Optimal treatment for metastatic bladder cancer

Rak pęcherza moczowego z przerzutami jest chorobą prowadzącą do zgonu. Standardem leczenia pierwszej linii jest chemioterapia oparta na cisplatynie, podawanej w skojarzeniu z gemcytabiną oraz metotreksatem, winblastyną i doksorubicyną. Leczenie drugiej linii wykazuje niewielką skuteczność, nie wpływając na poprawę wyników. Stosowano też chemioterapię w skojarzeniu z lekami ukierunkowanymi na cele molekularne w obrębie szlaków sygnałowych związanych ze wzrostem, przeżyciem i proliferacją komórek, ale dotychczas nie potwierdzono istotnej korzyści klinicznej. Obiecujące okazało się modulowanie odpowiedzi immunologicznej gospodarza przeciwko antygenom nowotworowym, a obecnie wiele nowych sposobów terapii jest w trakcie badań. Metody sekwencjonowania nowej generacji zastosowane w przypadku inwazyjnych raków urotelialnych dostarczyły wielu nowych informacji dotyczących biologii choroby oraz potencjalnych celów terapeutycznych. W zaawansowanej chorobie obejmują one zmiany kinazy tyrozynowej receptora/szlaku Ras oraz kinazy fosfatydyloinozytolu 3/białkowej kinazy B/szlaku ssaczego celu rapamycyny, przy czym obecnie trwają badania nad rozwojem wielu nowych leków. Opublikowane ostatnio dane z obserwacji chorych na raka pęcherza moczowego w ramach Cancer Genome Atlas Research Network oraz inne badania sugerują, że mutacje w genach regulujących chromatynę są bardzo powszechne w przebiegu inwazyjnego raka pęcherza moczowego i występują częściej niż w innych nowotworach. Odkrycie nowych zmian genomowych stanowi wyzwanie dla procesu opracowywania nowych leków, mających na celu zmianę przebiegu choroby.Metastatic bladder cancer is a lethal disease. Cisplatin-based chemotherapy, including the combination regimens gemcitabine–cisplatin and methotrexate–vinblastine–doxorubicin–cisplatin, are the standard first-line therapies. Second- line therapies have modest activity and no significant improvement in patient outcomes. Agents targeting growth, survival, and proliferation pathways have been added to cytotoxic therapy with limited added benefit to date. Modulating host immune response to cancer-associated antigens appears promising, with multiple new therapeutic approaches being pursued. Next-generation sequencing of invasive urothelial carcinoma has provided insights into the biology of this disease and potential actionable targets. Alterations in the receptor tyrosine kinase/Ras pathway and the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway represent potential therapeutic targets in advanced disease, and novel agents are in development. Recent data from the Cancer Genome Atlas Research Network bladder cancer cohort and other efforts suggest that mutations in chromatin-regulatory genes are very common in invasive bladder tumors, and are more frequent than in other studied tumors. The discovery of new genomic alterations challenges drug development to change the course of this disease

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments

The Florida pancreas collaborative next-generation biobank: Infrastructure to reduce disparities and improve survival for a diverse cohort of patients with pancreatic cancer

Background: Well-annotated, high-quality biorepositories provide a valuable platform to support translational research. However, most biorepositories have poor representation of minority groups, limiting the ability to address health disparities. Methods: We describe the establishment of the Florida Pancreas Collaborative (FPC), the first state-wide prospective cohort study and biorepository designed to address the higher burden of pancreatic cancer (PaCa) in African Americans (AA) compared to Non-Hispanic Whites (NHW) and Hispanic/Latinx (H/L). We provide an overview of stakeholders; study eligibility and design; recruitment strategies; standard operating procedures to collect, process, store, and transfer biospecimens, medical images, and data; our cloud-based data management platform; and progress regarding recruitment and biobanking. Results: The FPC consists of multidisciplinary teams from fifteen Florida medical institutions. From March 2019 through August 2020, 350 patients were assessed for eligibility, 323 met inclusion/exclusion criteria, and 305 (94%) enrolled, including 228 NHW, 30 AA, and 47 H/L, with 94%, 100%, and 94% participation rates, respectively. A high percentage of participants have donated blood (87%), pancreatic tumor tissue (41%), computed tomography scans (76%), and questionnaires (62%). Conclusions: This biorepository addresses a critical gap in PaCa research and has potential to advance translational studies intended to minimize disparities and reduce PaCa-related morbidity and mortality

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments

A Multidisciplinary Biospecimen Bank of Renal Cell Carcinomas Compatible with Discovery Platforms at Mayo Clinic, Scottsdale, Arizona

<div><p>To address the need to study frozen clinical specimens using next-generation RNA, DNA, chromatin immunoprecipitation (ChIP) sequencing and protein analyses, we developed a biobank work flow to prospectively collect biospecimens from patients with renal cell carcinoma (RCC). We describe our standard operating procedures and work flow to annotate pathologic results and clinical outcomes. We report quality control outcomes and nucleic acid yields of our RCC submissions (N=16) to The Cancer Genome Atlas (TCGA) project, as well as newer discovery platforms, by describing mass spectrometry analysis of albumin oxidation in plasma and 6 ChIP sequencing libraries generated from nephrectomy specimens after histone H3 lysine 36 trimethylation (H3K36me3) immunoprecipitation. From June 1, 2010, through January 1, 2013, we enrolled 328 patients with RCC. Our mean (SD) TCGA RNA integrity numbers (RINs) were 8.1 (0.8) for papillary RCC, with a 12.5% overall rate of sample disqualification for RIN <7. Banked plasma had significantly less albumin oxidation (by mass spectrometry analysis) than plasma kept at 25°C (<i>P</i><.001). For ChIP sequencing, the FastQC score for average read quality was at least 30 for 91% to 95% of paired-end reads. In parallel, we analyzed frozen tissue by RNA sequencing; after genome alignment, only 0.2% to 0.4% of total reads failed the default quality check steps of Bowtie2, which was comparable to the disqualification ratio (0.1%) of the 786-O RCC cell line that was prepared under optimal RNA isolation conditions. The overall correlation coefficients for gene expression between Mayo Clinic vs TCGA tissues ranged from 0.75 to 0.82. These data support the generation of high-quality nucleic acids for genomic analyses from banked RCC. Importantly, the protocol does not interfere with routine clinical care. Collections over defined time points during disease treatment further enhance collaborative efforts to integrate genomic information with outcomes.</p></div

Racial and ethnic disparities in a state‐wide registry of patients with pancreatic cancer and an exploratory investigation of cancer cachexia as a contributor to observed inequities

Pancreatic cancer (PC) is characterized by racial/ethnic disparities and the debilitating muscle‐wasting condition, cancer cachexia. Florida ranks second in the number of PC deaths and has a large and understudied minority population. We examined the primary hypothesis that PC incidence and mortality rates may be highest among Black Floridians and the secondary hypothesis that biological correlates of cancer cachexia may underlie disparities. PC incidence and mortality rates were estimated by race/ethnicity, gender, and county using publicly available state‐wide cancer registry data that included approximately 2700 Black, 25 200 Non‐Hispanic White (NHW), and 3300 Hispanic/Latino (H/L) Floridians diagnosed between 2004 and 2014. Blacks within Florida experienced a significantly (P < 0.05) higher incidence (12.5/100 000) and mortality (10.97/100 000) compared to NHW (incidence = 11.2/100 000; mortality = 10.3/100 000) and H/L (incidence = 9.6/100 000; mortality = 8.7/100 000), especially in rural counties. To investigate radiologic and blood‐based correlates of cachexia, we leveraged data from a subset of patients evaluated at two geographically distinct Florida Cancer Centers. In Blacks compared to NHW matched on stage, markers of PC‐induced cachexia were more frequent and included greater decreases in core musculature compared to corresponding healthy control patients (25.0% vs 10.1% lower), greater decreases in psoas musculature over time (10.5% vs 4.8% loss), lower baseline serum albumin levels (3.8 vs 4.0 gm/dL), and higher platelet counts (332.8 vs 268.7 k/UL). Together, these findings suggest for the first time that PC and cachexia may affect Blacks disproportionately. Given its nearly universal contribution to illness and PC‐related deaths, the early diagnosis and treatment of cachexia may represent an avenue to improve health equity, quality of life, and survival

Comparison of Mapped Reads Between the Mayo Clinic and TCGA Nephrectomy Samples.

<p>Abbreviation: TCGA, The Cancer Genome Atlas.</p><p>Comparison of Mapped Reads Between the Mayo Clinic and TCGA Nephrectomy Samples.</p

Quality Assessment of Chromatin Immunoprecipitation Coupled With High-throughput Sequkencing.

<p>A, First end-read and, B, second end-read average quality score per base pair (bp) position assessment using FastQC. Higher scores correspond to better base calls. C, Box plots of enrichment of H3K36me3 immunoprecipitation (IP; red) over the matched control input library (Input; green). The human genome was split into 500-bp nonoverlapping windows, and the number of mapped pairs per window was calculated using BEDTools and normalized to a library size of 10 million uniquely mapped reads. The plots represent the top 5% of the 500-bp windows with the highe st counts in IP and the corresponding windows in input. D, Gene-body coverage by H3K36me3-binding sites. H3K36me3-binding sites identified by SICER (Spatial Clustering for Identification of ChIP-Enriched Regions) were intersected with gene coordinates to calculate the gene-body coverage (y-axis). On the x-axis, 1 to 22 represents chromosomes 1 to 22; 23 represents the X chromosome; and 24 represents the Y chromosome. ccRCC1 indicates clear cell renal cell carcinoma 1; ccRCC2, clear cell renal cell carcinoma 2; ccRCC3, clear cell renal cell carcinoma 3; Uninv., uninvolved.</p

Albumin Oxidation (S-Cysteinylation) Observed in the Banked Renal Cell Carcinoma (RCC) Plasma Samples.

<p>Control plasma was freshly collected from a nominally healthy donor, and albumin oxidation levels were observed at 25°C Significantly less albumin oxidation was observed in samples from patients with RCC compared with albumin in plasma kept at 25°C for ≥17.5 hours (<i>P</i><.001; Mann-Whitney U test). (Data from Borges CR et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132831#pone.0132831.ref012" target="_blank">12</a>].)</p