Jenny Barrett

Premature coronary artery disease shows no evidence of linkage to loci encoding for tissue inhibitors of matrix metalloproteinases

AbstractTissue inhibitors of metalloproteinases (TIMP1, TIMP2, TIMP3) are naturally occurring inhibitors of matrix metalloproteinases (MMPs). It has been proposed that MMPs have a role in weakening the fibrous cap and subsequent plaque rupture. We hypothesized that TIMP polymorphisms could predispose to premature coronary artery disease. As a first step, we examined the relevant loci using a linkage approach. Sibling pairs recruited for the British Heart Foundation (BHF) Family Heart Study with premature coronary artery disease were examined. Two to three microsatellite markers were examined per TIMP gene. These markers were either intragenic or very close to the locus encoding for the gene. Products were analyzed by capillary gel electrophoresis. Single and multipoint linkage analysis based on the likelihood ratio test was performed using SPLINK and Mapmaker/Sibs software; 417 families were genotyped consisting of 385 sibling pairs, 27 trios, and five sets of four siblings. We were unable to detect linkage of premature coronary artery disease to loci encoding for TIMP1-3. Polymorphisms of the tissue inhibitors of MMP genes do not predispose to premature coronary artery disease in an epidemiologically significant way.

Role of derived neutrophil lymphocyte ratio as a biomarker in advanced colorectal cancer

Abstract Background The discovery and validation of prognostic and predictive biomarkers in advanced colorectal cancer is crucial for the personalisation of therapy. Inflammation-based prognostic scores have been developed, including the neutrophil lymphocyte ratio (NLR), and the derived NLR (dNLR) calculated using a differential white cell count. The NLR has been assessed in several cancers; in a retrospective series of advanced colorectal cancer, higher NLR was associated with reduced survival and poorer outcomes with chemotherapy. We aimed to validate the usefulness of the dNLR as a prognostic and a predictive biomarker to anti-epidermal growth factor receptor (EGFR) agents in advanced colorectal cancer. Methods We studied patients from a phase 3, open-label, randomised controlled trial that assessed the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer (PICCOLO trial). The prognostic analysis included all patients for whom dNLR data were available; a subset with KRAS wild-type tumours randomised to standard irinotecan with or without panitumumab was also analysed for predictive value. The dNLR was calculated from the prerandomisation blood count and categorised as high (≥2) or low ( Findings 1159 patients were included in the prognostic analysis, and 444 in the predictive analysis. In multivariate analysis, high dNLR was independently associated with reduced overall survival compared with low dNLR (hazard ratio 1·59, 95% CI 1·32–1·78; p KRAS, BRAF, NRAS , and PIK3CA ), and in the subset of 323 patients in this all-wild-type category panitumumab had a more marked effect on tumour response rate in patients with low dNLR (odds ratio 7·4, p Interpretation The dNLR seems to offer the clinician useful prognostic information. Since this information can easily be calculated from routine clinical data, its integration into routine patient assessment should be considered after further validation. We did not demonstrate significant predictive value for anti-EGFR therapy, but our finding of higher response with panitumumab in patients with a low dNLR is hypothesis generating. Further investigation in datasets from randomised controlled trials and exploratory translational work are warranted. Funding Cancer Research UK, Yorkshire Cancer Research.

509PDPRIMARY TUMOUR LOCATION (PTL) AS A PROGNOSTIC AND PREDICTIVE FACTOR IN ADVANCED COLORECTAL CANCER (ACRC): DATA FROM 2075 PATIENTS (PTS) IN RANDOMISED TRIALS

ABSTRACT Aim: Variations in tumour biology and outcomes depending upon PTL have been reported in aCRC. We tested effects of PTL in two phase III randomised trials. Methods: We studied 2075 pts, from FOCUS (1st-line; n = 1390; Lancet 370: 143-52) and PICCOLO (2nd-line; n = 685; Lancet Oncol 14:749-59). We compared: (1) right colon (RC) vs [left colon (LC) or rectum] and (2) LC vs rectum. Association of PTL with RAS/RAF, AREG/EREG and MMR was assessed where available. PTL was tested as a prognostic factor, then for predictive utility by testing PTL/treatment interactions on OS and PFS for: 1st line FU vs doublet (FOCUS); 1st-line irinotecan doublet vs oxaliplatin doublet (FOCUS); 2nd line irinotecan (Ir) +/- panitumumab (Pan) (KRAS-wt pts, PICCOLO). Results: PTL was RC in 575 (28%), LC in 801 (39%) and rectum in 699 (34%) pts. RC tumours had more BRAF mutations (n = 1136, 22% vs 6%, p Interaction test p-values for treatment comparisons Comparison Interaction Test p-values RC vs LC/rectum LC vs Rectum OS PFS OS PFS 1st line doublet vs single-agent FU (1334 pts) 0.39 0.84 0.48 0.8 1st line OxFU doublet vs IrFU doublet (452 pts) 0.99 0.67 0.18 0.50 2nd line Ir +/- Pan KRAS-WT (450 pts) 0.35 0.13 0.63 0.46 2nd line Ir +/- Pan KRAS/BRAF-WT (341 pts) 0.72 0.89 0.83 0.19 Conclusions: We confirm that RC tumours are biologically distinct, and have worse outcomes with 1st-line therapy. We did not find PTL to be predictive for the benefit of the drugs under test in these trials, so cannot recommend its use for selection of therapy. Better objective predictive biomarkers are required. Disclosure: All authors have declared no conflicts of interest.

553PTHE DERIVED NEUTROPHIL LYMPHOCYTE RATIO (DNLR) AS A BIOMARKER IN ADVANCED COLORECTAL CANCER (ACRC)

ABSTRACT Aim: Links between inflammation, the immune response and cancer outcomes are compelling. The dNLR, calculated from a standard blood count, is a simple measure of inflammatory response, and in retrospective series high dNLR has been reported to be associated with poorer outcomes in aCRC. We examined dNLR as a prognostic marker, and assessed its predictive utility for two treatments in large phase III trials in aCRC. Methods: 2484 patients (pts) were studied, from the FOCUS (Lancet 370:143, 2007) and PICCOLO trials (Lancet Oncol 14:749, 2013). dNLR was calculated from the pre-randomisation blood count and prospectively defined as “high” (≥2) or “low” ( Results: 52.8% pts had high dNLR; 47.2% had low dNLR. High dNLR was independently associated with reduced OS in both trials (FOCUS: n = 1810 HR 1.51, p 25% after 6 weeks of chemotherapy was associated with a higher risk of disease progression at 12 weeks (OR = 1.6, p = 0.02) and inferior PFS (HR = 1.34, p Conclusions: The dNLR provides prognostic information and may provide an early warning when chemotherapy is failing. It might also help identify patients who could be treated safely with less intensive 1st line chemotherapy, but confirmatory data are required. Given that dNLR is readily and freely calculated from routine clinical data, its integration into routine patient evaluation should be considered following further validation. Disclosure: All authors have declared no conflicts of interest.

A genomewide linkage study of 1,933 families affected by premature coronary artery disease

Coronary artery disease (CAD) and its most important complication, myocardial infarction (MI), are the leading cause of premature death in the Western world. CAD has a substantial genetic basis, especially when it occurs early. We investigated the genetic determinants of premature CAD by performing a genomewide linkage analysis of 4,175 affected subjects from 1,933 families recruited throughout the United Kingdom. Each family had at least two available siblings with CAD, with validated onset before age 66 years. Linkage analysis was performed using 416 microsatellite markers. We observed suggestive linkage, for both CAD and MI, to a region on chromosome 2. For CAD, a LOD score of 1.86 was observed at marker D2S2271, which, in an ordered subset analysis, increased to 2.70 in families (n=1,698) with a minimum age at diagnosis of 56 years or younger. For MI, an overlapping peak with a LOD score of 1.15 was observed at marker D2S2216, which increased to 2.1 in families (n=801) with a minimum age at diagnosis of 59 years or younger. Exclusion mapping showed that 100% of the autosomal genome could be excluded for locus-specific sibling relative risks of 1.5 and 1.6 for CAD and MI, respectively. The region identified on chromosome 2 overlaps linked regions observed in two other smaller genome scans for CAD. Together, these findings strongly suggest that there is a locus on chromosome 2 that influences coronary atherosclerosis risk. The exclusion of a common locus that increases risk of CAD to siblings by >50% has important implications for strategies for further defining the genetic basis of CAD.