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S1-2
Clinical Practice of Hybrid Capture-based Next-generation Sequencing for Lung Cancer
Alexander E. Drilon, M.D.
Memorial Sloan Kettering Cancer Center
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Therapeutic approaches to lung cancers have quickly shifted towards an emphasis on molecularly targeted therapy in genotypic subsets of atients. The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene in 2003 and rearrangements involving the anaplastic lymphoma kinase (ALK) gene in 2007 ushered in an era where the identification of key oncogenic alterations emerged as the critical determinant of benefit to targeted therapy. Phase III trials have demonstrated that response rate and progression-free survival are improved with targeted therapy in comparison to chemotherapy. In the United States, the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and afatinib, and the ALK TKIs crizotinib and ceritinib are approved for patients with EGFR-mutant and ALK-rearranged advanced lung cancers, respectively.
Recent data from The Cancer Genome Atlas (TCGA) revealed that lung cancers rank among the most genomically-complex of tumors among the 12 cancer types studied by the TCGA Pan-Cancer effort. This genomic complexity allows the opportunity to exploit the presence of other molecular alterations as therapeutic targets in patients. Over the last decade alone, the number of lung cancer drivers for which active targeted therapeutics have been identified has steadily risen. In lung adenocarcinomas, these include, beyond EGFR mutations and ALK fusions, mutations in ERBB2 (HER2), BRAF, PIK3CA, and AKT1, recurrent gene fusions involving ROS1, and RET, and MET amplification, with an ever-growing list of other potential candidates. Lung cancers from patients with a never smoking history have a unique molecular profile in comparison to lung cancers from smokers. Tumors from never smokers are characterized by lower overall mutation frequencies and are enriched for targetable drivers such as EGFR mutations, and ALK, ROS1, and RET fusions.
The evolution of molecular diagnostic platforms that permit rapid identification of oncogenic alterations has played a central role in allowing continued expansion of this approach. In the face of few targetable oncogenes, molecular testing previously followed a one driver-one test approach, with the use of Sanger sequencing to detect EGFR mutations and break apart fluorescence in situ hybridization (FISH) to detect ALK fusions. With an ever-expanding number of drivers of interest, multiplex polymerase chain reaction (PCR)-based platforms such as Sequenom (Sequenom, San Diego, CA) and SNaPShot (Applied Biosystems, Foster City, CA) were developed to simultaneously interrogate mutation hotspots in multiple oncogenes. In several larger centers, the pre-NGS approach to diagnostic testing commonly involved one of the latter methodologies in addition to multiplex sizing assays, FISH tests for recurrent gene fusions, and immunohistochemistry to determine overexpression or protein loss. However, from the perspective of the clinician, the clinical laboratories, and the patient, the amount of tissue, effort, and time required to complete such as an algorithm has become less and less feasible. |
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