RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study

被引：129

作者：

Bachet, J. B. ^{[1
,2
,3
,4
]}

Bouche, O. ^{[4
,5
]}

Taieb, J. ^{[4
,6
]}

Dubreuil, O. ^{[3
,4
]}

Garcia, M. L. ^{[4
,7
]}

Meurisse, A. ^{[8
]}

Normand, C. ^{[2
]}

Gornet, J. M. ^{[4
,9
]}

Artru, P. ^{[4
,10
]}

Louafi, S. ^{[4
,11
,12
]}

Bonnetain, F. ^{[8
]}

Thirot-Bidault, A. ^{[4
,13
]}

Baumgaertner, I ^{[4
,14
]}

Coriat, R. ^{[4
,15
]}

Tougeron, D. ^{[4
,16
]}

Lecomte, T. ^{[4
,17
]}

Mary, F. ^{[4
,18
]}

Aparicio, T. ^{[4
,9
,18
]}

Marthey, L. ^{[4
,19
]}

Taly, V ^{[2
]}

Blons, H. ^{[2
,20
]}

Vernerey, D. ^{[8
]}

Laurent-Puig, P. ^{[2
]}

机构：

[1] UPMC Univ, Sorbonne Univ, Paris, France

[2] Univ Sorbonne Paris Cite, INSERM UMR MEPPOT S1147, Equipe Labellisee Ligue Natl Canc, Ctr Univ St Peres,CNRS SNC5014, Paris, France

[3] Grp Hosp Pitie Salpetriere, Dept Hepatogastroenterol, Paris, France

[4] AGEO Assoc Gastroenterol Oncol, Paris, France

[5] Hop Robert Debre, Dept Hepatogastroenterol, Reims, France

[6] Hop Europeen Georges Pompidou, Dept Digest Oncol, Paris, France

[7] Hop St Antoine, Dept Oncol, Paris, France

[8] Hop Univ Besancon, Dept Methodol & Qual Life Oncol, INSERM UMR 1098, Besancon, France

[9] Hop St Louis, Dept Gastroenterol, Paris, France

[10] Hop Prive Jean Mermoz, Dept Gastroenterol, Lyon, France

[11] Ctr Hosp Sud Francilien, Dept Gastroenterol, Corbeil Essonnes, France

[12] Grp Hosp Nord Essonne, Dept Gastroenterol, Longjumeau, France

[13] Hop Kremlin Bicetre, Dept Gastroenterol, Le Kremlin Bicetre, France

[14] Hop Henri Mondor, Dept Oncol, Creteil, France

[15] Hop Cochin, Dept Gastroenterol, Paris, France

[16] CHU Poitiers, Dept Gastroenterol, Poitiers, France

[17] CHU Tours, Dept Gastroenterol, Tours, France

[18] Hop Avicenne, Dept Gastroenterol, Bobigny, France

[19] Hop Antoine Beclere, Dept Gastroenterol, Clamart, France

[20] Hop Europeen Georges Pompidou, Dept Biochem, Paris, France

来源：

ANNALS OF ONCOLOGY | 2018年 / 29卷 / 05期

关键词：

colorectal cancer; circulating tumor DNA; accuracy; liver metastases; NGS; methylated biomarker; PLASMA; KRAS;

D O I：

10.1093/annonc/mdy061

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: RAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort. Patients and methods: Plasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal kappa coefficient of 0.7, reflecting acceptable concordance (precision+/-0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary. Results: From July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the kappa coefficient was 0.71 [95% confidence interval (CI), 0.64-0.77] and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the kappa coefficient was 0.89 (95% CI, 0.84-0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results [odds ratio = 0.11 (95% CI, 0.06-0.21)]. In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers. Conclusion: This prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients.

引用

页码：1211 / 1219

页数：9

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