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Early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer.

ABSTRACT: The impact of ctDNA changes after chemotherapy on the clinical outcomes of patients with metastatic colorectal cancer (mCRC) remains unclear. The present study evaluated the clinical implications of the early change in ctDNA levels as a predictor of objective response and clinical outcome in mCRC patients who received chemotherapy. We investigated the effects of after/before ratio of ctDNA levels 2 and 8 weeks after initiation of second-line chemotherapy, on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). ctDNA was detected using amplicon-based deep sequencing with a molecular barcode encompassing >240 hotspot mutations in 14 colon cancer-related genes. In multivariate analysis, as compared to baseline, patients with lower ctDNA level (?50%) 8 weeks after initiation of chemotherapy showed significantly longer PFS and OS than the patients with higher (>50%) ctDNA level. In patients achieving a partial response or stable disease, the after/before ratio of ctDNA level 8 weeks after initiation of chemotherapy was significantly lower than those in patients with progressive disease. The present study suggests that an early change in the ctDNA level might serve as a biomarker to predict the chemotherapeutic efficacy and clinical outcomes in patients with mCRC.

SUBMITTER: Osumi H

PROVIDER: S-EPMC6874682 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer.

Osumi Hiroki H Shinozaki Eiji E Yamaguchi Kensei K Zembutsu Hitoshi H

Scientific reports 20191122 1

The impact of ctDNA changes after chemotherapy on the clinical outcomes of patients with metastatic colorectal cancer (mCRC) remains unclear. The present study evaluated the clinical implications of the early change in ctDNA levels as a predictor of objective response and clinical outcome in mCRC patients who received chemotherapy. We investigated the effects of after/before ratio of ctDNA levels 2 and 8 weeks after initiation of second-line chemotherapy, on objective response rate (ORR), progre ...[more]

PMID: 31758080

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Project description:Multiple genomic changes caused by clonal evolution induced by therapeutic pressure and corresponding intratumoral heterogeneity have posed great challenges for personalized therapy against metastatic colorectal cancer (mCRC) in the past decade. Liquid biopsy has emerged as an excellent molecular diagnostic tool for assessing predominant spatial and temporal intratumoral heterogeneity with minimal invasiveness.Previous studies have revealed that genomic alterations in RAS, BRAF, ERBB2, and MET, as well as other cancer-related genes associated with resistance to anti-epidermal growth factor receptor (EGFR) therapy, can be analyzed with high diagnostic accuracy by circulating tumor DNA (ctDNA) analysis. Furthermore, by longitudinally monitoring ctDNAs during anti-EGFR therapy, the emergence of genomic alterations can be detected as acquired resistance mechanisms in specific genes, mainly those associated with the mitogen-activated protein kinase signaling pathway. Analysis of ctDNA can also identify predictive biomarkers to immune checkpoint inhibitors, such as mutations in mismatch repair genes, microsatellite instability-high phenotype, and tumor mutation burden. Some prospective clinical trials evaluating targeted agents for genomic alterations in ctDNA or exploring resistance biomarkers by monitoring of ctDNA are ongoing.To determine the value of ctDNA analysis for decision-making by more accurate molecular marker-based selection of patients and identification of resistance mechanisms to targeted therapies or sensitive biomarkers for immune checkpoint inhibitors, clinical trials must be refined to evaluate the efficacy of study treatment in patients with targetable genomic alterations confirmed by ctDNA analysis, and resistance biomarkers should be explored by monitoring ctDNA in large-scale clinical trials. In the near future, ctDNA analysis will play an important role in precision medicine for mCRC. IMPLICATIONS FOR PRACTICE: Treatment strategies for metastatic colorectal cancer (mCRC) are determined according to the molecular profile, which is confirmed by analyzing tumor tissue. Analysis of circulating tumor DNA (ctDNA) may overcome the limitations of tissue-based analysis by capturing spatial and temporal intratumoral heterogeneity of mCRC. Clinical trials must be refined to test the value of ctDNA analysis in patient selection and identification of biomarkers. This review describes ctDNA analysis, which will have an important role in precision medicine for mCRC.

Project description:BackgroundMetastatic colorectal cancer (mCRC) is a heterogenous disease with limited precision medicine and targeted therapy options. Monoclonal antibodies against epidermal growth factor receptor (EGFR) have been a crucial treatment option for mCRC. However, proper biomarkers for predicting therapeutic response remain unknown. As a non-invasive test, circulating tumor DNA (ctDNA) is appropriately positioned to reveal tumor heterogeneity and evolution, as it can be used in real-time genomic profiling. To evaluate the significance of ctDNA in monitoring the dynamic therapeutic response and prognosis of mCRC, we detected the baseline and dynamic changes of ctDNA in mCRC patients receiving anti-EGFR therapies.MethodsA single-center study was conducted retrospectively. Plasma samples from mCRC patients who received anti-EGFR therapies were collected at baseline and continuous treatment points. The ctDNA was extracted and sequenced with a target panel of tumor-related genes via next-generation sequencing (NGS). Clinical information was also collected and analyzed.ResultsWe conducted dynamic sampling of 22 mCRC patients, analyzed 130 plasma samples, obtained a baseline genomic mutation profile of the patients. In total, 54 variations were detected in 22 plasma samples, with a positive rate of 77.3% (17/22). TP53 was the most mutated gene (59.1%, 13/22), followed by APC (18.2%, 4/22). There was a high concordance rate of genomic characteristics between the tumor tissue test by polymerase chain reaction and ctDNA test by NGS. The mutation discrepancy increased with an extended course of treatment. During remission TP53 and APC were the most frequently decreased clonal mutations and KRAS, NRAS, ERBB2 and PIK3CA were the most decreased subclonal mutations. Both mutation types were increased during progression. The ctDNA decreased earlier than did the responses of computed tomography and traditional tumor markers (carbohydrate antigen 19-9 and carcinoembryonic antigen [CEA]). Lactate dehydrogenase level (P = 0.041), CEA level (P = 0.038), and primary lesion site (P = 0.038) were independent risk factors that influenced overall survival. Moreover, patients with RAS mutations tended to have a worse prognosis (P = 0.072).ConclusionsThis study demonstrates that ctDNA is a promising biomarker for monitoring the dynamic response to treatment and determining the prognosis of mCRC.

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Early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer.

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Early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer.

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