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Treatment monitoring in metastatic colorectal cancer patients by quantification and KRAS genotyping of circulating cell-free DNA.

ABSTRACT: Treatment of metastatic colorectal cancer (CRC) has continuously improved over the last decade. However, disease monitoring remains underdeveloped and mostly dependent on imaging e.g. RECIST 1.1 criteria. The genetic landscape of individual cancers and subsequently occurring treatment-induced evolution remain neglected in current surveillance strategies. Novel biomarkers demand minimally invasive and repetitive tracking of the cancer mutagenome for therapy stratification and to make prognostic predictions. Carcinoembryonic antigen (CEA), a routinely used tumor marker for CRC, does not meet these goals and thus prevents its use as a reliable monitoring tool. A tumor-derived fraction of circulating cell-free DNA (cfDNA), isolated from blood samples, may bypass the limitations of currently available biomarkers and could be a tool for noninvasive disease monitoring. Here, total cfDNA levels differentiated a cohort of metastatic CRC patients from healthy controls. Furthermore, we correlated cfDNA during chemotherapy of 27 stage IV patients with clinical parameters to establish its prognostic and predictive value. Indeed, cfDNA levels in chemotherapy naive patients correlate with the tumor burden and CEA values at diagnosis and increase upon disease progression during 1st and 2nd line treatment. Moreover, we confirm the possibility of cfDNA-based genotyping of KRAS to early detect the emergence of resistance during chemotherapy. These data indicate that repetitive quantitative and mutational analysis of cfDNA might complement current treatment standards but may have also limited value in some patients.

SUBMITTER: Berger AW

PROVIDER: S-EPMC5362218 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Treatment monitoring in metastatic colorectal cancer patients by quantification and KRAS genotyping of circulating cell-free DNA.

Berger Andreas W AW Schwerdel Daniel D Welz Hanna H Marienfeld Ralf R Schmidt Stefan A SA Kleger Alexander A Ettrich Thomas J TJ Seufferlein Thomas T

PloS one 20170322 3

Treatment of metastatic colorectal cancer (CRC) has continuously improved over the last decade. However, disease monitoring remains underdeveloped and mostly dependent on imaging e.g. RECIST 1.1 criteria. The genetic landscape of individual cancers and subsequently occurring treatment-induced evolution remain neglected in current surveillance strategies. Novel biomarkers demand minimally invasive and repetitive tracking of the cancer mutagenome for therapy stratification and to make prognostic p ...[more]

PMID: 28328955

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Project description:Simple Summary Synovial sarcomas (SS) are rare soft tissue tumors of mesenchymal origin. Following resection of the primary tumor, about one third to half of the patients suffer from recurrence. Detection of local and distant recurrence during follow-up is commonly accomplished by imaging. There are no biomarkers available for routine diagnostics. We employ a highly sensitive targeted next-generation sequencing approach to monitor tumor dynamics by genotyping of circulating free DNA (cfDNA) in SS patients. cfDNA which harbors tumor-specific mutations (circulating tumor-DNA; ctDNA) correlated with the presence of viable tumor tissue. This enables timely and non-invasive detection of tumor recurrence and monitoring of treatment response independent of the anatomic location. Abstract Background: Synovial sarcoma (SS) is a malignant soft tissue tumor of mesenchymal origin that frequently occurs in young adults. Translocation of the SYT gene on chromosome 18 to the SSX genes on chromosome X leads to the formation of oncogenic fusion genes, which lead to initiation and proliferation of tumor cells. The detection and quantification of circulating tumor DNA (ctDNA) can serve as a non-invasive method for diagnostics of local or distant tumor recurrence, which could improve survival rates due to early detection. Methods: We developed a subtype-specific targeted next-generation sequencing (NGS) approach specifically targeting SS t(X;18)(p11;q11), which fuses SS18 (SYT) in chromosome 18 to SSX1 or SSX2 in chromosome x, and recurrent point mutations. In addition, patient-specific panels were designed from tumor exome sequencing. Both approaches were used to quantify ctDNA in patients’ plasma. Results: The subtype-specific assay allowed detection of somatic mutations from 25/25 tumors with a mean of 1.68 targetable mutations. The minimal limit of detection was determined at a variant allele frequency of 0.05%. Analysis of 29 plasma samples from 15 tumor patients identified breakpoint ctDNA in 6 patients (sensitivity: 40%, specificity 100%). The addition of more mutations further increased assay sensitivity. Quantification of ctDNA in plasma samples (n = 11) from one patient collected over 3 years, with a patient-specific panel based on tumor exome sequencing, correlated with the clinical course, response to treatment and tumor volume. Conclusions: Targeted NGS allows for highly sensitive tumor profiling and non-invasive detection of ctDNA in SS patients, enabling non-invasive monitoring of tumor dynamics.

Dataset Information

Treatment monitoring in metastatic colorectal cancer patients by quantification and KRAS genotyping of circulating cell-free DNA.

Publications

Treatment monitoring in metastatic colorectal cancer patients by quantification and KRAS genotyping of circulating cell-free DNA.

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