Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct ...prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%–60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.
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•A multi-institutional integrative clinical sequencing of mCRPC•Approximately 90% of mCRPC harbor clinically actionable molecular alterations•mCRPC harbors genomic alterations in PIK3CA/B, RSPO, RAF, APC, β-catenin, and ZBTB16•23% of mCRPC harbor DNA repair pathway aberrations, and 8% harbor germline findings
A multi-institutional integrative clinical sequencing analysis reveals that the majority of affected individuals with metastatic castration-resistant prostate cancer harbor clinically actionable molecular alterations, highlighting the need for genetic counseling to inform precision medicine in affected individuals with advanced prostate cancer.
Glycomic profiles derived from human blood sera of 10 healthy males were compared to those from 24 prostate cancer patients. The profiles were acquired using MALDI−MS of permethylated N-glycans ...released from 10-μL sample aliquots. Quantitative permethylation was attained using solid-phase permethylation. Principal component analysis of the glycomic profiles revealed significant differences among the two sets, allowing their distinct clustering. The first principal component distinguished the 24 prostate cancer patients from the healthy individuals. It was determined that fucosylation of glycan structures is generally higher in cancer samples (ANOVA test p-value of 0.0006). Although more than 50 N-glycan structures were determined, 12 glycan structures, of which six were fucosylated, were significantly different between the two sample sets. Significant differences were confirmed through two independent statistical tests (ANOVA and ROC analyses). Ten of these structures had significantly higher relative intensities in the case of the cancer samples, while the other two were less abundant in the cancer samples. All 12 structures were statistically significant, as suggested by their very low ANOVA scores (<0.001) and ROC analysis, with area under the curve values close to 1 or 0. Accordingly, these structures can be considered as cancer−specific glycans and potential prostate cancer biomarkers. Therefore, serum glycomic profiling appears worthy of further investigation to define its role in cancer early detection and prognostication. Keywords: prostate cancer • glycomics • human blood serum • biomarkers • MALDI-TOF • mass spectrometry
The purpose of this study is to determine the control of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC) and highly ...emetogenic chemotherapy (HEC) with the combined use of palonosetron and olanzapine, and dexamethasone with the dexamethasone given on day 1 only.
Forty chemotherapy-naive patients received on the day of chemotherapy, day 1, an anti-emetic regimen consisting of dexamethasone, palonosetron, and olanzapine. Patients continued olanzapine for days 2-4 after chemotherapy administration. Patients recorded daily episodes of emesis, daily symptoms utilizing the M.D. Anderson Symptom Inventory, and the utilization of rescue therapy.
For the first cycle of chemotherapy, the complete response (no emesis, no rescue) for the acute period (24 h post-chemotherapy) was 100%, the delayed period (days 2-5 post-chemotherapy) 75%, and the overall period (0 120 h post-chemotherapy) 75% in 8 patients receiving HEC and was 97, 75, and 72% in 32 patients receiving MEC. Patients with no nausea for the acute period was 100%, the delayed period 50%, and the overall period 50% in 8 patients receiving HEC and was 100, 78, and 78% in 32 patients receiving MEC.
The complete response and control of nausea in subsequent cycles of chemotherapy were not significantly different from cycle one.
Olanzapine combined with a single dose of dexamethasone and a single dose of palonosetron was very effective in controlling acute and delayed CINV in patients receiving both HEC and MEC.
Prostate cancer disproportionately affects racial and ethnic minority populations. Reasons for disparate outcomes among minority patients are multifaceted and complex, involving factors at the ...patient, provider, and system levels. Although advancements in our understanding of disease biology have led to novel therapeutics for men with advanced prostate cancer, including the introduction of biomarker-driven therapeutics, pivotal translational studies and clinical trials are underrepresented by minority populations. Despite attempts to bridge the disparities gap, there remains an unmet need to expand minority engagement and participation in clinical trials to better define the impact of therapy on efficacy outcomes, quality of life, and role of biomarkers in diverse patient populations. The IRONMAN registry (ClinicalTrials.gov identifier: NCT03151629), a global, prospective, population-based study, was borne from this unmet medical need to address persistent gaps in our knowledge of advanced prostate cancer. Through integrated collection of clinical outcomes, patient-reported outcomes, epidemiologic data, and biospecimens, IRONMAN has the goal of expanding our understanding of how and why prostate cancer outcomes differ by race and ethnicity. To this end, the Diversity Working Group of the IRONMAN registry has developed informed strategies for site selection, recruitment, engagement and retention, and trial design and eligibility criteria to ensure broad inclusion and needs awareness of minority participants. In concert with systematic strategies to tackle the complex levels of disparate care, our ultimate goal is to expand minority engagement in clinical research and bridge the disparities gap in prostate cancer care.
In a previous phase I study, olanzapine was demonstrated to be a safe and effective agent for the prevention of delayed emesis in chemotherapy-naïve cancer patients receiving cyclophosphamide, ...doxorubicin, and/or cisplatin. Using the maximum tolerated dose of olanzapine in the phase I trial, a phase II trial was performed for the prevention of chemotherapy-induced nausea and vomiting in chemotherapy-naïve patients. The regimen was 5 mg/day of oral olanzapine on the 2 days prior to chemotherapy, 10 mg on the day of chemotherapy, day 1, (added to intravenous granisetron, 10 mcg/kg and dexamethasone 20 mg), and 10 mg/day on days 2-4 after chemotherapy (added to dexamethasone, 8 mg p.o. BID days 2 and 3, and 4 mg p.o. BID day 4). Thirty patients (median age 58.5 years, range 25-84; 23 women; ECOG PS 0, 1) consented to the protocol, and all were evaluable. Complete response (CR) (no emesis, no rescue) was 100% for the acute period (24 h postchemotherapy), 80% for the delayed period (days 2-5 postchemotherapy), and 80% for the overall period (0-120 h postchemotherapy) in ten patients receiving highly emetogenic chemotherapy (cisplatin > or =70 mg/m(2)). CR was also 100% for the acute period, 85% for the delayed period, and 85% for the overall period in 20 patients receiving moderately emetogenic chemotherapy (doxorubicin > or =50 mg/m(2)). Nausea was very well controlled in the patients receiving highly emetogenic chemotherapy, with no patient having nausea 0 on scale of 0-10, M.D. Anderson Symptom Inventory (MDASI) in the acute or delayed periods. Nausea was also well controlled in patients receiving moderately emetogenic chemotherapy, with no nausea in 85% of patients in the acute period and 65% in the delayed and overall periods. There were no grade 3 or 4 toxicities and no significant pain, fatigue, disturbed sleep, memory changes, dyspnea, lack of appetite, drowsiness, dry mouth, mood changes, or restlessness experienced by the patients. Complete response and control of nausea in subsequent cycles of chemotherapy (25 patients, cycle 2; 25 patients, cycle 3; 21 patients, cycle 4) were equal to or greater than cycle 1. Olanzapine is safe and highly effective in controlling acute and delayed chemotherapy-induced nausea and vomiting in patients receiving highly and moderately emetogenic chemotherapy.
Chemotherapy-induced delayed emesis (DE) can affect up to 50% to 70% of patients receiving moderately and highly emetogenic chemotherapy, although rates are improving. DE most commonly occurs within ...the first 24 to 48 hours of chemotherapy administration and can persist for 2 to 5 days. Olanzapine, due to its activity at multiple dopaminergic, serotonergic, muscarinic, and histaminic receptor sites, has potential as antiemetic therapy. A phase I study was designed with olanzapine, using a four-cohort dose escalation of 3 to 6 patients per cohort, for the prevention of DE in cancer patients receiving their first cycle of chemotherapy consisting of cyclophosphamide, doxorubicin, platinum, and or irinotecan. All patients received standard premedication. Olanzapine was administered on days − 2 and − 1 prior to chemotherapy and continued for 8 days (days 0-7). Episodes of vomiting as well as daily measurements of nausea, sedation, and toxicity were monitored at each dose level. Fifteen patients completed the protocol. No grade 4 toxicities were seen, and three patients experienced a dose-limiting toxicity (grade 3) of a depressed level of consciousness during the study. The maximum tolerated dose appeared to be 5 mg (for days − 2 and − 1) and 10 mg (for days 0-7). Four of six patients receiving highly emetogenic chemotherapy (cisplatin, ≥ 70 mg m2) and nine of nine patients receiving moderately emetogenic chemotherapy (doxorubicin, ≥ 50 mg m2) had complete control (no vomiting episodes) of DE. Therefore, olanzapine may be an effective agent for the prevention of chemotherapy-induced DE. A phase II trial is underway.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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TPS190
Background: Men with advanced prostate cancer (APC) experience high mortality and severely impacted quality of life due to the disease itself as well as its therapies, with Black ...men facing the highest disease burden. The treatment landscape for APC is rapidly changing; however, little is known about the real-life experience of men receiving new therapies. There is an urgent need to identify disparities in treatment patterns and outcomes in advanced disease, based on patient and country demographics. The International Registry for Men with Advanced Prostate Cancer (IRONMAN) is uniquely equipped to meet these needs. Methods: IRONMAN is a population-based prospective cohort of men with newly diagnosed metastatic hormone-sensitive (mHSPC) and castration-resistant (CRPC) prostate cancer aiming to enroll 5,000 men across 16 countries (Australia, the Bahamas, Barbados, Brazil, Canada, Ireland, Jamaica, Kenya, Nigeria, Norway, South Africa, Spain, Sweden, Switzerland, United Kingdom, Untied States). Patients are followed prospectively for overall survival, clinically significant adverse events, changes in cancer treatments, biomarkers, and Patient-Reported Outcome Measures (PROMs). Data is collected via longitudinal electronic questionnaires from patients and providers as well as blood samples and medical records. IRONMAN is currently enrolling in 10 countries at 103 sites. Sites were selected to create a diverse cohort across race/ethnicity, rural/urban populations, socioeconomic factors, and geographic regions. Of the first 1,865 men enrolled to date, 60% have mHSPC and 40% have CRPC; overall, 9% of men (18% in the US) self-identify as Black and 82% identify as white (78% in the US). 60% (N = 1,111) of this cohort has been enrolled outside of the US, and the median age at study entry is 70 years. The distribution and demographics of patients are continuously monitored to inform ongoing enrollment efforts. The IRONMAN Diversity Working Group meets monthly to discuss barriers and strategies to enhance enrollment of a racially and ethnically diverse population. The Low- and Middle-Income Country Working Group addresses the unique needs of men being recruited from the Caribbean and African sites in addition to supporting broad oncology efforts in these regions. These efforts support IRONMAN’s larger goal to investigate disparities in the care of patients with APC, having potential implications for decreasing racial disparities in survival outcomes. Clinical trial information: NCT03151629.
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Background: While population-based estimates of advanced prostate cancer survivors are lacking, an estimated 180,000 men in the US are living with metastatic prostate cancer. Their ...survivorship experience is distinct from localized patients as they suffer quality of life detriments both due to the severity of disease and its therapies. We examined quality-of-life indictors among men in the IRONMAN global registry of advanced prostate cancer. Methods: IRONMAN (International Registry of Men with Advanced Prostate Cancer) is a population-based prospective study of men with newly diagnosed advanced, metastatic hormone-sensitive (mHSPC) and castration-resistant prostate cancer (CRPC) enrolled from 16 countries. We report data from first 1865 men enrolled, 1567 who completed a baseline Patient Reported Outcome Measure (PROM) in the US (N=581), Canada (N=245), Spain (N=166), UK (N=204), Australia (N=126), Switzerland (N=88), Sweden (N=70), Ireland (N=46), and Brazil (N=41). PROMs are collected at baseline and every three months using electronic (90%) or paper versions of validated questionnaires. Results: The cohort includes 1,128 men with mHSPC and 737 with CRPC. Based on self-report, 9% of men overall (18% in the US) are Black and 83% are white (78% in the US). Sleep problems were common among men at enrollment, with 59% of men reporting problems with insomnia. The prevalence was similarly high among men with mHSPC or CRPC disease. Ten percent of men reported that pain substantially interfered with daily activities, and 24% reported pain had some effect. Physical functioning was high among both mHSPC (median 93.3, 80-100) and CRPC (median 86.7, 73.3-100) patients based on EORTC QLQ-30. Global health status was similar between the two groups (median 75, 58.3 - 83.3). More than 25% of men reported some cognitive impairment at baseline. Financial difficulties due to the disease and treatment were quite high, ranging from 12% in Sweden, 16% in Canada and Spain, 34% in the US, and 46% in Brazil. Conclusions: Men with advanced prostate cancer experience a range of quality of life detriments which impair overall health. While at baseline, many of these measures were similar among men with mHSPC and CRPC, we will continue to monitor these over time to examine changes in quality of life associated with disease progression and treatments. A longer-term goal is to identify opportunities for intervention to improve quality of life and potentially improve survival. Clinical trial information: NCT03151629.
Although there are considerable racial and ethnic disparities in prostate cancer incidence and mortality in the United States and globally, clinical trials often do not reflect disease incidence ...across racial and ethnic subgroups. This study aims to comprehensively review the reporting of race and ethnicity data and the representation of race and ethnicity across prostate cancer treatment-, prevention-, and screening-based clinical trials.
Seventy-two global phase III and IV prevention, screening, and treatment prostate cancer clinical trials with enrollment start dates between 1987 and 2016 were analyzed in this study, representing a total of 893,378 individual trial participants. Availability and representation of race and ethnicity data by trial funding type, temporal changes in the racial/ethnic diversity of participants, and geographic representation of countries were assessed.
Of the 72 trials analyzed, 59 (81.9%) had available race data, and 11 (15.3%) of these trials additionally reported ethnicity. Of the trials reporting data, participants were overwhelmingly white men (with the highest proportion in U.S. nonpublicly funded trials), comprising over 96% of the study population. The proportion of white participants in prostate cancer clinical trials has remained at over 80% since 1990. Geographically, Africa and the Caribbean were particularly underrepresented with only 3% of countries included.
Trial participants continue to be majority white despite the known racial disparities in prostate cancer clinical outcomes.
Current and future trials must use novel recruitment strategies to ensure enrollment of underrepresented men. Targeting the inclusion of African and Caribbean medical centers is crucial to achieve equity in representation.
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