Systematic Analysis of Circulating Soluble Angiogenesis-Associated Proteins in ICON7 Identifies Tie2 as a Biomarker of Vascular Progression on Bevacizumab

background: There is a critical need for predictive/resistance biomarkers for VEGF inhibitors to optimise their use. methods: Blood samples were collected during and following treatment and, where appropriate, upon progression from ovarian cancer patients in ICON7, a randomised phase III trial of carboplatin and paclitaxel with or without bevacizumab. Plasma concentrations of 15 circulating angio-biomarkers were measured using a validated multiplex ELISA, analysed through a novel network analysis and their relevance to the PFS then determined. results: Samples (n=650) were analysed from 92 patients. Bevacizumab induced correlative relationships between Ang1 and Tie2 plasma concentrations, which reduced after initiation of treatment and remained decreased until progressive disease occurred. A 50% increase from the nadir in the concentration of circulating Tie2 (or the product of circulating Ang1 and Tie2) predicted tumour progression. Combining Tie2 with GCIG-defined Ca125 data yielded a significant improvement in the prediction of progressive disease in patients receiving bevacizumab in comparison with Ca125 alone (74.1% vs 47.3%, P<1 × 10−9). conclusions: Tie2 is a vascular progression marker for bevacizumab-treated ovarian cancer patients. Tie2 in combination with Ca125 provides superior information to clinicians on progressive disease in patients with VEGFi-treated ovarian cancers

Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial

BACKGROUND: Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gemcitabine [CisGem], improved the response rate, but did not improve the progression-free survival (PFS) in the ABC-03 study. Minimally invasive biomarkers predictive of cediranib benefit may improve patient outcomes. METHODS: Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC). RESULTS: Samples were available from n=117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of the therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analysis revealed CK18 and VEGFR2 increases correlated with poorer OS in all patients (P< 0.001 and P=0.02, respectively). CONCLUSIONS: Rising circulating VEGFA levels in patients with ABC, treated with CisGem, are associated with worse PFS and OS, not seen in patients receiving cediranib. Rising levels of markers of tumour burden (CK18) and potential resistance (VEGFR2) are associated with worse outcomes and warrant validation

Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer

Fibroblast Growth Factors (FGFs) have been implicated in malignant transformation, tumor mitogenesis, angiogenesis and chemoresistance. The aim of this study was to determine which FGFs and FGFRs play functional roles in epithelial ovarian cancer. Restriction enzyme analysis of mRNA revealed that transformation was associated with a switch in FGFR2 and FGFR3, from the IIIc to the IIIb isoform. There was widespread expression of FGFs, including FGF7, in all tissues but, FGF3 and FGF19 were expressed by malignant cell lines and cancer tissue but were not present in normal tissue. Using FGFR-specific shRNAi we demonstrated that reductions in FGFR2 inhibited proliferation of ovarian cancer cell lines in vitro (>50%, p < 0.006) and reduced cisplatin IC50 (>60%, p < 0.0001). Cell cycle analysis revealed increased cisplatin sensitivity was associated with increased G2/M arrest and increased apoptosis. FGFR2 shRNAi reduced growth rates of ovarian tumor xenografts by 20% (p < 0.006) and when combined with cisplatin caused a 40% reduction in proliferation rates (p < 0.007). In contrast, RNAi-induced reductions in FGFR1 increased SKOV3 cell numbers, with associated changes in cell cycle but had no effect on ES 2 cells. However, the cisplatin IC50 was reduced (>50%, p < 0.0001) by FGFR1 shRNAi in both cell lines and there was increased apoptosis (46–50%) compared with control cells (35%) (p < 0.004). Together our data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. However, data on the inhibition of FGFR1 suggest that broad spectrum FGFR inhibitors may have unexpected effects on proliferation

Targeting the Epidermal Growth Factor Receptor in Addition to Chemotherapy in Patients with Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

Overexpression of epidermal growth factor receptors (EGFR) occurs in &gt;90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA)/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs). Meta-regression was utilised to explore factors associated with improved prognosis (all studies) and benefit from EGFR-targeted therapy (RCTs). Twenty-eight studies (7 RCTs and 21 cohort studies) comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR): 0.90, <i>p</i> = 0.15) or overall survival (HR: 0.94, <i>p</i> = 0.18). EGFR-targeted therapy was associated with increased treatment-related deaths (pooled odds ratio (OR): 5.18, <i>p</i> = 0.007), and grade (G)3/4 rash (OR: 4.82, <i>p</i> = 0.03). There was a borderline significant increase in G3/4 diarrhoea (OR: 1.75, <i>p</i> = 0.06), but no effect on treatment discontinuation without progression (OR: 0.87, <i>p</i> = 0.25). Neither G3/4 rash nor diarrhoea were associated with increased survival benefit from EGFR-targeted therapy. The effect of EGFR-targeted therapy on overall survival (OS) appeared greater in studies with a greater proportion of LA rather than metastatic patients (<i>R</i> = −0.69, <i>p</i> &lt; 0.001). Further studies in unselected patients with advanced PDAC are not warranted. The benefit from EGFR inhibitors may be limited to patient subgroups not yet clearly defined

Intrahepatic cholangiocarcinoma hidden within cancer of unknown primary

BACKGROUND: Many patients referred with a provisional diagnosis of cancer of unknown primary (pCUP) present with presumed metastatic disease to the liver. Due to the lack of definitive histological markers, intrahepatic cholangiocarcinoma (iCCA) may be overlooked. This study assessed the frequency of iCCA within a pCUP cohort. METHODS: A single UK cancer-center study of sequential patients referred with pCUP from January 2017 to April 2020. Baseline diagnostic imaging was reviewed independently by a radiologist and oncologist; those with radiological features of iCCA (dominant liver lesion, capsular retraction) were identified. RESULTS: Of 228 patients referred with pCUP, 72 (32%) had malignancy involving the liver. 24/72 patients had radiological features consistent with iCCA; they were predominantly female (75%) with an average age of 63 years and 63% had an ECOG PS ≤ 2. The median overall survival (OS) of the iCCA group and the remaining liver-involved CUP group were similar (OS 4.1 vs 4.4 months, p-value = 0.805). Patients, where a primary diagnosis was subsequently determined, had better OS (10.2 months, p-values: iCCA = 0.0279: cCUP = 0.0230). CONCLUSIONS: In this study, 34% of patients with liver-involved pCUP, fulfilled the radiological criteria for an iCCA diagnosis. Consideration of an iCCA diagnosis in patients with CUP could improve timely diagnosis, molecular characterisation and treatment

Discovery and validation of predictive biomarkers of survival for Non-Small Cell Lung Cancer patients undergoing radical radiotherapy: 2 proteins with predictive value

AbstractLung cancer is the most frequent cause of cancer-related death world-wide. Radiotherapy alone or in conjunction with chemotherapy is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Currently there is no predictive marker with clinical utility to guide treatment decisions in NSCLC patients undergoing radiotherapy. Identification of such markers would allow treatment options to be considered for more effective therapy. To enable the identification of appropriate protein biomarkers, plasma samples were collected from patients with non-small cell lung cancer before and during radiotherapy for longitudinal comparison following a protocol that carries sufficient power for effective discovery proteomics. Plasma samples from patients pre- and during radiotherapy who had survived >18mo were compared to the same time points from patients who survived <14mo using an 8 channel isobaric tagging tandem mass spectrometry discovery proteomics platform. Over 650 proteins were detected and relatively quantified. Proteins which showed a change during radiotherapy were selected for validation using an orthogonal antibody-based approach. Two of these proteins were verified in a separate patient cohort: values of CRP and LRG1 combined gave a highly significant indication of extended survival post one week of radiotherapy treatment