Dataset Information

Therapeutic Monitoring of Circulating DNA Mutations in Metastatic Cancer with Personalized Digital PCR.

ABSTRACT: As a high-performance solution for longitudinal monitoring of patients being treated for metastatic cancer, a single-color digital PCR (dPCR) assay that detects and quantifies specific cancer mutations present in circulating tumor DNA (ctDNA) was developed. This customizable assay has a high sensitivity of detection. One can detect a mutation allelic fraction of 0.1%, equivalent to three mutation-bearing DNA molecules among 3000 genome equivalents. The objective of this study was to validate the use of personalized dPCR mutation assays to monitor patients with metastatic cancer. The dPCR results were compared with serum biomarkers indicating disease progression or response. Patients had metastatic colorectal, biliary, breast, lung, and melanoma cancers. Mutations occurred in essential cancer drivers such as BRAF, KRAS, and PIK3CA. Patients were monitored over multiple cycles of treatment for up to a year. All patients had detectable ctDNA mutations. The results correlated with serum markers of metastatic cancer burden, including carcinoembryonic antigen, CA-19-9, and CA-15-3, and qualitatively corresponding to imaging studies. Corresponding trends were observed among these patients receiving active treatment with chemotherapy or targeted agents. For example, in one patient under active treatment, increasing quantities of ctDNA molecules were detected over time, indicating recurrence of tumor. This study demonstrates that personalized dPCR enables longitudinal monitoring of patients with metastatic cancer and may be a useful indicator for treatment response.

SUBMITTER: Wood-Bouwens CM

PROVIDER: S-EPMC7031679 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Therapeutic Monitoring of Circulating DNA Mutations in Metastatic Cancer with Personalized Digital PCR.

Wood-Bouwens Christina M CM Haslem Derrick D Moulton Bryce B Almeda Alison F AF Lee Hojoon H Heestand Gregory M GM Nadauld Lincoln D LD Ji Hanlee P HP

The Journal of molecular diagnostics : JMD 20191216 2

As a high-performance solution for longitudinal monitoring of patients being treated for metastatic cancer, a single-color digital PCR (dPCR) assay that detects and quantifies specific cancer mutations present in circulating tumor DNA (ctDNA) was developed. This customizable assay has a high sensitivity of detection. One can detect a mutation allelic fraction of 0.1%, equivalent to three mutation-bearing DNA molecules among 3000 genome equivalents. The objective of this study was to validate the ...[more]

PMID: 31837432

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Project description:BACKGROUND:ESR1 mutations are frequently detected in ER+ MBC, and have been reported to be associated with endocrine therapy resistance. However, there are little researches to validate whether dynamic monitoring of ESR1 mutations could serve as a predictive plasma biomarker of acquired resistance to endocrine therapy. Therefore, in this study, we performed longitudinal circulating tumor DNA (ctDNA) detection to evaluate the clinical implications of monitoring ESR1 mutations. METHODS:We performed longitudinal dynamic mutation analyses of plasma samples from 45 patients with metastatic breast cancer (MBC) and sequencing paired biopsy tissues, using a targeted NGS panel of 425 genes. These patients were treated at the Second Affiliated Hospital of Dalian Medical University between January 2017 and February 2019 with written informed consent. RESULTS:Mutations profiles were highly concordant between plasma and paired tissue samples from 45 MBC patients (r = 0.96, P < 0.0001). ESR1 mutations were enriched in ER+ MBC patients after AI therapy (17.8%, 8/45). The median time from AI endocrine therapies to the initial detection of ESR1 mutation was 39 months (95% CI 21.32-57.57). Some hotspot mutations (Y537S (n = 5), Y537N (n = 1), D538G (n = 2), E380Q (n = 2)) and several rare mutations (L345SfsX7, 24fs, G344delinsGC) were identified in our cohort. In addition, we observed that two patients obtained multiple ESR1 mutations over the course of treatment (Y537N/Y537S/D538G, L345SfsX7/24fs/E380Q). Through dynamically monitoring ESR1 mutations by ctDNA, we demonstrated that the change of allele frequency of ESR1 mutations was an important biomarker, which could predict endocrine resistance of ER+ MBC in our study. We also observed that the combination of everolimus in four cases with acquired ESR1 mutations showed longer PFS than other therapies without everolimus. CONCLUSION:The dynamic monitoring of ESR1 mutations by ctDNA is a promising tool to predict endocrine therapy resistance in ER+ MBC patients.

Dataset Information

Therapeutic Monitoring of Circulating DNA Mutations in Metastatic Cancer with Personalized Digital PCR.

Publications

Therapeutic Monitoring of Circulating DNA Mutations in Metastatic Cancer with Personalized Digital PCR.

Similar Datasets

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