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The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Clinical Cancer Research is published. Click on the article title to view the complete article.
View the Table of Contents for the February 1 issue of Clinical Cancer Research.
Maekita et al. Page 989
Helicobacter pylori (HP) is a definite carcinogen to the human stomach. At the same time, DNA methylation is deeply involved in gastric cancers. By quantification of methylated DNA molecules in the gastric mucosae of healthy volunteers, Maekita et al. showed that high levels of DNA methylation are present in currently HP-positive individuals. In addition, HP-negative gastric cancer patients had higher methylation levels than HP-negative healthy volunteers. It was suggested that active HP infection potently and temporarily induces methylation, and that methylation levels in noncancerous gastric mucosae may reflect gastric cancer risk in HP-negative individuals.
Roy et al. Page 961
Exploitation of the field effect has great potential for colorectal cancer screening, however, current biomarkers have suboptimal accuracy. Roy et al. have recently developed a novel optics technology, enhanced backscattering spectroscopy (EBS) that allows depth-selective quantitative analysis of tissue microarchitecture thus providing the structural correlates to the genetic/epenetic alterations in the field effect. In the present study, we show that EBS markers had outstanding sensitivity for identifying colon carcinogenesis in the histologically normal mucosa of experimental models at timepoints that preceded conventional biomarkers. Furthermore, EBS analysis of endoscopically normal colonic mucosa was able to predict occurrence of adenomas in patients undergoing colonoscopy.
Riely et al. Page 839
In patients with non–small cell lung cancer, mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain are associated with sensitivity to erlotinib and gefitinib. Riely et al. correlated the specific EGFR mutation type with clinical characteristics and outcomes following treatment with gefitinib or erlotinib. Patients with EGFR exon 19 deletions had a significantly longer survival rate than patients with EGFR L858R point mutations (34 vs 8 months, log-rank P = 0.01). These are the first data to show a difference in survival between the two most common EGFR mutations in patients treated with erlotinib or gefitinib.
Jänne et al. Page 751
EGFR mutations are strong predictors of the efficacy of EGFR tyrosine kinase inhibitors gefitinib and erlotinib in non–small cell lung cancer. The current method of EGFR mutation, direct sequencing, requires isolation of DNA from a relatively pure population of tumor cells, cannot be performed on small diagnostic specimens, and lacks sensitivity. Jänne et al. compared direct sequencing with an alternative technology using a DNA endonuclease, SURVEYOR, which cleaves heteroduplexed DNA, and fluorescent detection as a method for EGFR mutation screening. This method requires no tumor dissection, has 100% sensitivity, and is able to detect mutations not identified by direct sequencing.
Reardon et al. Page 860
Adult malignant gliomas frequently show EGFR overactivity and dysregulated PI3k/AKT pathway signaling, yet most patients do not respond to EGFR-directed inhibition. Preclinical studies confirm that simultaneous targeting of upstream and downstream PI3k/AKT pathway mediators produces synergistic anti-glioma activity. The current phase 1 trial shows that the EGFR inhibitor gefitinib (upstream PI3k/AKT inhibitor) can be safely administered simultaneously with the mTOR inhibitor, sirolimus (downstream PI3k/AKT inhibitor). Combinatorial regimens designed to inhibit both upstream and downstream mediators of signaling pathways may provide greater inhibition of overall pathway activity and may help overcome some mechanisms of resistance.