DNA-Mutation Inventory to Refine and Enhance Cancer Treatment (DIRECT): A Catalog of Clinically Relevant Cancer Mutations to Enable Genome-Directed Anticancer Therapy

Abstract

Purpose Tumor gene mutation status is becoming increasingly important in the treatment of patients with cancer. A comprehensive catalog of tumor gene–response outcomes from individual patients is needed, especially for actionable mutations and rare variants. We created a proof-of-principle database [DNA-mutation Inventory to Refine and Enhance Cancer Treatment (DIRECT)], starting with lung cancer-associated EGF receptor (EGFR) mutations, to provide a resource for clinicians to prioritize treatment decisions based on a patient’s tumor mutations at the point of care. Methods A systematic search of literature published between June 2005 and May 2011 was conducted through PubMed to identify patient-level, mutation–drug response in patients with non–small cell lung cancer (NSCLC) with EGFR mutant tumors. Minimum inclusion criteria included patient’s EGFR mutation, corresponding treatment, and an associated radiographic outcome. Results A total of 1,021 patients with 1,070 separate EGFR tyrosine kinase inhibitor therapy responses from 116 different publications were included. About 188 unique EGFR mutations occurring in 207 different combinations were identified: 149 different mutation combinations were associated with disease control and 42 were associated with disease progression. Four secondary mutations, in 16 different combinations, were associated with acquired resistance. Conclusions As tumor sequencing becomes more common in oncology, this comprehensive electronic catalog can enable genome-directed anticancer therapy. DIRECT will eventually encompass all tumor mutations associated with clinical outcomes on targeted therapies. Users can make specific queries at http:// www.mycancergenome.org/about/direct to obtain clinically relevant data associated with various mutations.

Emerging treatment for advanced lung cancer withEGFRmutation

“…It was observed in 2.7% of patients with squamous cell carcinoma. Its prevalence increases up to 10% in Western patient population with adenocarcinoma and up to 50% of Asian patients, with higher EGFR mutation frequency in Asian, non-smokers, women and non-mucinous cancers [7,8].…”

“…Competitive environment (emerging treatment) 7.1 Second-generation EGFR TKIs Acquired resistance to first-generation EGFR TKIs is a major clinical problem and most commonly characterized by secondary mutations in EGFR such as T790M in exon 20. Multiple second-generation EGFR TKIs were developed to overcome T790M-mediated resistance, however, the results are mostly disappointing due to dose-limiting toxicities.…”

MSEA: detection and quantification of mutation hotspots through mutation set enrichment analysis

“…Many driver mutations, especially nonsynonymous ones, recurrently occur in the functional regions of proteins (for example, kinase domains or binding domains) [17] or interrupt active sites (for example, phosphorylation sites) [18]. For example, mutations residing in the loops responsible for nucleotide binding (codons 12, 13, and 61) occur with high frequency in the RAS gene family (KRAS, HRAS, and NRAS) [17]; mutations at codons 154, 157, 158, 245, 248, and 273 of TP53 fall in the DNA binding domain of its protein product [19]; and mutations in PIK3CA form two clusters in the helical (E542K and E545K in exon 9) and catalytic (H1047R in exon 20) domains, respectively [20][21][22][23]. In extreme cases, many oncogenes are observed with highly recurrent substitutions that change the same amino acid, such as in the case of the substitution of arginine at codon 132 in isocitrate dehydrogenase 1 (IDH1) protein [24] and the V600 mutation in BRAF [25,26].…”

Section I: Integrating laboratory medicine with tissue specimens

“…Finally, the data outputs should be formatted to allow for rapid comparison with welldocumented public data sets, such as the Cancer Genome Atlas and DNA-Mutation Inventory to Refine and Enhance Cancer Treatment, to allow for the most accurate reporting information. 54 …”