ABSTRACT
BACKGROUND: The genomic knowledge on urothelial carcinoma is expanding. It is recognised that urothelial carcinoma is a disease with a high somatic mutation rate and a high prevalence of genetic alterations, as discussed by Thomas and Sonpavde (2022). In the context of a disease rich with somatic alterations, continuing efforts to better identify which patients may benefit most from targeted therapy, immunotherapy and combination therapy may ultimately lead to improved outcomes for patients with this disease. AIMS: We aimed to ascertain the frequency of next-generation sequencing (NGS) and the prevalence of genomic alterations amongst patients with metastatic urothelial cancer (mUC) in Ireland. We studied patients who received a targeted therapy following the detection of an oncogenic alteration on NGS and assessed their outcomes. METHODS: Patients with a diagnosis of mUC between 2017 and 2022 were identified from Urology MDT databases as well as pharmacy databases across three Irish cancer centres. A retrospective review of patient notes including a comprehensive review of histopathology, radiology data, prior therapies and NGS reports was carried out for each patient. RESULTS: 111 patients diagnosed with mUC between 2017 and 2022 were identified for inclusion across three hospital sites. NGS was carried out on the tumour specimens of 66 patients (59%). Thirty-six potentially therapeutically targetable alterations were identified amongst thirty-five patients. The most frequent alterations identified were PIK3CA mutations, FGFR3 mutations or fusions and ERBB2 somatic mutations. Fifteen patients (13.5%) received therapy directed at a genetic alteration. The most common targeted therapy received was erdafitinib (60%) followed by trastuzumab (33%) with one patient receiving alpelisib monotherapy. The median duration of treatment with targeted therapy was 3 months (range 1-34 months). Two patients were observed to have durable responses to erdafitinib approaching 3 years duration. CONCLUSIONS: This study provides an understanding of the use of NGS and prevalence of genomic alterations in an Irish patient population.
ABSTRACT
Immune checkpoint inhibitors are monoclonal antibodies that are used to treat over one in three cancer patients. While they have changed the natural history of disease, prolonging life and preserving quality of life, they are highly active in less than 40% of patients, even in the most responsive malignancies such as melanoma, and cause significant autoimmune side effects. Licenced biomarkers include tumour Programmed Death Ligand 1 expression by immunohistochemistry, microsatellite instability, and tumour mutational burden, none of which are particularly sensitive or specific. Emerging tumour and immune tissue biomarkers such as novel immunohistochemistry scores, tumour, stromal and immune cell gene expression profiling, and liquid biomarkers such as systemic inflammatory markers, kynurenine/tryptophan ratio, circulating immune cells, cytokines and DNA are discussed in this review. We also examine the influence of the faecal microbiome on treatment outcome and its use as a biomarker of response and toxicity.
ABSTRACT
BACKGROUND: Enzalutamide is part of the treatment regimen for metastatic castration-resistant prostate cancer (MCRPC). However, both intrinsic and acquired resistance to the drug remain substantial clinical quandaries. circRNAs, a novel type of non-coding RNA, have been identified in a number of cancers including prostate cancer and have been associated with cancer development and progression. circRNAs have shown great potential as clinically useful blood-based 'liquid biopsies' and as therapeutic targets in prostate cancer. The aim of this study was to examine the role of circRNA transcripts in enzalutamide-resistant prostate cancer cells and assess their utility as biomarkers. METHODS: An isogenic cell line model of enzalutamide resistance was subjected to circRNA microarray profiling. Several differentially expressed circRNAs, along with their putative parental genes were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). circRNAs of interest were stably overexpressed in the control cell line and drug sensitivity was assessed using an ELISA-based proliferation assay. The candidate circRNA, hsa_circ_0001275, was measured in patient plasma samples using RT-droplet digital PCR (RT-ddPCR). RESULTS: hsa_circ_0001275 and its parental gene, PLCL2, were significantly up-regulated in strongly resistant clones vs. control (p < 0.05). Overexpression of hsa_circ_0001275 in the control cell line resulted in increased resistance to enzalutamide (p < 0.05). While RT-ddPCR analysis of hsa_circ_0001275 expression in plasma samples of 44 clinical trial participants showed a trend that mirrored the stages of disease activity (as defined by PSA level), the association did not reach statistical significance. CONCLUSIONS: Our data suggest that increased levels of hsa_circ_0001275 contribute to enzalutamide resistance. hsa_circ_0001275 plasma expression showed a trend that mirrors the PSA level at specific disease time points, indicating that circRNAs mirror disease recurrence and burden and may be associated with enzalutamide resistance.
ABSTRACT
Lung cancer is a leading cause of cancer-related deaths, contributing to 18.4% of cancer deaths globally. Treatment of non-small cell lung carcinoma has seen rapid progression with targeted therapies tailored to specific genetic drivers. However, identifying genetic alterations can be difficult due to lack of tissue, inaccessible tumors and the risk of complications for the patient with serial tissue sampling. The liquid biopsy provides a minimally invasive method which can obtain circulating biomarkers shed from the tumor and could be a safer alternative to tissue biopsy. While tissue biopsy remains the gold standard, liquid biopsies could be very beneficial where serial sampling is required, such as monitoring disease progression or development of resistance mutations to current targeted therapies. Liquid biopsies also have a potential role in identifying patients at risk of relapse post treatment and as a component of future lung cancer screening protocols. Rapid developments have led to multiple platforms for isolating circulating tumor cells (CTCs) and detecting circulating tumor DNA (ctDNA); however, standardization is lacking, especially in lung carcinoma. Additionally, clonal hematopoiesis of uncertain clinical significance must be taken into consideration in genetic sequencing, as it introduces the potential for false positives. Various biomarkers have been investigated in liquid biopsies; however, in this review, we will concentrate on the current use of ctDNA and CTCs, focusing on the clinical relevance, current and possible future applications and limitations of each.
