|Title||Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Beltran H, Eng K, Mosquera JMiguel, Sigaras A, Romanel A, Rennert H, Kossai M, Pauli C, Faltas B, Fontugne J, Park K, Banfelder J, Prandi D, Madhukar N, Zhang T, Padilla J, Greco N, McNary TJ, Herrscher E, Wilkes D, MacDonald TY, Xue H, Vacic V, Emde A-K, Oschwald D, Tan AY, Chen Z, Collins C, Gleave ME, Wang Y, Chakravarty D, Schiffman M, Kim R, Campagne F, Robinson BD, Nanus DM, Tagawa ST, Xiang JZ, Smogorzewska A, Demichelis F, Rickman DS, Sboner A, Elemento O, Rubin MA|
|Date Published||2015 Jul|
|Keywords||Academic Medical Centers, Animals, Biomarkers, Tumor, Computational Biology, DNA Copy Number Variations, DNA Mutational Analysis, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Exome, Feasibility Studies, Female, Gene Dosage, Genetic Testing, Humans, INDEL Mutation, Male, Mice, Molecular Targeted Therapy, Mutation, Neoplasm Metastasis, Neoplasms, Patient Selection, Precision Medicine, Predictive Value of Tests, Prospective Studies, Time Factors, Treatment Outcome, Tumor Cells, Cultured, Xenograft Model Antitumor Assays|
IMPORTANCE: Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low-frequency mutations. We describe a whole-exome sequencing (WES) precision medicine trial focused on patients with advanced cancer.
OBJECTIVE: To understand how WES data affect therapeutic decision making in patients with advanced cancer and to identify novel biomarkers of response.
DESIGN, SETTING, AND PATIENTS: Patients with metastatic and treatment-resistant cancer were prospectively enrolled at a single academic center for paired metastatic tumor and normal tissue WES during a 19-month period (February 2013 through September 2014). A comprehensive computational pipeline was used to detect point mutations, indels, and copy number alterations. Mutations were categorized as category 1, 2, or 3 on the basis of actionability; clinical reports were generated and discussed in precision tumor board. Patients were observed for 7 to 25 months for correlation of molecular information with clinical response.
MAIN OUTCOMES AND MEASURES: Feasibility, use of WES for decision making, and identification of novel biomarkers.
RESULTS: A total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced, with a mean coverage of 95X and 16 somatic alterations detected per patient. In total, 16 mutations were category 1 (targeted therapy available), 98 were category 2 (biologically relevant), and 1474 were category 3 (unknown significance). Overall, WES provided informative results in 91 cases (94%), including alterations for which there is an approved drug, there are therapies in clinical or preclinical development, or they are considered drivers and potentially actionable (category 1-2); however, treatment was guided in only 5 patients (5%) on the basis of these recommendations because of access to clinical trials and/or off-label use of drugs. Among unexpected findings, a patient with prostate cancer with exceptional response to treatment was identified who harbored a somatic hemizygous deletion of the DNA repair gene FANCA and putative partial loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response.
CONCLUSIONS AND RELEVANCE: The majority of advanced, treatment-resistant tumors across tumor types harbor biologically informative alterations. The establishment of a clinical trial for WES of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.
|Alternate Journal||JAMA Oncol|
|PubMed Central ID||PMC4505739|
|Grant List||R01 CA179100 / CA / NCI NIH HHS / United States |
UL1 RR024996 / RR / NCRR NIH HHS / United States
KL2TR000458 / TR / NCATS NIH HHS / United States
T32 GM083937 / GM / NIGMS NIH HHS / United States
KL2 TR000458 / TR / NCATS NIH HHS / United States
CA111275 / CA / NCI NIH HHS / United States
R01 CA116337 / CA / NCI NIH HHS / United States
U01 CA111275 / CA / NCI NIH HHS / United States