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

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

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.

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.

© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

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% (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% (red line) in terms of PFS (A) and OS (B). HR and P‐values are shown.

References

    1. Arnold D, Lueza B, Douillard JY, Peeters M, Lenz HJ, Venook A, Heinemann V, Van Cutsem E, Pignon JP, Tabernero J et al (2017) Prognostic and predictive value of primary tumour side in patients with RAS wild‐type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol 28, 1713–1729.
    1. Azuara D, Santos C, Lopez‐Doriga A, Grasselli J, Nadal M, Sanjuan X, Marin F, Vidal J, Montal R, Moreno V et al (2016) Nanofluidic digital PCR and extended genotyping of RAS and BRAF for improved selection of metastatic colorectal cancer patients for Anti‐EGFR therapies. Mol Cancer Ther 15, 1106–1112.
    1. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM et al (2014) Detection of circulating tumor DNA in early‐ and late‐stage human malignancies. Sci Transl Med 6, 224ra24.
    1. Ciardiello F, Normanno N, Maiello E, Martinelli E, Troiani T, Pisconti S, Giuliani F, Barone C, Cartenì G, Rachiglio AM et al (2014) Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next‐generation sequencing: findings from the CAPRI‐GOIM trial. Ann Oncol 25, 1756–1761.
    1. Contal C and O'Quigley J (1999) An application of changepoint methods in studying the effect of age on survival in breast cancer. Comput Stat Data Anal 30, 253–270.
    1. El Messaoudi S, Mouliere F, Du Manoir S, Bascoul‐Mollevi C, Gillet B, Nouaille M, Fiess C, Crapez E, Bibeau F, Theillet C et al (2016) Circulating DNA as a strong multimarker prognostic tool for metastatic colorectal cancer patient management care. Clin Cancer Res 22, 3067–3077.
    1. Grasselli J, Elez E, Caratù G, Matito J, Santos C, Macarulla T, Vidal J, Garcia M, Viéitez JM, Paéz D et al (2017) Concordance of blood‐ and tumor‐based detection of RAS mutations to guide anti‐EGFR therapy in metastatic colorectal cancer. Ann Oncol 28, 1294–1301.
    1. Laurent‐Puig P, Pekin D, Normand C, Kotsopoulos SK, Nizard P, Perez‐Toralla K, Rowell R, Olson J, Srinivasan P, Le Corre D et al (2015) Clinical relevance of KRAS‐mutated subclones detected with picodroplet digital PCR in advanced colorectal cancer treated with anti‐EGFR therapy. Clin Cancer Res 21, 1087–1097.
    1. Mandrekar J, Mandrekar S and Cha S (2003) Cutpoint Determination Methods in Survival Analysis using SAS Proc 28th SAS Users Gr Int. Conf (SUGI), 261–228.
    1. Normanno N, Esposito Abate R, Lambiase M, Forgione L, Cardone C, Iannaccone A, Sacco A, Rachiglio AM, Martinelli E, Rizzi D et al (2017) RAS testing of liquid biopsy correlates with the outcome of metastatic colorectal cancer patients treated with first‐line FOLFIRI plus cetuximab in the CAPRI‐GOIM trial. Ann Oncol 29, 112–118.
    1. Ono A, Kenmotsu H, Watanabe M, Serizawa M, Mori K, Imai H, Taira T, Naito T, Murakami H, Nakajima T et al (2014) Mutant allele frequency predicts the efficacy of EGFR‐TKIs in lung adenocarcinoma harboring the L858R mutation. Ann Oncol 25, 1948–1953.
    1. Petrelli F, Tomasello G, Borgonovo K, Ghidini M, Turati L, Dallera P, Passalacqua R, Sgroi G and Barni S (2017) Prognostic survival associated with left‐sided vs right‐sided colon cancer. JAMA Oncol 3, 211.
    1. Rahbari NN, Schölch S, Bork U, Kahlert C, Schneider M, Rahbari M, Büchler MW, Weitz J and Reissfelder C (2017) Prognostic value of circulating endothelial cells in metastatic colorectal cancer. Oncotarget 8, 37491–37501.
    1. Riihimäki M, Hemminki A, Sundquist J and Hemminki K (2016) Patterns of metastasis in colon and rectal cancer. Sci Rep 6, 29765.
    1. Siegel R, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A and Jemal A (2017) Colorectal cancer statistics, 2017. CA Cancer J Clin 67, 177–193.
    1. Siravegna G, Marsoni S, Siena S and Bardelli A (2017) Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol 14, 531–548.
    1. Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, Ponzetti A, Cremolini C, Amatu A, Lauricella C et al (2015) Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 21, 795–801.
    1. Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S et al (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first‐line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29, 2011–2019.
    1. Vidal J, Muinelo L, Dalmases A, Jones F, Edelstein D, Iglesias M, Orrillo M, Abalo A, Rodríguez C, Brozos E et al (2017) Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients. Ann Oncol 28, 1325–1332.
    1. Yaeger R, Cowell E, Chou JF, Gewirtz AN, Borsu L, Vakiani E, Solit DB, Rosen N, Capanu M, Ladanyi M et al (2015) RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer. Cancer 121, 1195–1203.
    1. Zhou Q, Zhang XC, Chen ZH, Yin XL, Yang JJ, Xu CR, Yan HH, Chen HJ, Su J, Zhong WZ et al (2011) Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non‐small‐cell lung cancer. J Clin Oncol 29, 3316–3321.

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