Clinical Application of Liquid Biopsy in Targeted Therapy of Metastatic Colorectal Cancer

Trojan, Jörg; Klein-Scory, Susanne; Koch, Christine; Schmiegel, Wolff; Baraniskin, Alexander

doi:10.1155/2017/6139634

Cited by 12 publications

(11 citation statements)

References 11 publications

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“…Some studies identified RAS mutations in ctDNA after anti‐EGFR therapy. A case series indicated that detection of RAS mutations in the plasma during anti‐EGFR therapy provided early warning of impending resistance, which was confirmed several months later by imaging . A retrospective analysis of ctDNA from mCRC patients refractory to anti‐EGFR therapy showed that KRAS codon 61 and 146 mutations were more common than in treatment‐naïve patients and the frequency of acquired KRAS mutations was inversely correlated with the time since last anti‐EGFR therapy .…”

Section: Identification Of Biomarkers Related To Resistance To Epidermentioning

confidence: 97%

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

Nakamura

Yoshino

2018

The Oncologist

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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 ,, , and, 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.

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Section: Identification Of Biomarkers Related To Resistance To Epidermentioning

confidence: 97%

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

Nakamura

Yoshino

2018

The Oncologist

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“…To personalize EGFR-directed treatment, we need to gain insight into alternative ways to target this essential pathway. This may include the development of liquid biopsy approaches to monitor for resistant subclones (40,41), drug holiday strategies to hamper the selection of RAS-mutant subclones (42), and the development of agents with alternative or multiple epitope recognition that may overcome resistance by acquired EGFR ectodomain mutations or that prevent their selection in the first place (22,43).…”

Section: Discussionmentioning

confidence: 99%

Nanobody Targeting of Epidermal Growth Factor Receptor (EGFR) Ectodomain Variants Overcomes Resistance to Therapeutic EGFR Antibodies

Tintelnot

Baum

Braig

et al. 2019

Molecular Cancer Therapeutics

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Epidermal growth factor receptor (EGFR) ectodomain variants mediating primary resistance or secondary treatment failure in cancer patients treated with cetuximab or panitumumab support the need for more resistance-preventive or personalized ways of targeting this essential pathway. Here, we tested the hypothesis that the EGFR nanobody 7D12 fused to an IgG1 Fc portion (7D12-hcAb) would overcome EGFR ectodomain-mediated resistance because it targets a very small binding epitope within domain III of EGFR. Indeed, we found that 7D12-hcAb bound and inhibited all tested cell lines expressing common resistance-mediating EGFR ectodomain variants. Moreover, we assessed receptor functionality and binding properties in synthetic mutants of the 7D12-hcAb epitope to model resistance to 7D12-hcAb. Because the 7D12-hcAb epitope almost completely overlaps with the EGFbinding site, only position R377 could be mutated without simultaneous loss of receptor functionality, suggesting a low risk of developing secondary resistance toward 7D12-hcAb. Our binding data indicated that if 7D12-hcAb resistance mutations occurred in position R377, which is located within the cetuximab and panitumumab epitope, cells expressing these receptor variants would retain sensitivity to these antibodies. However, 7D12-hcAb was equally ineffective as cetuximab in killing cells expressing the cetuximab/panitumumabresistant aberrantly N-glycosylated EGFR R521K variant. Yet, this resistance could be overcome by introducing mutations into the Fc portion of 7D12-hcAb, which enhanced immune effector functions and thereby allowed killing of cells expressing this variant. Taken together, our data demonstrate a broad range of activity of 7D12-hcAb across cells expressing different EGFR variants involved in primary and secondary EGFR antibody resistance.

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“…This is reasoned by predominant suppression of RAS wild-type clones during anti-EGFR mAb therapy and, in this manner, indirect selection of RAS mutated clones. However, after the discontinuation of EGFR inhibition, RAS mutational load rapidly decreases within a few weeks, probably due to the lack of selective pressure by the anti-EGFR mAb therapy [7] , [15] , [16] , [17] . Supported by data of Santini et al, retreatment (aka rechallenge) with anti-EGFR mAb therapy is currently under active investigation in clinical trials [18] .…”

Section: Discussionmentioning

confidence: 99%

Significance of Liquid Biopsy for Monitoring and Therapy Decision of Colorectal Cancer

Klein-Scory

Маслова

Pohl

et al. 2018

Translational Oncology

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PURPOSE: Despite therapeutic improvements, all patients with nonresectable metastatic colorectal cancer (mCRC) acquire resistance to treatment probably due to the growth of mutated clones. In contrast to tissue-based studies, liquid biopsies have enabled the opportunity to reveal emerging resistance to treatment by detecting mutated clones and noninvasively monitoring clonal dynamics during therapy. METHODS: The courses of three patients with mCRC who were initially RAS wild-type were monitored longitudinally using liquid biopsy with long-term follow-up of up to 20 sequential samples. Detection of fragmented RAS mutated circulating cell-free DNA (cf)DNA in plasma was performed by BEAMing. In addition, plasma digital droplet PCR was used to detect and quantify BRAF and PIK3CA mutated cfDNA. Changes of mutational load were correlated with imaging data. RESULTS: A combination of liquid biopsy and radiological imaging enabled visualization of the occurrence of clonal redistribution after discontinuation of anti-EGFR mAb therapy, as well as emerging RAS mutations during therapy with anti-EGFR mAb indicating resistance. Furthermore, we found that growth of RAS mutated clones is independent of direct selective pressure by anti-EGFR therapy, which is a significant and new finding of this study. CONCLUSIONS: Our findings demonstrated the whole spectrum of clonal selection and redistribution of mutated cell clones leading to acquired resistance. Given our observation that the growth of RAS mutated clones can evolve even in the absence of anti-EGFR mAb therapy, there is a clear imperative to monitor RAS mutations in serial blood draws in all RAS wild-type patients in general and independent of the therapy.

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Clinical Application of Liquid Biopsy in Targeted Therapy of Metastatic Colorectal Cancer

Cited by 12 publications

References 11 publications

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

Nanobody Targeting of Epidermal Growth Factor Receptor (EGFR) Ectodomain Variants Overcomes Resistance to Therapeutic EGFR Antibodies

Significance of Liquid Biopsy for Monitoring and Therapy Decision of Colorectal Cancer

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