Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer

Rothé, Françoise; Laes, J.-F.; Lambrechts, Diether; Smeets, Dominiek; Vincent, Delphine; Maetens, Marion; Fumagalli, Debora; Michiels, Stefan; Drisis, Stylianos; Moerman, Carine; Detiffe, J-P; Larsimont, Denis; Awada, Ahmad; Piccart, Martine; Sotiriou, Christos; Ignatiadis, Michail

doi:10.1093/annonc/mdu288

Cited by 216 publications

(154 citation statements)

References 20 publications

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“…Roth e and colleagues found a sensitivity of cfDNA estimated at 82% in 11 patients with mutated metastatic breast cancer (27). Another study found a sensitivity rate of 58% in 50 mutated metastatic lung cancer patients (28).…”

Section: Discussionmentioning

confidence: 98%

Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial

Jovelet

Ileana

Deley

et al. 2016

Clinical Cancer Research

101

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Purpose: Liquid biopsies based on circulating cell-free DNA (cfDNA) analysis are described as surrogate samples for molecular analysis. We evaluated the concordance between tumor DNA (tDNA) and cfDNA analysis on a large cohort of patients with advanced or metastatic solid tumor, eligible for phase I trial and with good performance status, enrolled in MOSCATO 01 trial (clinical trial NCT01566019).Experimental Design: Blood samples were collected at inclusion and cfDNA was extracted from plasma for 334 patients. Hotspot mutations were screened using next-generation sequencing for 50 cancer genes.Results: Among the 283 patients with tDNA-cfDNA pairs, 121 had mutation in both, 99 in tumor only, 5 in cfDNA only, and for 58 patients no mutation was detected, leading to a 55.0% estimated sensitivity [95% confidence interval (CI), 48.4%-61.6%] at the patient level. Among the 220 patients with mutations in tDNA, the sensitivity of cfDNA analysis was significantly linked to the number of metastatic sites, albumin level, tumor type, and number of lines of treatment. A sensitivity prediction score could be derived from clinical parameters. Sensitivity is 83% in patients with a high score (!8). In addition, we analyzed cfDNA for 51 patients without available tissue sample. Mutations were detected for 22 patients, including 19 oncogenic variants and 8 actionable mutations.Conclusions: Detection of somatic mutations in cfDNA is feasible for prescreening phase I candidates with a satisfactory specificity; overall sensitivity can be improved by a sensitivity score allowing to select patients for whom cfDNA constitutes a reliable noninvasive surrogate to screen mutations.

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Section: Discussionmentioning

confidence: 98%

Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial

Jovelet

Ileana

Deley

et al. 2016

Clinical Cancer Research

101

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“…17 The use of dPCR for ctDNA analysis has been reported previously for MBC, but only after deep sequencing of the primary tumor to define the non-recurrent driver mutations of TP53, PI3KCA or PTEN. 13,17,20,21 For ESR1, few activating mutations confined to codons 537 and 538 in exon 8 represent 74% of the described mutations, limiting the number of contributing designs 8 and the requirement for sequencing metastases. A more complex and non-invasive method for the determination of the ESR1 mutational status using a culture of circulating tumor cells has been described previously.…”

Section: Short Reportmentioning

confidence: 99%

Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer

Sefrioui

Perdrix

Sarafan-Vasseur

et al. 2015

Intl Journal of Cancer

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Acquired estrogen receptor gene (ESR1) mutations have been recently reported as a marker of resistance to aromatase inhibitors in hormone receptor positive metastatic breast cancer. We retrospectively considered seven patients treated for metastatic breast cancer with available samples from the primary tumor before any treatment, cryopreserved metastasis removed during progression and concomitant plasmas. All these seven patients were in disease progression after previous exposure to aromatase inhibitors for at least 6 months, and were assessed for ESR1 mutations detection in tumor and circulating DNA. For these patients, Sanger sequencing identified four metastases with clear ESR1 mutation and one possible, whereas digital PCR identified six mutated metastases. Then, under blind conditions and using digital PCR, corresponding circulating ESR1 mutations were successfully detected in four of these six metastatic breast cancer patients. Moreover, in two patients with serial blood samples following treatments exposure, the monitoring of circulating ESR1 mutations clearly predicted disease evolution. In the context of high interest for ESR1 mutations, our results highlight that these acquired recurrent mutations may be tracked in circulating tumor DNA and may be of clinical relevance for metastatic breast cancer patient monitoring.Nearly 70% of breast cancers are hormone receptor positive (HR1) and potentially sensitive to hormonal therapy. Aromatase inhibitors (AI) or tamoxifen is the recommended first line hormonal therapy in postmenopausal HR1 metastatic breast cancer (MBC).1,2 Nevertheless, disease progression is usually observed within a few months after treatment initiation.3,4 Acquired resistance to hormonal therapy may be based on activating mutations in the estrogen receptor gene (ESR1). These mutations have been detected in HR1 MBC patients previously exposed to hormonal therapy, including treatment with an AI in all cases. The frequencies of ESR1 mutations was 25% (nine of 36), 38% (five of 13) and 54% (six of 11) among these cohorts. [5][6][7] Approximately 12 ESR1 point mutations have been described, with a hot spot confined to codons 537 and 538 in exon 8. 8 These mutations result in a ligand-independent estrogen receptor (ER) activity. In vitro and preclinical data suggest that ESR1 mutations lead to complete AI resistance and to partial resistance to ER agonists and antagonists.9,10 The detection of ESR1-activating mutations may be relevant for guiding clinicians between endocrine and nonendocrine therapy.11 Thus far, ESR1 genotyping must be performed on metastases: this method is hardly compatible with repetitive sampling analyses for disease monitoring. Circulating tumor DNA (ctDNA) analysis is considered a promising tool for providing relevant prognostic and/or predictive information instead of tumor sampling. 12,13

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“…Rothé et al described that known mutations can be detected in the blood using a targeted NGS approach when a coverage of 25,000x is used. 56 Since the isolation of CTCs is more challenging than the isolation of ctDNA, clinical studies are ongoing to test whether CTCs can be used for monitoring treatment response. 56,57 In conclusion, liquid biopsies seem a reliable, non-invasive method to detect low-level molecular alterations for the follow-up of cancer treatment.…”

Section: Liquid Biopsymentioning

confidence: 99%

Molecular Diagnostics in Breast Cancer Routine Practice

Hoeve¹,

Moelans²,

Schrijver³

et al. 2017

European Oncology &Amp; Haematology

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T he portfolio of adjuvant systemic treatment of breast cancer nowadays contains novel anti-hormonal and chemotherapeutic drugs, immunotherapeutic approaches and small molecules that are only effective in a limited number of patients and are often associated with high costs and significant side effects. Therefore, a personalised approach based on individual tumour biomarkers is required to arrive at the optimal balance between effectiveness on the one hand, and costs and side effects on the other. The aim of this paper is to provide an overview of the molecular biomarkers and associated molecular tests that are currently relevant in pathology of invasive breast cancer. KeywordsBreast cancer, pathology, molecular biomarkers Disclosure: Natalie D ter Hoeve, Cathy B Moelans, Willemijne AME Schrijver, Wendy de Leng and Paul J van Diest have nothing to disclose in relation to this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. No funding was received for the publication of this article.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Adjuvant systemic treatment of breast cancer is moving away from the limited portfolio of traditional hormonal drugs and chemotherapy, towards a gamma of novel anti-hormonal and chemotherapeutic drugs, immunotherapeutic approaches and small molecules. All these therapeutic approaches are unfortunately effective in a limited number of patients and are often associated with high costs and significant side effects. Therefore, the traditional "one size fits all" approach can no longer be upheld, and a personalised approach based on individual tumour biomarkers is required to arrive at the optimal balance between effectiveness on the one hand and costs and side effects on the other.Over recent years, progress in molecular techniques has made it possible to analyse formalin fixed paraffin embedded (FFPE) tumour material of larger cohorts of patients. This has incentivised many translational studies relating molecular tumour biomarkers to diagnosis, prognosis and/or response to therapy, yielding many relevant molecular biomarkers that have rather quickly made it to clinical pathology practice. The aim of this paper is to provide an overview of the molecular biomarkers and associated molecular tests that are currently relevant in pathology of invasive breast cancer. Diagnostic markers Hereditary breast cancersAbout 5-10% of breast cancer cases are due to a hereditary predisposition.1 In most of these cases, mutations are found in we...

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Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer

Abstract: Plasma can be prospectively tested as an alternative to metastatic biopsies in molecular screening programs.

Cited by 216 publications

References 20 publications

Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial

Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial

Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer

Molecular Diagnostics in Breast Cancer Routine Practice

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