Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment

Morelli, Maria Pia; Overman, Michael J.; Dasari, Arvind; Kazmi, Syed Mohammad Ali; Mazard, Thibault; Vilar, Eduardo; Morris, Van K.; Lee, M. S.; Herron, David S.; Eng, Cathy; Morris, James A.; Kee, Bryan K.; Janků, Filip; Deaton, F. L.; Garrett, Christopher R.; Maru, Dipen M.; Diehl, Frank; Angenendt, Philipp; Kopetz, Scott

doi:10.1093/annonc/mdv005

Cited by 227 publications

(227 citation statements)

References 25 publications

(30 reference statements)

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“…The purpose was to demonstrate the presence of pre-existing mutated clones as mechanism of resistance to panitumumab. In contrast, Morelli et al recently measured the sums of lesion volumes measured (manually on each image, by three independent readers in a total of 23 patients), but found no significant correlation between tumor volume and percentage of acquired mutant reads in the plasma [78]. In a Danish group of patients with mCRC, both total cfDNA and mutated DNA were analyzed in relation to positron emission tomography-computed tomography (PET-CT) parameters similar to a study published in lung cancer [79].…”

Section: Methodsmentioning

confidence: 96%

“…In this study, KRAS amplifications rather than mutations were detected at the time of progression and were suggested to be a previously under-investigated mechanism of EGFR resistance. In a recent report, newly detectable mutations were demonstrated with highly sensitive BEAMing analysis in plasma from a total of 32/62 patients, including 11 with multiple new mutations [78]. When 20 tumor samples from the 27 cases with new detected plasma KRAS mutations were re-analyzed, seven (36%) tested positive for low-frequency sub-clones, indicating that the developed mutations derive from rare pre-existing clones in the primary tumor tissue, and that the relative clonal burden may develop over time.…”

Section: Cell-free Dna and Importance Of Tumor Dynamics During Therapymentioning

confidence: 99%

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Methodological, biological and clinical aspects of circulating free DNA in metastatic colorectal cancer

Spindler

2016

Acta Oncologica

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Background: Circulating DNA can be used to measure the total cell-free DNA (cfDNA) and for detection and quantification of tumor-specific genetic alterations in the peripheral blood, and the broad clinical potential of circulating DNA has attracted increasing focus over the past decade. Concentrations of circulating DNA are high in metastatic colorectal cancer (CRC), and the total levels of cfDNA have been reported to hold strong prognostic value. Colorectal tumors are characterized by a high frequency of well known, clinically relevant genetic alteration, which is readily detected in the cfDNA and holds potential for tailoring of palliative therapy and for monitoring during treatment. This review aims to present the current literature which has specifically reported data on the potential utility of cfDNA and on tumor-specific mutations in metastatic colorectal cancer (mCRC). Method: Methodological, biological and clinical aspects are discussed based on the most recent development in this specific setting, and eligible studies were identified by systematic literature searched from Pubmed and EMBASE in addition to conference papers and communications. Results: The literature regarding cfDNA in CRC is broad and heterogeneous concerning aims, nomenclature, methods, cohorts and clinical endpoints and consequently difficult to include in a single systematic search. However, the available data underline a strong clinical value of measuring both total cfDNA levels and tumor-specific mutations in the plasma of patients with mCRC, pre-and during systemic therapy. Conclusion: This paper had gathered the most recent literature on several aspects of cfDNA in mCRC, including methodological, biological and clinical aspects, and discussed the large clinical potential in this specific setting, which needs to be validated in carefully designed prospective studies in statistically relevant cohorts.

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Section: Methodsmentioning

confidence: 96%

Section: Cell-free Dna and Importance Of Tumor Dynamics During Therapymentioning

confidence: 99%

Methodological, biological and clinical aspects of circulating free DNA in metastatic colorectal cancer

Spindler

2016

Acta Oncologica

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“…Установлено, что мутации тирозинкиназного до-мена EGFR встречаются при РТК редко -в 0,5-1 % случаев [5,8]. В то же время вплоть до 10-20 % первоначально отвечающих на терапию цетукси-мабом больных РТК становятся вторично рези-стентны к ней в результате появления мутаций во внеклеточном домене EGFR [4,34,35]. Эти вновь приобретённые мутации препятствуют связыва-нию EGFR с цетуксимабом.…”

Section: статус гена Egfrunclassified

Molecular Markers of Sensitivity and Resistance of Colorectal Cancer to Anti-Egfr Therapy

Ivantsov¹,

Yanus²,

Suspitsin³

et al. 2016

Siberian Journal of Oncology

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“…The first reported mutation of resistance was a change of a Serine to an Arginine at position 492 (S492R; ref. 3), which occurs in approximately 16% of patients treated with cetuximab, as assessed by ctDNA (9,10). More recently, other mutations in EGFR ECD have been identified in patients treated with anti-EGFR mAb (R451C, K467T, G465R) and in preclinical models of resistance to anti-EGFR therapy (S464L, I491M; refs.…”

Section: Introductionmentioning

confidence: 99%

The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal Cancer

Sánchez-Martín

Bellosillo

Gelabert-Baldrich

et al. 2016

Clinical Cancer Research

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Purpose: Approved anti-EGFR antibodies cetuximab and panitumumab provide significant clinical benefit in patients with metastatic colorectal cancer (MCRC). However, patients ultimately develop disease progression, often driven by acquisition of mutations in the extracellular domain (ECD) of EGFR. Sym004 is a novel 1:1 mixture of two nonoverlapping anti-EGFR mAbs that recently showed promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations. Experimental Design: Functional studies were performed to assess drug–receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of cetuximab, panitumumab, and Sym004. Cell viability and molecular effects of the drugs were assayed in cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored EGFR mutation in the post-cetuximab tumor sample. Results: Contrary to cetuximab and panitumumab, Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to cetuximab harboring mutations in EGFR maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As proof-of-principle, a patient with a tumor harboring an EGFR mutation (G465R) following cetuximab therapy benefited from Sym004 therapy. Conclusions: Sym004 is an active drug in MCRC resistant to cetuximab/panitumumab mediated by EGFR mutations. EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials. Clin Cancer Res; 22(13); 3260–7. ©2016 AACR.

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Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment

Cited by 227 publications

References 25 publications

Methodological, biological and clinical aspects of circulating free DNA in metastatic colorectal cancer

Methodological, biological and clinical aspects of circulating free DNA in metastatic colorectal cancer

Molecular Markers of Sensitivity and Resistance of Colorectal Cancer to Anti-Egfr Therapy

The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal Cancer

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