patient recruitment and s le collection overview.
Publisher: Elsevier BV
Date: 06-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2003
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-01-2022
DOI: 10.1200/JCO.21.02923
Abstract: Patients with metastatic urothelial carcinoma have poor prognosis after failure of standard first-line chemotherapy. Immune check point programmed death 1-programmed death ligand 1 antibodies have low response rates and thus there exists a major unmet need. In this phase II trial, patients with metastatic urothelial carcinoma that recurred or progressed after platinum-based chemotherapy received soluble EphB4-human serum albumin (sEphB4-HSA) in combination with pembrolizumab. The primary end points were tolerability and overall survival (OS). The secondary end points were progression-free survival (PFS), objective response rate (ORR), duration of response, and toxicity. The expression of sEphB4-HSA target EphrinB2 was correlated with outcomes. Seventy patients were enrolled. The median follow up was 22.9 months (range, 1.3-54.7). The regimen had acceptable toxicity. In the intent-to-treat analysis (N = 70), the median OS was 14.6 months (95% CI, 9.2 to 21.5). Twenty-six (37%) patients had an objective response (95% CI, 26 to 48). The median PFS was 4.1 (95% CI, 1.5 to 5.7) months. Forty-six (66%) patients expressed EphrinB2, and among them, the median OS was 21.5 months (95% CI, 12.4 to not reached), the ORR was 52% (95% CI, 37 to 67), including a complete response rate of 24% (11 of 46 95% CI, 12 to 36). The median PFS was 5.7 (95% CI, 2.7 to 27.9) months. Response was maintained at 6, 12, and 24 months in 88%, 74%, and 69% of the patients, respectively. The combination of sEphB4-HSA and pembrolizumab appears synergistic with improved OS and ORR compared with historical data for programmed death 1 rogrammed death ligand 1 monotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626885
Abstract: Supplementary Data for Antonarakis et al
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626882
Abstract: Supplementary Fig 1 Analysis of Survival by Baseline Median PSA across the two studies using the study-specific median and quartiles.
Start Date: 2009
End Date: 2014
Funder: National Institutes of Health
View Funded ActivityStart Date: 2004
End Date: 2008
Funder: National Cancer Institute
View Funded ActivityStart Date: 2008
End Date: 2011
Funder: V Foundation for Cancer Research
View Funded ActivityStart Date: 2011
End Date: 2016
Funder: National Cancer Institute - ECTN
View Funded ActivityStart Date: 2014
End Date: 2015
Funder: National Cancer Institute - ECTN
View Funded Activity