Clinical next generation sequencing to identify actionable aberrations in a phase I program

// Genevieve M. Boland 1,2 , Sarina A. Piha-Paul 3 , Vivek Subbiah 3 , Mark Routbort 4 , Shelley M. Herbrich 5 , Keith Baggerly 6 , Keyur P. Patel 4 , Lauren Brusco 3 , Chacha Horombe 7 , Aung Naing 3 , Siqing Fu 3 , David S. Hong 3 , Filip Janku 3 , Amber Johnson 7 , Russell Broaddus 8 , Raja Luthra 4 , Kenna Shaw 7 , John Mendelsohn 7 , Gordon B. Mills 7,9 and Funda Meric-Bernstam 2,3,7 1 Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 7 Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 8 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Funda Meric-Bernstam, email: // Keywords : genomic sequencing, actionable genes Received : November 10, 2014 Accepted : April 23, 2015 Published : May 08, 2015 Abstract Purpose: We determined the frequency of recurrent hotspot mutations in 46 cancer-related genes across tumor histologies in patients with advanced cancer. Methods: We reviewed data from 500 consecutive patients who underwent genomic profiling on an IRB-approved prospective clinical protocol in the Phase I program at the MD Anderson Cancer Center. Archival tumor DNA was tested for 740 hotspot mutations in 46 genes (Ampli-Seq Cancer Panel; Life Technologies, CA). Results: Of the 500 patients, 362 had at least one reported mutation/variant. The most common likely somatic mutations were within TP53 (36%), KRAS (11%), and PIK3CA (9%) genes. Sarcoma (20%) and kidney (30%) had the lowest proportion of likely somatic mutations detected, while pancreas (100%), colorectal (89%), melanoma (86%), and endometrial (75%) had the highest. There was high concordance in 62 patients with paired primary tumors and metastases analyzed. 151 (30%) patients had alterations in potentially actionable genes. 37 tumor types were enrolled; both rare actionable mutations in common tumor types and actionable mutations in rare tumor types were identified. Conclusion: Multiplex testing in the CLIA environment facilitates genomic characterization across multiple tumor lineages and identification of novel opportunities for genotype-driven trials .