BACKGROUND:The TRAVASTIN study dentified plasma Tie2 as the first vascular response biomarker for bevacizumab in metastatic colorectal cancer. Tie2-defined vascular responders had significantly longer progression-free survival (PFS) compared to nonresponders. Here, we report overall survival (OS) in TRAVASTIN after 7.7 years of follow-up, explore efficacy of bevacizumab use and reuse, and assess plasma Tie2 performance as a response biomarker. METHODS:This single-center, prospective study recruited 70 patients with newly diagnosed, large volume, metastatic colorectal cancer. Patients received first-line oxaliplatin-fluoropyrimidine chemotherapy plus bevacizumab. After disease progression, 22 patients were randomized to receive second-line fluorouracil-irinotecan chemotherapy with or without bevacizumab. A vascular response was defined as a 5% or more reduction in plasma Tie2 within 9 weeks of starting treatment. Survival outcomes were estimated using Kaplan-Meier statistics and analyzed using Cox proportional hazards regression. RESULTS:The updated median PFS and OS were 9.7 months (95% confidence interval [CI] 8.7-11.6) and 19.2 months (95% CI, 16.7-22.0), respectively. Multivariable analysis of key prognostic variables showed Tie2-defined vascular response associated with a significantly improved PFS (hazard ratio [HR] 0.49, 95% CI, 0.29-0.85, P = .011) and moderately improved OS (HR 0.71, 95% CI, 0.42-1.2, P = .195). Patients with a Tie2-defined vascular response to first-line bevacizumab therapy had a 3.7-month longer median OS with bevacizumab reuse than chemotherapy alone (10.5 months vs. 6.8 months, respectively), although this was not statistically significant. CONCLUSION:Plasma Tie2 is a response biomarker for PFS benefit with first-line bevacizumab in metastatic colorectal cancer, although OS benefit was not significant in TRAVASTIN. Our study highlights the promising use of Tie2 to guide bevacizumab treatment, including retreatment, in colorectal cancer.

Aim: The Ovarian Cancer Retrospective European (O'CaRE) study assessed the cumulative impact of high-risk factors on progression-free survival (PFS) and overall survival (OS) following first-line treatment in patients diagnosed with advanced ovarian cancer.Patients & methods: Medical records were collected from five European countries (2014 and 2015). Patients were grouped by number of high-risk factors: stage IV diagnosis, no known BRCA mutation, interval debulking surgery or no surgery, or visible residual disease.Results: Our analysis included 405 patients grouped based on having one (20.4%); two (32.3%); three (33.7%) or four (11.9%) high-risk factors. Increasing cumulative numbers of high-risk factors were associated with numerically shorter PFS and OS.Conclusion: Risk profiles should be carefully considered when planning clinical care.

Introduction/Background The O’CaRE study assessed real-world burden of disease, treatment patterns, and outcomes in patients with OC in 5 European countries (UK, France, Germany, Spain, and Italy). The analysis presented provides real-world data on the cumulative impact of risk factors (RFs) on disease progression and survival following 1L treatment. Methodology O’CaRE was a multicentre, noninterventional retrospective medical chart review study of patients aged ≥18 years diagnosed with epithelial ovarian, fallopian tube, or primary peritoneal cancer from 1 January 2014 to 31 December 2015. Patients were classified into moderate- or high-risk categories based on number of RFs for progression (Table). High-risk patients were further grouped by total number of RFs. Patients were followed from index date (date of diagnosis) until last activity or study end (maximum follow of 4 years). Kaplan-Meier methodology was used to estimate progression-free survival (PFS) and overall survival (OS). Results The analysis included 412 patients: 7 (1.7%) had moderate risk of progression, whereas 405 (98%) had high risk of progression (table 1). For those with high risk, 84 (20.4%), 133 (32.3%), 139 (33.7%), and 49 (11.9%) had 1, 2, 3, and 4 RFs, respectively. Median PFS was 31.3 months for patients with 0 RFs and 12.6, 7.9, 5.9, and 3.5 months for patients with 1, 2, 3, or 4 RFs, respectively. Median OS was 41.9 months for patients with 0 RFs and not reached, 25.0, 18.0, and 7.4 months for patients with 1, 2, 3, or 4 RFs, respectively. Conclusion This real-world analysis of patients with OC from 5 European countries demonstrated that higher numbers of RFs were associated with shorter median PFS and OS. This analysis provides real-world data relating to 1L treatment outcomes for patients with OC; if validated in clinical trials, the number of RFs could be a stratification factor for future 1L OC trials.

Background Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. Methods A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). Results Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, K trans , increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01–1.20, p = 0.025). Conclusions In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, K trans , offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer ( n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, K trans ( R :−0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease ( p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.

11521 Background: VEGF inhibitor (VEGFi) use is compromised by lack of predictive/ response biomarkers. Previously, we identified plasma Tie2 (pTie2) as a vascular response biomarker (VRB) for bevacizumab (bev) in ovarian cancer (OC). Here, we applied dynamic contrast-enhanced MRI (DCE-MRI) and circulating biomarkers in colorectal cancer (CRC), to validate pTie2 as the first tumor VRB. Methods: Seventy patients were recruited, with untreated, mCRC and ≥1 lesion of 3-10cm diameter for DCE-MRI. Patients received bev 10mg/kg for 2 weeks to elicit a biomarker response and then FOLFOX6/bev until progressive disease (PD) Thirteen circulating and 6 imaging biomarkers were measured before and during treatment and at PD. Unsupervised correlation analysis identified bev-induced biomarker correlations. Biomarkers were evaluated by clustered parameter-time course studies to determine their epithelial or vascular origin. Clinical significance was determined by relating the biomarker data to tumor 3D volumetric change assessed by MRI and PFS. The emergent vascular biomarker signal was modelled with epithelial biomarkers to assess the independent contribution of the vascular compartment to PD. Results: Bev induced significant correlations between pTie2, Ang2 and Ktrans. Cluster analysis of Tie2 concentration-time course curves showed that pTie2 reflected tumor Ktransbut not CK18, an epithelial antigen, i.e. changes in pTie2 reflected tumor vascular biology Patients who had the greatest area under the pTie2-time curve had tumors with high Ktransand/or low pVEGFR2, pre-treatment. They also had the greatest reduction in tumor volume and longest PFS. Fusion of pTie2 and CK18 data significantly improved modelling of PD. Conclusions: Bev impacts tumor vasculature causing proportional changes in pTie2. Information from pTie2 adds clinical value to that derived from the epithelial compartment. Thus (i) pTie2 is the first vascular response biomarker for bev and probably all VEGFi and (ii) demonstration of separate vascular and epithelial compartments in ovarian and CRC validates the vascular compartment as a target. This work identifies the first assay that could optimise use of VEGFi. Clinical trial information: 2009-011377-33.

Introduction: Definitive Chemo-Radiotherapy (CRT) is an important treatment option for localised oesophageal cancer, and definitive CRT with close surveillance and salvage surgery for local tumour persistence can be considered to be a recommended treatment for locally advanced SCC of the oesophagus (ESMO guidelines). Non-randomised data show that long term quality of life scores may be better with CRT than with surgery (Rees et al, 2015). Our audit aimed to evaluate the 30 day mortality in patients with oesophageal cancer treated with cisplatin-based CRT. It also explored possible risk factors for mortality within 30 days of cisplatin-based CRT. Methods: Local audit and Caldicott approval was obtained. Electronic medical notes report identified patients with oesophageal cancer who received cisplatin-based CRT with radical intent between May 2002 & Feb 2015 within the Merseyside Cancer Network. Local guidelines are based on radiotherapy schedules described in the SCOPE1 trial (updated Crosby et al 2017). The date and cause of death was ascertained from death certificates & medical notes. The 30 day mortality rate was defined as death within 30 days of receiving the last dose of chemotherapy or the last fraction of radiotherapy. WHO Performance Status (PS) and age at the start of CRT were explored as possible risk factors for 30 day mortality. Results: Fifty-seven patients met the specified inclusion criteria. The median age of the patient cohort was 64 years (range 43-79 years). Seventy-four percent of patients had a PS of 0 or 1; with 23% having a PS of 2 or 3. PS was not recorded in 3% of patients. Sixty-eight percent of patients had squamous cell carcinoma; 30% had adenocarcinoma and 1% had carcinoma of a non specified type. Four patients died within 30 days of treatment (7% of total). All four of these patients had PS 2 or 3 at presentation, meaning that 31% of patients with PS 2 or 3 died within 30 days of treatment. There was a significant difference in PS between those who died and those who did not (chi-squared test, p = 0.0002). All four patients who died were 70 years or older, with a median age of 74.5 years. This median age was significantly higher than the cohort median (Mann-Whitney test, p = 0.011). The overall survival in this cohort was 21.5 months. Conclusion: WHO PS of 2 or above and age of 70 years or above were risk factors for death within 30 days of treatment with definitive CRT in this cohort. This should be taken into account when considering therapeutic options in this patient population.

PURPOSE OF REVIEW:Angiogenesis has been validated as a target in ovarian cancer through four randomized trials that have reported improved progression-free survival (PFS) in patients with ovarian cancer whose conventional treatment was supplemented with concurrent and maintenance administration of the antivascular endothelial growth factor (VEGF) antibody, bevacizumab. These trials [the International Collaborative Ovarian Neoplasm Group trial (ICON7), the Gynecologic Oncology Group trial (GOG218), OCEANS and AURELIA] have shown that the tumour vasculature is a valid target throughout the lifetime of patients with ovarian cancer. This review seeks to address some of the remaining questions surrounding the optimal strategy for the use of bevacizumab in ovarian cancer.RECENT FINDINGS:The first-line trials, ICON7 and GOG218, showed improvements in PFS and in the case of ICON7, an early analysis reported increased overall survival in a predefined group of patients at high risk of disease progression. Trials in recurrent disease, OCEANS and AURELIA, also showed improvements in PFS, raising questions about whether VEGF-inhibiting agents should be confined to first-line therapy, second-line therapy or both.SUMMARY:Both the first-line trials stopped maintenance bevacizumab after 12 and 15 months, respectively; yet, current data suggest that maintenance therapy should continue at least until progression. In addition, current research is focussing on the identification of predictive biomarkers for VEGF inhibitors and candidates have been identified. Thus, the true clinical benefit from VEGF pathway inhibitors in the first-line treatment of ovarian cancer is likely to increase over the next few years.

4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) is a water-soluble mitochondrial toxin that binds to adenine nucleotide translocase in the inner mitochondrial membrane, thereby targeting cell proliferation. This phase 1 study investigated safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSAO as a daily 1-h infusion for 5 days a week for 2 weeks in every three. Pharmacodynamics of GSAO was evaluated by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and circulating markers of angiogenesis.

Abstract Background: The PI3K-AKT-mTOR signaling pathway is deregulated in a wide variety of cancers. GDC-0980 is a potent, selective, oral inhibitor of class I PI3K and mTOR kinase demonstrating broad activity in xenograft cancer models (breast, ovarian, lung, and prostate). Methods: A Phase I dose escalation study using a 3+3 design has been initiated in patients (pts) with advanced solid tumors or non-Hodgkin's lymphoma. GDC-0980 is administered QW. The objectives are to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD), evaluate PK and PD effects, and describe observed anti-tumor activity of GDC-0980 on this schedule. PD assessments include evaluating pAKT levels in platelet-rich plasma (PRP), biomarker pS6 in paired pre- and on-treatment tumor biopsies, tumor FDG avidity via PET imaging (FDG-PET), and tumor vasculature changes via DCE-MRI. Archival tumor tissue is evaluated for PTEN expression and PIK3CA mutations. Results: Thirty-two pts have been enrolled in 7 successive cohorts evaluating 6 to 200 mg of GDC-0980 QW. Drug-related adverse events (AEs) reported in ≥10% of pts were nausea, diarrhea, hyperglycemia, vomiting, and fatigue. The only Grade (g) ≥3 drug-related AEs have been g3 hyperglycemia at ≥150 mg GDC-0980. Hyperglycemic events have been asymptomatic and generally well managed after initiation of an oral diabetic agent. One patient each at 150 and 200 mg GDC-0980 experienced the DLT of a repeat fasting g3 hyperglycemia following a subsequent dose of GDC-0980 during the DLT assessment period despite initiation of oral diabetic therapy. The patient with the DLT at 150 mg has continued on-treatment for more than 8 months with isolated g3 events. Analyses of PK data suggest dose-proportional increases in fasting mean Cmax and AUC. Levels of pAKT in PRP were inversely correlated with GDC-0980 plasma concentrations. All patients treated at ≥25 mg with evaluable-paired tumor biopsies demonstrated significant decreases in pS6 IHC staining of up to 100%. Signs of clinical activity include 3 pts [gastrointestinal stromal tumor (GIST), solitary fibrous tumor, and ovarian cancer] treated at 150 mg QW who are all currently on study after 7 months. Clinical and PD activity was also observed in a pt with epithelioid sarcoma who was treated at 25 mg QW for 11 mo with a 22% decrease in tumor FDG avidity and a pt with ovarian cancer who was treated at 100 mg for 6.2 months and demonstrated a 22% decrease in tumor lesions by RECIST and 48% decrease in serum CA-125. By DCE-MRI, the pt with GIST on 150 mg QW demonstrated a 60% decrease in the blood-normalized area under the signal intensity-time curve (AUCBN) in liver lesions as assessed by DCE-MRI after 2 doses of GDC-0980 suggesting a potential anti-angiogenic effect. Conclusions: GDC-0980 is generally well tolerated when administered QW up to 200 mg with signs of anti-tumor activity. Decreases in the PD markers pAKT and pS6 are consistent with downstream modulation of the PI3K pathway. Dose-escalation continues and updated PK/PD data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B153.