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The Nuffield Department of Medicine (NDM) at the University of Oxford has a global reach and significant breadth in terms of capabilities and capacity.
Biomarkers in Early-Stage Colorectal Cancer: Ready for Prime Time?
<b><i>Background/Aims:</i></b> During the last two decades, hundreds of reports have detailed putative prognostic and predictive biomarkers for colorectal cancer (CRC). However, the majority of these studies have been small and retrospective, reporting results that are highly likely to represent false positives. Consequently, their relevance to clinical practice requires definition. <b><i>Methods:</i></b> Review of published literature on CRC biomarkers, focusing on early-stage disease. <b><i>Results:</i></b> Although most putative biomarkers have failed to be validated in subsequent studies, level I evidence now indicates that tumour microsatellite instability can be used to identify a cohort of patients with stage IIA disease at low risk of relapse who can be spared adjuvant chemotherapy. Emerging data suggest that gene expression arrays may have a role in selecting patients with stage IIA disease and mismatch repair-proficient tumours for chemotherapy following tumour resection. <b><i>Conclusion:</i></b> Despite the profusion of biomarker literature, only mismatch repair status can be recommended as routine in current clinical practice. High-quality, adequately powered studies are essential to accurately define the utility of existing and putative biomarkers, and to support their rational application in the clinic.
Insulin‐like growth factor ligands, receptors, and binding proteins in cancer
AbstractThis review aims to summarize experimental evidence supporting the role of the insulin‐like growth factor (IGF) signalling system in the progression, maintenance, and treatment of cancer. These data implicate the IGF system as an important modifier of cancer cell proliferation, survival, growth, and treatment sensitivity. The role of the IGF system in cancer should be examined in the context of the extra‐cellular and intra‐cellular signalling networks, in particular: phosphatidylinositol 3‐kinase (PI3K), protein kinase B (Akt/PKB), mammalian target of rapamycin (mTOR), and forkhead transcription factors (FOXO). This review highlights evidence derived from molecular structure and functional genetics with respect to how the extra‐cellular components of the IGF system function normally, and their subsequent modifications in cancer. The therapeutic relevance of the research evidence described is also addressed, as the challenge is to apply this knowledge to human health. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Screening for Lynch syndrome and referral to clinical genetics by selective mismatch repair protein immunohistochemistry testing: an audit and cost analysis
Lynch syndrome (LS) accounts for around 3% of colorectal cancers (CRCs) and is caused by germline mutations in mismatch repair (MMR) genes. Recently, screening strategies to identify patients with LS have become popular. We audited CRCs screened with MMR immunohistochemistry (IHC) in 2013. 209 tumours had MMR IHC performed at a cost of £12 540. 47/209 (21%) cases showed IHC loss of expression in at least one MMR protein. 28/44 cases with loss of MLH1 had additional BRAF V600E testing, at a cost of £5040. MMR IHC reduced the number of potential clinical genetics referrals from 209 to 47. BRAF mutation testing, performed in a subset of cases with MLH1 loss, further reduced this to 21. At a cost of £1340 per referral, this model of LS screening for clinical genetics referral had significant potential savings (£234 340) and can be easily implemented in parallel with MMR IHC done for prognostication in CRCs.
Stage II colon cancer.
Colorectal cancer (CRC) is the third commonest cancer in the Western world. Approximately one-quarter of cases are classified as Stage II/Dukes' B, meaning that the disease has breached the bowel wall but not spread to draining lymph nodes or distant sites. Stage II colon cancer is a heterogeneous disease both biologically and in terms of outcome. Although pivotal data have confirmed the benefit of adjuvant 5-fluorouracil (FU) chemotherapy following resection of stage II tumours the absolute reduction in risk of recurrence is small - 3 to 4 percentage points - and so most patients treated fail to gain from therapy. In contrast to stage III disease, the addition of oxaliplatin to FU as adjuvant chemotherapy for stage II disease does not improve outcome. Much attention has focused on the identification of biomarkers that identify patients more or less likely to benefit from treatment. Recent data confirm that patients with T3 primary and tumour microsatellite instability (MSI) have excellent prognosis and do not require adjuvant chemotherapy. For patients with microsatellite-stable disease, a validated recurrence score based on gene expression provides greater prognostic information than conventional clinicopathological features alone and can be used to inform discussion on the benefits of adjuvant chemotherapy.