Two of the allele-specific PCR-based methods and one PCR/direct sequencing method demonstrated high to good agreement with direct sequencing, whereas an oligonucleotide hybridization method showed poor agreement

Two of the allele-specific PCR-based methods and one PCR/direct sequencing method demonstrated high to good agreement with direct sequencing, whereas an oligonucleotide hybridization method showed poor agreement. AZD2858 3.?RESULTS The authors of the present article conducted a small study involving six Canadian laboratories to compare the accuracy and sensitivity of three methods of mutation analysis C the TheraScreen K-RAS testing kit only (1 laboratory), the TheraScreen K-RAS testing kit in combination with direct sequencing (2 laboratories), the TheraScreen K-RAS testing kit in combination with direct sequencing and RFLP (1 laboratory), and RFLP plus sequencing (2 laboratories). to predict non-response to cetuximab and panitumumab. The role of KRAS as a marker of efficacy of anti-EGFR therapies is usually reviewed. oncogene have consistently been shown to predict nonresponse to cetuximab and panitumumab. This marker is usually of particular importance, given the prevalence of mutations among patients with AZD2858 CRC; up to half of patients with CRC are found to have the mutant version of the gene3C6. 1.1. and the EGFR pathway is usually a signal transducer downstream of tyrosine kinase receptors including EGFR C a complex signaling cascade involved in the development and progression of cancer. The EGFR pathway is usually activated by the binding of the cell-surface EGFR/HER family receptors to their ligands, such as transforming growth factor alpha (TGF- ) and EGF. This leads to activation of genes that regulate cell cycle progression, tumor cell survival, metastases and angiogenesis DUSP10 (Fig. 1). Monoclonal antibodies against EGFR, such as cetuximab and panitumumab, block the receptor signaling and its downstream events, including those mediated by is usually active for a short period and the signaling activities to the downstream RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) pathway are tightly controlled. Mutated protein becomes constitutively activated, thereby making the cascade impartial of upstream signaling by tyrosine kinase receptors such as the EGFR. Therefore, blocking of EGFR with cetuximab or panitumumab may not affect downstream events. Mutations within the gene resulting in constitutive protein activity are found in approximately 30% to 50% of all CRCs3C6. 1.2. The role of and BRAF as markers of efficacy of the anti-EGFR therapy 1.2.1. KRAS As reviewed by Fakih and Wong in this supplement, the efficacy of the anti-EGFR antibodies cetuximab and panitumumab in the treatment of mCRC has consistently been shown to rely on the status of the tumor (Tables 1 and ?and2).2). Post hoc analyses of both randomized and single-arm trials of cetuximab or panitumumab have exhibited that these monoclonal antibodies are only effective against tumors with wild-type mutations in codon 12 or 13 do not derive any AZD2858 benefit from these treatments3,4,6C11. Table I. Randomized clinical trial evidence on the relationship of KRAS mutation status to efficacy of anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer Wild-typeMutatedbest supportive caren12411984100RR (%)17000Median PFS (wks)12.37.37.47.3HR0.450.9995% CI0.34C0.590.73C1.36Karapetis et al, 20089; second- or subsequent-line therapyCetuximab best supportive caren1171138183RR (%)12.801.20Median PFS (mo)3.71.91.81.8HR0.400.9995% CI0.30C0.540.73C1.36P 0.0010.96Median OS (mo)9.54.84.54.6P0.01 (for conversation, mutation status and treatment arm)OS at 1 yr (%)28.320.113.219.6HR (death)0.550.9895% CI0.41C0.740.70C1.37P 0.0010.89 Open in a separate window EGFR = Epidermal growth factor receptor; HR = hazard AZD2858 ratio; OR = odds ratio; PFS = progression-free survival; FOLFIRI = folinic acid, fluorouracil, and irinotecan; FOLFOX = folinic acid, fluorouracil, and oxaliplatin; CRYSTAL = Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer; OPUS = Oxaliplatin and Cetuximab in First-Line Treatment of mCRC; CAIRO2, Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer; RR = Risk reduction Adapted with permission: BlueCross BlueShield Association. Technology Evaluation Center. KRAS Mutations and Epidermal Growth Factor Receptor Inhibitor Therapy in Metastatic Colorectal Cancer TEC Assessments 2008; volume 23, tab 6. Copyright ? 2008, BlueCross BlueShield Association. Table II. Single-arm studies of treatment of metastatic colorectal cancer with anti-EGFR monoclonal antibodies and KRAS mutational status status and the efficacy of AZD2858 the monoclonal anti-EGFR antibody panitumumab was Amados analysis of tumors from 427 mCRC patients who were randomly assigned to treatment with panitumumab or best supportive care (BSC)6. Treatment response and improvement in progression-free survival (PFS) with panitumumab monotherapy were both limited to patients with wild-type mutations, none responded to the treatment. In contrast, 21 of 124 antibody-treated patients with wild-type tumors experienced a partial response. Among patients with wild-type (HR 0.99; 95% CI 0.73C1.36; median PFS of 7.4 weeks for panitumumab vs. 7.3 weeks for BSC). Comparable results have been exhibited with cetuximab. In a retrospective analysis of 540 mutation assessable patients in the CRYSTAL (Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial, mutations were identified in 35.6%4. For patients with wild-type mutations, treatment with cetuximab.