title: Mutation-Enrichment Next-Generation Sequencing for Quantitative Detection ofKRASMutations in Urine Cell-Free DNA from Patients with Advanced Cancers.
abstract: Purpose:Tumor-derived cell-free DNA (cfDNA) from urine of patients with cancer offers noninvasive biological material for detection of cancer-related molecular abnormalities such as mutations in Exon 2 ofKRASExperimental Design:A quantitative, mutation-enrichment next-generation sequencing test for detectingKRASG12/G13mutations in urine cfDNA was developed, and results were compared with clinical testing of archival tumor tissue and plasma cfDNA from patients with advanced cancer.Results:With 90 to 110 mL of urine, theKRASG12/G13cfDNA test had an analytical sensitivity of 0.002% to 0.006% mutant copies in wild-type background. In 71 patients, the concordance between urine cfDNA and tumor was 73% (sensitivity, 63%; specificity, 96%) for all patients and 89% (sensitivity, 80%; specificity, 100%) for patients with urine samples of 90 to 110 mL. Patients had significantly fewerKRASG12/G13copies in urine cfDNA during systemic therapy than at baseline or disease progression (P= 0.002). Compared with no changes or increases in urine cfDNAKRASG12/G13copies during therapy, decreases in these measures were associated with longer median time to treatment failure (P= 0.03).Conclusions:A quantitative, mutation-enrichment next-generation sequencing test for detectingKRASG12/G13mutations in urine cfDNA had good concordance with testing of archival tumor tissue. Changes in mutated urine cfDNA were associated with time to treatment failure.Clin Cancer Res; 23(14); 3657-66. ©2017 AACR.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Takeo
authors.initials: T
authors.lastname: Fujii
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Barzi
authors.affiliation: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda and Università degli Studi di Milano, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda and Università degli Studi di Milano, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cassingena
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.|Department of Oncology, University of Torino, Candiolo, Torino, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Siravegna
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Karp
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Huang
authors.affiliation: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda and Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Veronese
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.|Department of Oncology, University of Torino, Candiolo, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Trovagene, San Diego, California.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Pingle
authors.affiliation: Trovagene, San Diego, California.
authors.forename: Cecile Rose T
authors.initials: CRT
authors.lastname: Vibat
authors.affiliation: Trovagene, San Diego, California.
authors.forename: Saege
authors.initials: S
authors.lastname: Hancock
authors.affiliation: Beverly Hills Cancer Center, Beverly Hills, California.|City of Hope, Duarte, California.
authors.forename: David
authors.initials: D
authors.lastname: Berz
authors.affiliation: Trovagene, San Diego, California.
authors.forename: Vladislava O
authors.initials: VO
authors.lastname: Melnikova
authors.affiliation: Trovagene, San Diego, California.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Erlander
authors.affiliation: Department of Hematopathology, Molecular Diagnostic Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Kopetz
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda and Università degli Studi di Milano, Milano, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.|Department of Oncology, University of Torino, Candiolo, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas. fjanku@mdanderson.org.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000652:urine*; D000073888:Cell-Free Nucleic Acids / Q000235:genetics / Q000652:urine*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000652:urine; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000652:urine*
chemical_list: D014408:Biomarkers, Tumor; D000073888:Cell-Free Nucleic Acids; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)