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Hershey, PA
Dr. Zander is Professor and Chair, Department of Pathology, Penn State Milton S. Hershey Medical Center.
Correspondence to: Dani S. Zander, MD, Professor and Chair, Department of Pathology, Penn State Milton S. Hershey Medical Center-M.C. H083, PO Box 850, 500 University Dr, Hershey, PA 17033-0850; e-mail: dzander{at}hmc.psu.edu
In this issue of CHEST (see page 1628), Horiike and colleagues1 present us with a demonstration of modern technological magic applied to the diagnosis and treatment of lung cancer. They illustrate how the combination of a sensitive diagnostic technique and a sensitive molecular assay can extract information from small samples that is comparable to that achieved by more conventional approaches. Although bronchoscopic sampling techniques of biopsy, brushing, washing, and BAL have become standard approaches for diagnosis of lung cancers, transbronchial fine-needle aspiration (TBNA) is less commonly used. Its success in obtaining diagnostic material is highly dependent on the skills of the operators, including the person performing the procedure and the person interpreting the slides produced. Horiike and colleagues1 collected TBNA samples from 93 patients with a cytologically confirmed diagnosis of non-small cell carcinoma (established from the TBNA samples) and subjected the TBNA samples to molecular analysis for epidermal growth factor receptor (EGFR) mutations. The latter testing was performed using two methodologies: direct sequencing, which is currently the routine method used for detecting EGFR mutations in tumor samples, and a newer assay (Scorpion Amplification Refractory Mutation System [ARMS]; DxS; Manchester, UK), which employs primers consisting of a specific probe sequence held in a hairpin loop configuration by complementary stem sequences on the 5' and 3' sides of the probe.23 Sufficient polymerase chain reaction products were obtained to allow for direct sequencing in samples from 83 patients, while EGFR mutation status could be analyzed in 91 patients using the EGFR Scorpion ARMS method. EGFR mutations were detectable in 31 patients, with detection by both methods in 9 patients, Scorpion ARMS alone in 18 patients, and direct sequencing alone in 4 patients, leading the authors to conclude that the Scorpion ARMS method is more sensitive for detecting the most common EGFR mutations than direct sequencing.
This study illustrates our growing ability to obtain information of diagnostic and prognostic relevance from smaller and smaller samples, eliminating the need for more invasive procedures in patients with advanced disease. It also represents an expression of the expanding array of testing that is targeting toward predicting response to specific therapeutic agents and survival. Assessment for HER2 amplification is the most well-vetted example of this approach, and is now a standard component of the pathologic evaluation of breast cancers.4 With regard to non-small cell lung cancer, the EGFR mutation status of the tumor has emerged as a predictive variable, with clinical responsiveness to EGFR tyrosine kinase inhibitors associated with somatic EGFR mutations in tumors.56789
In fact, increasing numbers of genes and gene products are claimed to have prognostic relevance for many types of tumors, with varying degrees of evidence supporting these contentions, and a panoply of different experimental approaches and study populations. Distilling coherent recommendations from this data has been approached, in the case of HER2 testing in breast cancer, through focused analysis by a multidisciplinary consensus panel.4 The NCCN HER2 Testing in Breast Cancer Task Force convened recently to critically evaluate the ability of the level of HER2 expression or gene amplification in breast tumors to serve as a prognostic and a predictive factor in metastatic and adjuvant settings, to assess the reliability of the methods of measuring HER2 expression or gene amplification in the laboratory, and to make recommendations regarding the interpretation of test results, which will be widely adopted. The expansion of data on prognostic markers has also been accompanied by the appearance of personalized tumor testing for genes and gene products predictive of responsiveness to specific therapeutic agents.101112 Although substantial outcomes-based research is needed to substantiate the prognostic relevance of some of the putatively important genes or gene products, these molecular profiling approaches have the potential to sort the patients likely to benefit from specific agents, from those who are unlikely to respond, and for whom the morbidity and mortality risks associated with therapy may not be warranted. Robust and well validated testing systems are a precondition for the clinical trials that will follow to determine the linkages between disease process, genomic or proteomic characteristic, specific therapeutic agent, and therapeutic response. Testing paradigms like those employed by Horiike and colleagues, which utilize innovative new technologies to maximize the information gained from small samples, are well worth a look.
Footnotes
The author has no conflict of interest to disclose.
References
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