Clinical next generation sequencing to identify actionable aberrations in a phase I program
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Genevieve M. Boland1,2, Sarina A. Piha-Paul3, Vivek Subbiah3, Mark Routbort4, Shelley M. Herbrich5, Keith Baggerly6, Keyur P. Patel4, Lauren Brusco3, Chacha Horombe7, Aung Naing3, Siqing Fu3, David S. Hong3, Filip Janku3, Amber Johnson7, Russell Broaddus8, Raja Luthra4, Kenna Shaw7, John Mendelsohn7, Gordon B. Mills7,9 and Funda Meric-Bernstam2,3,7
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
Funda Meric-Bernstam, email:
Keywords: genomic sequencing, actionable genes
Received: November 10, 2014 Accepted: April 23, 2015 Published: May 08, 2015
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.
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