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Clinical Trial
. 2019 Sep;13(9):1827-1835.
doi: 10.1002/1878-0261.12547. Epub 2019 Jul 31.

Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer

Elena Elez  1   2 , Chiara Chianese  3 , Enrique Sanz-García  1   2 , Erica Martinelli  4 , Alba Noguerido  1   2 , Francesco Mattia Mancuso  3 , Ginevra Caratù  3 , Judit Matito  3 , Julieta Grasselli  1   5 , Claudia Cardone  4 , Riziero Esposito Abate  6 , Giulia Martini  1   2 , Cristina Santos  5 , Teresa Macarulla  1   2 , Guillem Argilés  1   2 , Jaume Capdevila  1   2 , Ariadna Garcia  1   2 , Nuria Mulet  1   2   5 , Evaristo Maiello  7 , Nicola Normanno  6 , Frederick Jones  8 , Josep Tabernero  1   2 , Fortunato Ciardello  4 , Ramon Salazar  5 , Ana Vivancos  3
Affiliations
Clinical Trial

Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer

Elena Elez et al. Mol Oncol. 2019 Sep.

Abstract

Despite major advances in the treatment of metastatic colorectal cancer (mCRC), the survival rate remains very poor. This study aims at exploring the prognostic value of RAS-mutant allele fraction (MAF) in plasma in mCRC. Forty-seven plasma samples from 37 RAS-mutated patients with nonresectable metastases were tested for RAS in circulating tumor DNA using BEAMing before first- and/or second-line treatment. RAS MAF was correlated with several clinical parameters (number of metastatic sites, hepatic volume, carcinoembryonic antigen, CA19-9 levels, primary site location, and treatment line) and clinical outcome [progression-free survival (PFS) and overall survival (OS)]. An independent cohort of 32 patients from the CAPRI-GOIM trial was assessed for clinical outcome based on plasma baseline MAF. RAS MAF analysis at baseline revealed a significant correlation with longer OS [Hazard ratios (HR) = 3.514; P = 0.00066]. Patients with lower MAF also showed a tendency to longer PFS, although not statistically significant. Multivariate analysis showed RAS MAFs as an independent prognostic factor in both OS (HR = 2.73; P = 0.006) and first-line PFS (HR = 3.74; P = 0.049). Tumor response to treatment in patients with higher MAF was progression disease (P = 0.007). Patients with low MAFs at baseline in the CAPRI-GOIM group also showed better OS [HR = 3.84; 95% confidence intervals (CI) 1.5-9.6; P = 0.004] and better PFS (HR = 2.5; 95% CI: 1.07-5.62; P = 0.033). This minimally invasive test may help in adding an independent factor to better estimate outcomes before initiating treatment. Further prospective studies using MAF as a stratification factor could further validate its utility in clinical practice.

Keywords: MAF; RAS analysis; circulating tumor DNA; metastatic colorectal cancer; prognostic biomarker.

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Conflict of interest statement

JT has served in a consulting or advisory role for Amgen, Boehringer Ingelheim, Celgene, Chugai, ImClone, Lilly, Merck, S.L., Madrid, Merck Serono, Millennium Pharmaceuticals, Inc., Novartis, Roche, Sanofi, and Taiho. RS has served in a consulting or advisory role for Amgen, Merck, S.L., Madrid, and Roche Dx and obtained research funding from Roche Dx. AV has served in a consulting or advisory role for Merck, S.L., Madrid, Merck Serono, and Sysmex. All remaining authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
MAF distribution. Representation of MAF (%) distributions according to: (A) the two lines of treatment; (B) tumor laterality; (C) number of metastatic lesions; and (D) metastatic site. Box plots show the interquartile range (IQR) with median, 25th and 75th percentile, outliers, and P‐values. Continued lines (in graph D) indicate the comparison between two variables. Statistically significant P‐values are marked with a (*). Samples are represented by light blue dots.
Figure 2
Figure 2
PFS and OS analyses in first‐line treatment. Survival curves are shown for samples with MAF < 5.8% (black line) and MAF> 5.8% (red line) in terms of PFS (A) and OS (B) in the 1st line. HR and P‐values are shown. (C) MAF distribution according to best response to treatment.
Figure 3
Figure 3
PFS and OS analyses in the validation cohort (CAPRI‐GOIM trial). Survival curves are shown for samples with MAF < 5.8% (black line) and MAF > 5.8% (red line) in terms of PFS (A) and OS (B). HR and P‐values are shown.
See this image and copyright information in PMC

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