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Liquid biopsy to identify resistance to GI cancer therapy
Parikh AR, Leshchiner I, Elagina L et al. Liquid vs tissue biopsy for detecting acquired resistance and tumour heterogeneity in gastrointestinal cancers. Nature Medicine 2019;25(9):1415–1421.
Tumour heterogeneity and the development of resistant subclones can lead to resistance to therapy. Liquid biopsy (sampling blood plasma to obtain circulating tumour DNA) may be able to capture this acquired resistance more effectively than solid tumour biopsy. Forty-two patients with partial response to targeted therapy underwent liquid biopsy. Twenty-three of these patients had a matched tumour biopsy. Oesophageal, gastric, colorectal and bile duct tumours were included, of seven molecular subtypes. Targeted next-generation sequencing and parallel whole-exome sequencing were used to identify validated resistance mechanisms. Cell-free DNA (cfDNA) identified resistance alterations in 76% of patients and 53% of these exhibited >1 resistance alteration. In the 23 patients who underwent both types of biopsy, 87% of cfDNA identified a resistance alteration versus 48% of tumour biopsies. Multiple alterations were only found in 9% of tumour biopsies. There was one resistance alteration detected by tumour biopsy which was not seen in cfDNA, although this was detected using a high-sensitivity assay. Five patients who underwent subsequent tumour biopsies showed the same resistance alterations seen in the earlier cfDNA. Patients who progressed on standard chemotherapy did not develop resistance alterations, hence these occur only under selective pressure. cfDNA represents resistance alterations from both the tumour and multiple metastatic lesions. Novel and non-genetic resistance mechanisms would not be detected by cfDNA, hence tumour biopsy continues to play a role. Liquid biopsy adds important information about acquired resistance and may be a tool to guide targeted molecular therapy in the future.
LECT2-Tie1 interactions are a novel therapeutic target for liver fibrosis
Xu M, Xu H-H, Lin Y, et al. LECT2, a ligand for Tie1, plays a crucial role in liver fibrogenesis. Cell 2019 Sep 5;178(6):1478–1492.e20. doi: 10.1016/j.cell.2019.07.021. (Epub ahead of print: 2019 Aug 29)
Liver fibrosis, a common feature of all causes of chronic liver disease, correlates with adverse clinical outcomes. However, the development of effective antifibrotic therapies remains elusive. Here, the authors identify leucocyte cell-derived chemotaxin 2 (LECT2) signalling via the receptor Tie1, as a key driver of liver fibrosis. LECT2 levels were increased in the liver and serum of patients with chronic liver disease, and were higher in patients with more advanced disease. Additonally, LECT2 levels were elevated in murine models of liver fibrosis. LECT2-deficient mice had attenuated liver fibrosis in several liver models of liver injury, while overexpression of LECT2 in mice enhanced liver fibrosis. New blood vessel formation (angiogenesis) is closely related to hepatic fibrogenesis. Cell culture experiments and the quantification of hepatic blood vessels in liver fibrosis models demonstrated that LECT2 had an antiangiogenic function in the portal regions of the liver, while promoting capillarisation (loss of fenestrae) of liver sinusoidal endothelial cells. These functions were mediated by the Tie1 receptor on endothelial cells. Finally, hepatic knockdown of LECT2 (using shRNA delivered by a virus) in mice with liver injury, inhibited capillarisation of sinusoids and reduced liver fibrosis. Hence, LECT2 may represent both a novel biomarker for liver fibrosis and a potential therapeutic target for the treatment of chronic liver diseases.
The immune cancer signature as new prognostic marker for colorectal cancer
Fakih M, Ouyang C, Wang C, et al. Immune overdrive signature in colorectal tumor subset predicts poor clinical outcome. J Clin Invest 2019;129(10):4464–4476.
The Immunoscore, composed of the mean density of CD3+ and CD8+ central and marginal tumour-infiltrating T cells, is a superior prognostic marker for recurrence in colorectal cancer (CRC) than traditional TNM stage. Genomic studies have demonstrated that Th1 immune responses promote favourable outcomes in other cancer types. In this study the authors evaluate immune genes as prognostic biomarkers in CRC. Adopting the melanoma mode where tumour-infiltrating lymphocytes and CD272 expression denote response to checkpoint inhibitors, Fakih et al analysed publicly accessible data repositories (TCGA RNA-Seq and GSE39582 from NCBI-GEO) and stratified CRC samples by CD8A and CD272 expression. Four groups were identified: CD8AloCD272lo; CD8AloCD272h i; CD8AhiCD272lo; CD8Ahi*CD272hi* . The authors demonstrate, using the City of Hope 71 sample CRC cohort, that CD272 expression occurs mostly in CD68+ tumour-associated macrophages (TAM). The CD8Ahi*CD272hi* group displays the highest CD68+/CD272 TAM density and relapse rate. This is also true when applied to the other two public data sets. Microsatellite instability which is usually associated with good prognosis, is associated with CD8Ahi*CD272hi* and CD8AhiCD272lo (worst and best outcomes), with the highest proportion in CD8Ahi*CD272hi* . Theper one gene signature and an additional 625 gene expression across immune response and checkpoint expression was analysed in the data sets: CD8Ahi*CD272hi* had the highest immune gene expression. Moreover CD8Ahi*CD272hi* was associated with the lowest number of tumour cells but the highest immune cell infiltration. These findings suggest that CD8A/CD272 stratification has independent prognostic implications to the standard staging system for CRC.
Dietary modifications as a treatment in Crohn’s disease
Levine A, Wine E, Assa A, et al. Crohn's disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial. Gastroenterology 2019;157(2):440–450.e8.
Possible therapeutic effects by dietary intervention has been a matter of debate in the treatment of patients with IBD. Levine et al conducted a prospective, randomised trial in 78 children with mild-to-moderate Crohn’s disease (CD) comparing CD exclusion diet (CDED) with exclusive enteral nutrition (EEN). The children were randomly assigned to either the intervention group, which received CDED and 50% partial enteral nutrition (PEN) for 6 weeks, followed by another 6-week period with CDED and 25% PEN, or the control group, which received EEN in the ﬁrst 6 weeks followed by 25% PEN and free diet in the second 6-week period. The primary end point, dietary tolerance by week 6 was achieved by 97.5% (39/40) in the intervention and 73.6% (28/34) in the control group (p=0.002). Seventy-five per cent (30/40) in the intervention vs 59% (20/34) in the control group were in corticosteroid-free remission at week 6 (p=0.38). At week 12, corticosteroid-free remission was noted in 75.6% (28/37) in the intervention and 45.1% (14/31) in the control group (p=0.01). Statistically significant reduction of median CRP and faecal calprotectin levels at week 6 compared with baseline were recorded in both groups. The faecal microbial profile also improved in patients that responded to therapies and demonstrated reduction of faecal Proteobacteria. Endoscopic response data were not assessed in the trial and limit the assessment of the otherwise observed therapeutic efficacy of CDED in combination with PEN. Additional trials will further explore the possibility of integrating dietary modifications into our therapeutic algorithm for treating patients with IBD.
Identifying biomarkers to improve treatment and preventive strategies for pancreatic adenocarcinoma in the era of precision medicine
Singhi DA, George B, Greenbowe JR, et al. Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers. Gastroenterology 2019 Jun;156(8):2242–2253.e4.
Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer mortality with a 5-year survival rate of around 9%. Precision medicine by pairing genomic alterations with targeted therapy has shown promise in certain cancers. Singhi et al report the results of genomic characterisation of known targetable alterations and predictive biomarkers in a large international cohort of 3594 PDAC samples. DNA from primary and distant metastatic tumours was used for targeted next-generation sequencing for all coding exons from 315 cancer-related genes and select introns from 28 genes frequently rearranged in cancer. Seventeen per cent of the 3594 PDACs had genomic alterations that may confer susceptibility to currently available chemotherapy agents. Alterations in DNA damage repair were found in 81% of the samples. Most predictive treatment biomarkers in this study were found in the DNA damage repair pathway, especially the BRCA-FANC family of genes. A comparison of primary and metastatic PDACs showed that several gene alterations were most common in metastases. KRAS mutations were more frequent in primary PDAC, with a prevalence of 91%. In contrast to previous studies (<5%), they found that 12% of PDACs were KRAS wild type. Interestingly alterations in certain genes such as FGF23, CCND2, PIK3CA and FGF6 were commonly seen in IPMN-associated PDACs. By identifying several candidate genes involved in the malignant transformation of IPMNs this study helps in the development of preventive strategies. For future studies, improvement in tissue acquisition through endoscopic ultrasound biopsy provides opportunities to gather further evidence in this area of unmet need in PDAC.
HCV retreatment: can we resolve this issue?
Wilson E, Covert E, Hoffmann J, et al. A pilot study of safety and efficacy of HCV retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with or without HIV (RESOLVE STUDY). J Hepatol 2019;71(3):498–504.
HCV infection remains a global health problem with 170 million people worldwide estimated to be chronically infected. The treatment of patients with HCV has however changed dramatically over the last few years, with combinations of direct-acting antivirals (DAAs) achieving high rates of sustained virological response (SVR). This paper reports a multicentre, open-labelled, phase IIb study investigating the safety, tolerability and efficacy of sofosbuvir/velpatasvir/voxilaprevir in 77 patients with virological rebound following previous combination DAA therapy. Efficacy was defined as an SVR at 12 weeks after the end of therapy. Intention-to-treat analysis reported 70 patients (90.9%) achieved SVR, including 14/17 HIV-coinfected patients and 18/22 of those with previous non-completion of DAA therapy. Seventy-one patients in total completed 12 weeks of study medication, with 99% achieving SVR. No difference in treatment response was reported in the HIV coinfection group. Reported side effects were similar in HIV-coinfected patients compared with the non-coinfection group. Five patients reported a grade 3/4 adverse event, but all were unrelated to study medication. The authors conclude that retreatment with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir was safe, well tolerated and effective in patients with previous virological rebound after DAA treatment. This regimen appears to be safe and equally effective in HIV-coinfected patients but further larger randomised studies are required to clarify further.
Dr Sujata Biswas, Dr Prakash Ramachandran, Dr Francesca Moroni, Prof Raja Atreya, Dr Umesh Basavaraju, Dr Norma McAvoy
Nature Medicine, Cell, Journal of Clinical Investigation, Gastroenterology, Journal of Hepatology
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
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