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 of KRASExperimental Design: A quantitative, mutation-enrichment next-generation sequencing test for detecting KRASG12/G13 mutations 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, the KRASG12/G13 cfDNA 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 fewer KRASG12/G13 copies in urine cfDNA during systemic therapy than at baseline or disease progression (P = 0.002). Compared with no changes or increases in urine cfDNA KRASG12/G13 copies 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 detecting KRASG12/G13 mutations 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.
Highlights
Detecting molecular alterations can provide guidance for personalized cancer therapy in patients with melanoma, non–small cell lung cancer (NSCLC), colorectal cancer, and other cancers [1,2,3,4,5]
Compared with no changes or increases in urine cell-free DNA (cfDNA) KRASG12/G13 copies during therapy, decreases in these measures were associated with longer median time to treatment failure (P 1⁄4 0.03)
Changes in mutated urine cfDNA were associated with time to treatment failure
Summary
Detecting molecular alterations can provide guidance for personalized cancer therapy in patients with melanoma, non–small cell lung cancer (NSCLC), colorectal cancer, and other cancers [1,2,3,4,5]. KRAS mutations are associated with poor prognosis in diverse cancer types and with lack of benefit from anti–EGFRtargeted monoclonal antibodies in colorectal cancer [3, 6,7,8]. Oncogenic alterations such as KRAS mutations are assessed in archival tumor tissue, but the tissue availability is often a limiting factor that precludes molecular analysis [9, 10]. Mutation assessment of primary tumor tissue or an isolated metastasis does not necessarily reflect the genetic makeup of metastatic disease owing to tumor heterogeneity [11,12,13]. Translational studies in EGFR-mutated NSCLC suggest that cancer genotype can change over time; for example, Sequist and colleagues demonstrated in a group of 37 patients with EGFR-mutant NSCLC who had pretreatment and www.aacrjournals.org
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