Association of ctDNA RAS mutational status and clinical benefits in first-line metastatic colorectal cancer therapy with chemotherapy plus anti-EGFR (overall response rate and progression-free survival): a brief report of systematic review and meta-analysis
Brief Report

Association of ctDNA RAS mutational status and clinical benefits in first-line metastatic colorectal cancer therapy with chemotherapy plus anti-EGFR (overall response rate and progression-free survival): a brief report of systematic review and meta-analysis

Manuel Valladares-Ayerbes1, Pilar García Alfonso2, Volker Heinemann3, Paolo Manca4, Sebastian Stintzing5, Filipo Pietrantonio4, Clara Montagut6, Maria José Safont Aguilera7, Joan Maurel8,9,10, Encarna González Flores11, Joana Vidal6, Vincenzo Formica12, Montse Sabaté-Pina13, Verónica Alfonso-González13, Gerard Prat-Llorens14

1Medical Oncology Department, Hospital Universitario Virgen del Rocio (HUVR), Institute of Biomedicine of Seville (IBiS), Seville, Spain; 2Medical Oncology Service, Medical Oncology Service, General University Hospital Gregorio Marañón, Gregorio Marañón Health Research Institute (IiSGM), Universidad Complutense, Madrid, Spain; 3Department of Hematology/Oncology, LMU Klinikum, University of Munich, Comprehensive Cancer Center, Munich, Germany; 4Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 5Department of Hematology, Oncology, and Cancer Immunology (CCM) of Charité - Universitaetsmedizin Berlin, Germany; 6Medical Oncology Department, Hospital del Mar, Colorectal Cancer Precision Medicine Group, CIBERONC, Hospital del Mar Research Institute;Universitat Pompeu Fabra, Barcelona, Spain; 7Medical Oncology, General University Hospital Consortium of Valencia, Valencia University, Valencia, Spain; 8Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; 9Gastrointestinal and Pancreatic Oncology Group, Institut D’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 10Medical Oncology Department, Hospital Clínic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, University of Barcelona, Barcelona, Spain; 11Medical Oncology, Hospital Virgen de las Nieves, Instituto de Investigación Biosanitaria ibs, Granada, Spain; 12Medical Oncology Unit, Department of Internal Medicine, ‘Tor Vergata’ University Hospital, Rome, Italy; 13TFS HealthScience, Barcelona, Spain; 14AMGEN S.A., Barcelona, Spain

Correspondence to: Dr. Manuel Valladares-Ayerbes, MD, PhD. Medical Oncology Department, Hospital Universitario Virgen del Rocio (HUVR), Institute of Biomedicine of Seville (IBiS), Avenida de Manuel Siurot s/n, 41013 Seville, Spain. Email: mvalaye@icloud.com.

Abstract: Monitoring RAS mutations in circulating tumor DNA (ctDNA) is increasingly relevant in metastatic colorectal cancer (mCRC). In patients with tissue RAS wild-type (WT) tumors treated with first-line chemotherapy plus anti-epidermal growth factor receptor therapy (1LChT + anti-EGFR), some studies suggest that RAS WT ctDNA is associated with better outcomes, whereas others reported no differences according to ctDNA RAS mutational status. These inconsistencies may be related to small sample sizes, methodological heterogeneity, differences in assay sensitivity and tumor heterogeneity. We performed a systematic review in patients with tissue RAS WT treated with 1LChT + anti-EGFR. PubMed, Web of Science, and Scopus were searched up to April 2026. Risk of bias was assessed using the QUIPS tool, and random-effect models were applied. Fourteen studies met the inclusion criteria (ten non-interventional studies and four clinical trials). Compared with ctDNA RAS mutated tumors, ctDNA RAS WT tumors showed significantly higher overall response rates [ORR: pooled odds ratio (OR) 2.1, 95% confidence interval (CI): 1.3–3.4; P=0.002] and longer progression-free survival [PFS: pooled hazard ratio (HR) 1.6, 95% CI: 1.3–1.9; P<0.001] [non-interventional studies (NIS) + clinical trials (CT) data]. The pooled prevalence of ctDNA RAS mutations was 10.5% (95% CI: 6.2–14.8%). These findings support ctDNA RAS status as a potential biomarker of benefit from anti-EGFR-based therapy in mCRC, although methodological standardization and prospective validation remain necessary.

Keywords: Circulating tumor DNA (ctDNA); colorectal cancer; RAS; anti-epidermal growth factor receptor (anti-EGFR)

Submitted Feb 09, 2026. Accepted for publication Jun 12, 2026. Published online Jul 08, 2026.

doi: 10.21037/jgo-2025-1-879

In patients with metastatic colorectal cancer (mCRC), the RAS mutational status determined from tissue biopsy currently guides the therapeutic use of epidermal growth factor receptor (EGFR) inhibitors. The use of anti-EGFR monoclonal antibodies is restricted to patients with RAS wild-type (WT) and BRAF WT tumors and is preferred in those with a left sided primary tumor (1). Conversely, the presence of RAS mutations has been established as a negative associated factor for response to EGFR-targeted monoclonal antibodies.

In this context, analysis of circulating tumor DNA (ctDNA), also known as liquid biopsy, has emerged as a minimally invasive approach to monitor tumor evolution and to identify patients eligible for anti-EGFR therapy initiation or rechallenge (2,3). Although ctDNA assessment for RAS and BRAF is recommended before considering anti-EGFR rechallenge, there is still no clear consensus on the clinical value of liquid biopsy for selecting first-line treatment in patients with RAS- and BRAF-WT tumors.

Previous studies evaluating RAS mutational status in liquid biopsies from RAS WT mCRC prior to first-line treatment with chemotherapy plus anti-EGFR mAbs (1LChT + anti-EGFR) have shown a trend toward greater clinical benefit in ctDNA RAS WT compared with RAS mutant tumors (4-6), but the small number of ctDNA-mutated cases has limited the statistical power to confirm these associations. By contrast, other studies have demonstrated comparable results, which (according to the authors) may be attributed to the small number of patients with baseline ctDNA RAS tumors (7). These results show that the predictive value of ctDNA RAS remains clinically uncertain. Moreover, the heterogeneity across studies due to different ctDNA detection platforms (e.g., NGS, BEAMing, PCR, IdyllaTM, among others), variability in analytical sensitivity, and the lack of VAF standardization are key factors that can plausibly drive inconsistent results across studies (3,8,9). In addition, some ctDNA-tissue discordance reported, the tumor heterogeneity and the subclonal RAS mutations may also incorporate biological uncertainty (10-14). All these heterogeneous contexts could impact the detection of mutations and clinical association between ctDNA mutational status and treatment outcomes. Despite ctDNA seems to be a prognostic biomarker in mCRC, there is a lack of clinical utility (15). The aim of the present study was to perform a systematic literature review and meta-analysis to provide stronger evidence on the association between baseline ctDNA RAS mutational status and clinical benefit from 1LChT+ anti-EGFR therapy in mCRC.

This study followed the PRISMA reporting guidelines. It was registered on the international prospective register of systematic reviews (PROSPERO) (ID CRD420250605161).

PubMed, Web of Science, and Scopus were searched to identify eligible studies published up to April 15, 2026. The following search strategy was used: (first-line) AND ((cell-free nucleic acids OR circulating tum OR liquid biops* OR cell-free DNA OR ctDNA) AND (panitumumab OR cetuximab) AND (colorectal neoplasm* OR colorectal cancer* OR colorectal carcinoma OR colorectal tum* OR mCRC) AND (RAS))*.

The eligibility criteria based on the PICOS framework were as follows: (I) population: adult patients with tissue-confirmed RAS wild-type mCRC, (II) interventions and comparisons: receiving first-line treatment with anti-EGFR therapy (panitumumab or cetuximab) plus chemotherapy, (III) outcomes: studies that reported progression-free survival (PFS) and/or overall response rate (ORR) data (overall survival was not analyzed due to the few available data), (IV) study design; clinical trials (CT) or non-interventional studies (NIS) were considered. Included studies should provide baseline ctDNA RAS mutational status. There were no restrictions by country or language. Unpublished studies, opinion papers, case series, dissertations, and other forms of grey literature were excluded according to a predefined protocol.

Data extraction and study selection were performed independently by two investigators. This approach enhances clinical accuracy by minimizing sampling bias and providing internal validation through reviewer agreement and consensus resolution. Risk of bias (RoB) was assessed using the Quality In Prognosis Studies (QUIPS) tool (16), which evaluates six domains. Each domain was rated as low, moderate, or high RoB, and an overall judgment was derived qualitatively from domain-level assessments. QUIPS was applied to all studies assessing the relation between ctDNA alterations and clinical outcomes. For studies primarily designed to evaluate molecular dynamics or assay concordance, the prognostic interpretation was considered exploratory.

Clinical benefit was evaluated using PFS and ORR. Survival outcomes were expressed as the logarithm of hazard ratios (HRs, WT as a reference group) with 95% confidence intervals (CIs), calculated using the generic inverse variance method (for fixed effects) or the DerSimonian-Laird model (for random effects). HRs and 95% CIs were extracted directly from individual studies or, when not reported, estimated from available data. A HR >1 indicated a higher risk of disease progression for RAS mutant compared with RAS WT mCRC. For ORR, pooled odds ratios (ORs, mutant as a reference group) with 95% CIs were computed using the Mantel-Haenszel method (for fixed effects) or the DerSimonian-Laird model (for random effects). Event rates were converted to proportions, and corresponding standard errors (SEs) and variances were calculated. An OR >1 represented a more favorable outcome in RAS WT compared with RAS mutant mCRC. Statistical significance was defined as a 95% CI not including 1. The Rosenthal index, which estimates the number of non-significant studies required to nullify a statistically significant summary effect, was also determined (17,18).

The RAS mutation-positivity pool rate in ctDNA was assessed through a meta-analysis of proportions using the DerSimonian-Laird model (for random effects) or the Mantel-Haenszel model (for fixed effects). For each included study, the event rate (number of RAS-mutant cases divided by total sample size) was transformed into a proportion, and SEs and variances were computed accordingly.

Heterogeneity among studies was assessed using Cochran’s Q statistic and the I2 index. High heterogeneity was defined as I2>50% or a P value <0.10 for the Q statistic. If heterogeneity was absent, pooled parameters were calculated using a fixed-effects model (Mantel-Haenszel). For limited number of studies (as the present study) that reduces the power of these tests to detect true heterogeneity (19), a random-effects model was applied in all analyses, regardless of heterogeneity. All analyses were performed using the Meta-DiSc 1.4 software (20).

A total of 224 articles were screened, and 14 were found to be eligible (Figure 1). This includes ten NIS and four CT. The characteristics of the studies are detailed in Table 1.

Figure 1 PRISMA flow diagram. Inclusion criteria: 1: ≥18 years old; 2: mCRC; 3: baseline RAS wild-type; 4: first-line treatment with anti-EGFR (panitumumab or cetuximab) + chemotherapy; 5: Baseline RAS mutational status measured with ctDNA; Exclusion criteria: data from opinion articles, case series, dissertations, study protocols, gray literature, or meta-analysis. *, results based on HER-2 mutations, no RAS mutations (n=2); BRAF mutations evaluated, no RAS mutations (n=1). **, methylation of ctDNA analyzed, no assessment of RAS mutations (n=1); RAS/BRAF mutations assessed, not limited to RAS mutations alone (n=1); Subgroup analysis involving patients with additional characteristics (n=2). CT, clinical trials; mCRC, metastatic colorectal cancer; NIS, non-interventional studies; ORR, overall response rate; PFS, progression-free survival.

Table 1

Characteristics of studies selected

Source Year of publication Study design Patients (number) Institution Country/region Age (years) Anti-EGFR drug Liquid biopsy method †ORR ctDNA RAS (WT/mutant) †PFS ctDNA RAS (WT/mutant) (median)
Valladares-Ayerbes et al. (4) 2024 NIS 103 Multi-center Spain 65.0 (mean) Panitumumab IdyllaTM 81.3% vs. 71.4% 12.9 vs. 9.7 months
Tsai et al. (21) 2023 NIS 108§ Multi-center Taiwan 65.0 (median) Cetuximab Cobas 60.2% vs. 50.0% 19.0 vs. 8.0 months
Vidal et al. (22) 2023 NIS 99 Multi-center Spain 66.0 (median) Cetuximab Oncomine CRC NGS/BeaMing VAF ≥0.01% (64% vs. 62.5%) VAF ≥0.01% (16.0 vs. 10.4 months)
Formica et al. (23) 2021 NIS 24^ Single center Italy NA Panitumumab ctDNA Extraction Kit (RBC Biosciences Corp) NA 23.3 vs. 9.6 months
Lim et al. (24) 2021 NIS 92 Single center South Korea 61.0 (median) Cetuximab cfKaptureTM kit 77.1% vs. 40.0% 10.8 vs. 3.7 months
Yamada et al. (6) 2020 NIS 30 NA NA NA Panitumumab or cetuximab dPCR 92.0% vs. 0.0% 16.0 months RAS WT
Valladares-Ayerbes et al. (5) 2022 NIS 102Þ Multi-center Spain 62.2 (mean) Panitumumab BeaMing MAF≥0.01% (76.7% vs. 33.3%) MAF≥0.01% (12.1 vs. 5.9 months)
Maurel et al. (25) 2019 NIS 144 Multi-center Spain 62.9 (mean) Panitumumab or cetuximab IdyllaTM 84.4% vs. 60.0% 13.6 vs. 8.2 months
Normanno et al. (26) 2018 NIS 92 Multi-center Italy NA Cetuximab BEAMing 59.3% vs. 51.5% 13.8 vs. 7.8 months
Shitara et al. (12)‡ 2024 CT 368 Multi-center Japan NAβ Panitumumab NGS panel NA NA
Stintzing et al. (27) 2025 CT 270 Multi-center Germany NA Cetuximab BEAMing NA 10.1 vs. 6.4 months
Rachiglio et al. (28)α 2022 CT 37 Multi-center Italy NA Cetuximab IdyllaTM/Oncomine assay NA NA
Manca et al. (29) 2022 CT 135 Multi-center Italy NAε Panitumumab NGS panel NA# NA#
Kim et al. (7) 2025 NIS 46 Single center South Korea NA Cetuximab OncoBEAMTM RAS CRC assay NA 12.7 vs. 11.6 months

†, the definition of PFS in the different studies (when described) was: 1-for NIS “the time from the start of chemotherapy to date of disease progression or death from any cause”, except for Maurel et al. that was “the time from enrollment to disease progression, death, or end of follow-up, whichever came first”, 2-for CT “the time from randomization to documentation of progressive disease/death”. The definition of ORR in the different studies (when described) was “the proportion of patients who had a partial or complete response to therapy according to the RECIST criteria, not including stable disease”. In one case (Yamada et al.), the ORR was not reported, but it was calculated using the previous definition. Finally, there were 3 studies (Lim et al., Maurel et al., and Normanno et al.) where the term “response rate” was used without a definition. ‡, no data added as the definition of “gene altered” as defined as detection of any of the following in ctDNA: a mutation in BRAF V600E, KRAS, PTEN, EGFR ECD exons 1–16 and/or NRAS, amplification of HER2 and/or MET, and gene fusion of RET, NRTK1 and/or ALK., a total of 107 patients were included, 103 of them in the panitumumab population. §, N=108 patients in the PP population and 120 in the ITT population. ^, a total of 45 patients were included, 24 of them were treated with panitumumab. #, data not available in the publication, provided personally by the investigators. α, no data added as they were only available for patients with KRAS/NRAS/BRAF mutations vs. WT. Þ, a total of 119 patients were included, 102 of them in the panitumumab population. β, 59.5% (age 65–79 years); ε, 22.2% (age ≥70 years). CT, clinical trials; EGFR, epidermal growth factor receptor; ITT, Intention-to-treat; MAF, mutant allele frequency; Multi, multi-institution; NA, not available; NIS, non-interventional study; ORR, overall response rate; PFS, progression-free survival; PP, per protocol; VAF, variant allele frequency; WT, wild-type.

The assessment of RoB is presented in Table S1. Half of the studies presented moderate- and half of them high overall RoB, mainly driven by confounding and prognostic factor measurement domains, underscoring the need for cautious interpretation of pooled prognostic estimates.

The PFS results showed a pooled HR of 1.5 (95% CI: 1.2–2.0, P<0.001) for NIS only, and 1.6 (95% CI: 1.3–1.9, P<0.001) for NIS + CT data, demonstrating a significant improvement in PFS among RAS WT compared with RAS mutations, consistent across analyses including only NIS or both NIS and CT. No heterogeneity was detected in either analysis (by Q statistic or I2). The Rosenthal index values were 56 and 100, respectively, indicating that 56 and 100 non-significant studies would be required to overturn these findings (Figure 2A,2B).

Figure 2 Forest plots of RAS WT and RAS mutated mCRC in patients with EGFR first-line therapy. (A) PFS results in NIS studies. Q of heterogeneity 9.58; P=0.21, I2=27% (95% CI: 0–67%). Test for overall effect: Z=3.87, P<0.001. Rosental Index 55. The same results were observed when analyzed by FE. (B) PFS results in NIS and CT studies. Q of heterogeneity 10.02; P=0.35, I2=10% (95% CI: 0–50%). Test for overall effect: Z=5.32, P<0.001. Rosental Index 100. The same results were observed when analyzed by FE. (C) ORR results in NIS studies. Q of heterogeneity 3.46; P=0.63, I2=0% (95% CI: 0–63%). Test for overall effect: Z=2.25, P=0.02. Rosental Index 6. Similar results were observed when analyzed by FE [OR 1.77 (95% CI: 1.05–2.98), test for overall effect: Z=2.15, P=0.03]. (D) ORR results in NIS and CT studies. Q of heterogeneity 5.19; P=0.51, I2=0% (95% CI: 0–66%). Test for overall effect: Z=3.08, P=0.002. Rosental Index 18. Similar results were observed when analyzed by FE [OR 2.03 (95% CI: 1.27–3.25), test for overall effect: Z=2.94, P=0.003]. CI, confidence interval; CT, clinical trials; EGFR, epidermal growth factor receptor; FE, fixed-effects; HR, hazard ratio; NIS, non-interventional studies; OR, odds ratio; ORR, overall response rate; PFS, progression-free survival; RE, random-effects; WT, wild-type.

Similarly, ORR was significantly higher in RAS WT compared with RAS mutations, both in analyses limited to NIS and those including NIS + CT data, with pooled ORs of 1.8 (95% CI: 1.1–3.1, P=0.02) and 2.1 (95% CI: 1.3–3.4, P=0.002), respectively. Again, no heterogeneity was observed. The corresponding Rosenthal index values were six and 18, suggesting that six and 18 non-significant studies, respectively, would be needed to render the results non-significant (Figure 2C,2D). As expected, the Rosenthal index increased with the number of studies included in each analysis.

The pooled prevalence of RAS mutations in ctDNA in the intended population before the initiation of first-line therapy [which included eight studies (4,5,7,21,22,25,26,29)] was 10.5% (95% CI: 6.2–14.8%). Previous studies evaluating baseline ctDNA RAS status in patients treated with 1LChT plus anti-EGFR have reported inconsistent results. Some showed similar outcomes between RAS WT and mutant mCRC (PFS: 12.7 vs. 11.6 months) (7), whereas others reported better outcomes in RAS WT tumors [e.g., ORR: 92.0% vs. 0% (6); ORR: 81.3% vs. 71.4% and PFS: 12.9 vs. 9.7 months (4); and ORR: 76.7% vs. 33.3% and PFS: 12.1 vs. 5.9 months (5)]. Across studies, the number of patients with baseline ctDNA RAS mutations was consistently small.

In contrast, our meta-analysis showed that patients with ctDNA RAS WT achieved significantly higher ORR and longer PFS than those with RAS mutations, both in NIS alone and in the combined analysis of NIS and CT. Recent evidence suggests that early changes in ctDNA levels are associated with treatment efficacy in mCRC, with significant correlations between early ctDNA dynamics, treatment intensity, and prognosis (30). These observations support the concept of dynamic ctDNA monitoring to optimize therapeutic strategies, personalize treatment intensity, and anticipate resistance mechanisms.

Of note, variant allele fraction (VAF) is an important parameter in cell free DNA studies, as it reflects the proportion of ctDNA carrying a specific mutation. However, not all analytical platforms routinely report this value, and there is still no clear consensus on which VAF thresholds are clinically relevant. Therefore, interpretation of ctDNA data requires consideration of VAF (31), as higher VAF values are more likely to reflect clonal, biologically relevant alterations, whereas low-VAF variants may represent subclonal populations or emerging resistance mechanisms; thus, integrating VAF with concordance data could help to distinguish actionable drivers from transient or minor clones and could support the complementary use of ctDNA.

Ultimately, the results of the pooled prevalence of RAS mutations in ctDNA among patients without RAS mutations in tumor tissue is consistent with the prevalence reported previously [9.6% (15/156) patients with tumor RAS/BRAFv600 mutations and 10.9% (5/46) patients with tumor RAS mutation] (7,32). This relevant prevalence of RAS mutation among mCRC is clinically important, and the use of ctDNA enables non-invasive detection of tumor genotypes, guiding anti-EGFR therapy decisions and longitudinal monitoring.

Some limitations should be acknowledged. Despite the rigorous methodology of this systematic review and meta-analysis, several limitations should be acknowledged. Methodological limitations include the limited number of studies reporting ctDNA RAS status and the small size of ctDNA-mutated cohorts; the absence of sensitivity analyses to determine if high-bias studies are driving the observed effects; the lack of standardization in adjustment factors across studies; the observational nature of the included studies; and the heterogeneous and incompletely reported adjustment strategies. In addition, the determination of the RAS mutation-positivity pool rate was based only on available baseline metadata, which may introduce bias, and slight variations in the definition of PFS and ORR across studies require cautious interpretation. Moreover, the clinical and methodological heterogeneity of included studies may have influenced pooled estimates. Technical limitations relate to the heterogeneity of ctDNA detection platforms (limits of detection, sensitivities, assay performance parameters, and reporting standards), as well as the lack of standardized protocols and established thresholds, which may affect consistency and reproducibility across studies (33); additionally, low ctDNA levels in some samples may reduce assay sensitivity, leading to potential false-negative results (34,35), and the absence of sensitivity analyses prevents evaluation of the impact of studies at high RoB on pooled findings. Generalizability limitations include the small cohort sizes and the possibility that pooled study populations may not fully represent the intended-to-use population, as well as language and geographical bias due to the exclusion of major Chinese databases (CNKI, Wanfang, and CBM-SinoMed), despite there were no formal restrictions by country or language. Notwithstanding, although heterogeneity across studies represents a limitation, this pragmatic approach may also be considered a strength, as it better reflects real-world mCRC practice and enhances the external applicability of the findings.

The results of this study underscore the ctDNA RAS testing as a potential biomarker associated with clinical benefits in mCRC. While ctDNA analysis is already implemented in clinical practice, important questions remain regarding its optimal use. Specifically, further studies are needed to determine the best timing for liquid biopsy, whether to test only RAS or broader gene panels (e.g., via NGS), appropriate VAF thresholds, and strategies for longitudinal monitoring to guide therapy and clinical decision-making. Addressing these points will help maximize the clinical utility of ctDNA testing and optimize patient management in first-line and subsequent anti-EGFR treatments.

Overall, the results support the potential clinical utility of ctDNA RAS testing in the management of mCRC as a biomarker associated with clinical benefits among patients with confirmed RAS WT mCRC by tissue analysis (corresponding to the patients selected in this study). Prospective studies with standardized ctDNA assays and larger cohorts are warranted to validate these findings and further define the role of ctDNA-guided therapy, including in anti-EGFR rechallenge strategies. The meta-analysis evaluates association/prognostic enrichment rather than establishing ctDNA RAS as an independently validated predictive biomarker.

Acknowledgments

We gratefully acknowledge all authors for sharing data from their studies, making this work possible. We sincerely thank Dr. Manuel Valladares-Ayerbes for conceiving the study and for his scientific leadership and coordination throughout the project. We also acknowledge TFS for study execution and medical writing support, and Amgen S.A. for funding for this work.

Footnote

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-879/prf

Funding: Funding for the study was provided by AMGEN S.A. to TFS HealthScience to perform the work and develop the manuscript.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-879/coif). M.V.A. reports consulting fees from AMGEN S.A., SERVIER, and MERCK, honoraria from MSD, Bristol-Myers, and Merck, speakers’ bureau from MSD, Bristol-Myers, Merck , Servier, and Takeda, as well as support for attending meetings and/or travel from Merck, SERVIER, and AMGEN S.A. P.G.A. reports consulting fees from AMGEN S.A., Merck, Servier, Takeda, MSD, and BMS, support for attending meetings and/or travel from MSD, Merck, Astra Zeneca, and AMGEN S.A., as well as Other financial or non-financial interests from AMGEN S.A., Merck, MSD, BMS, Servier, and Takeda. V.H. reports consulting fees from Merck, Roche, AstraZeneca, GSK, Amgen, Servier, Novartis, Pierre-Fabre, MSD, Janssen, Terumo, SIRTEX, Oncosil, NORDIC, and SYSMEX, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Merck, AstraZeneca, GSK, AMGEN S.A., Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, BMS, MSD, Novartis, Seagen, and SYSMEX, payment for expert testimony from Servier and Oncosil, support for attending meetings and/or travel from Merck, Nordic, AstraZeneca, GSK, AMGEN S.A., MSD, as well as research funding from Merck (Inst), AMGEN S.A. (Inst), Roche (Inst), and Servier (Inst). S.S. reports payment or honoraria for talks from AMGEN S.A., AstraZeneca, Bayer, BMS, ESAI, Leo-Pharma, Lilly, Merck KGaA, Darmstadt, Germany, MSD, Pierre-Fabre, Roche, Sanofi, Servier, Taiho, and Takeda, and research funding from Merck KGaA, Darmstadt, Germany, Pierre-Fabre, Servier, and Roche. F.P. reports consulting fees from BMS, MSD, AMGEN S.A., Pierre-Fabre, Johnson&Johnson, Servier, Bayer, Takeda, Astellas, GSK, Daiichi-Sankyo, Pfizer, BeOne, Jazz Pharmaceuticals, Incyte, Rottapharm, Merck-Serono, Italfarmaco, Gilead, AstraZeneca, Agenus, and Revolution Medicine, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BeOne, Daiichi-Sankyo, Seagen, Astellas, Ipsen, AstraZeneca, Servier, Bayer, Takeda, Johnson&Johnson, BMS, MSD, AMGEN S.A, Merck-Serono, Pierre-Fabre, Incyte, and AstraZeneca, support for attending meetings and/or travel from AMGEN S.A, Merck-Serono, Pierre-Fabre, Servier, Astellas, Incyte, and Johnson&Johnson, as well as research funding from Lilly, BMS, Incyte, AstraZeneca, AMGEN S.A., Agenus, Rottapharm, Johnson&Johnson, GSK, and Tempus. C.M. reports consulting fees from AMGEN S.A., Pfizer, Merck-Serono, Bayer, and Sanofi, speakers bureau from Guardant Health, Pfizer, Merck, and Patents planned, issued or pending from Licensed discovery of anti-EGFR resistance biomarker, and Biocartis. M.J.S.A. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AMGEN S.A., BMS, GSK, MERCK, MSD, PIERRE FABRE, SERVIER, and TAKEDA, support for attending meetings and/or travel from AMGEN S.A., MERCK, SERVIER, and TAKEDA, as well as research funding from AMGEN S.A., BMS, GSK, SERVIER, and PFIZER. J.M. reports consulting fees by AMGEN S.A., Delcath Systems, GSK, MSD, and Incyte, support for attending meetings and/or travel from AMGEN S.A., and MSD, as well as research funding from Incyte, Terumo, and Guardant. J.V. reports consulting fees from BMS, Merck, and Pierre Fabre, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AMGEN S.A., BMS, Merck, MSD, Novartis, Pierre Fabre, Regeneron, and Takeda, as well as support for attending meetings and/or travel from Merck and Pierre Fabre. V.F. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Merck, AMGEN S.A., Servier, and Takeda. M.S.P. and V.A.G. are employees of TFS HealthScience which received funding from Amgen S.A. G.P.L. is employee of AMGEN S.A. and owns stocks in Amgen Inc. The other author has no conflicts of interest to declare.

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Cite this article as: Valladares-Ayerbes M, García Alfonso P, Heinemann V, Manca P, Stintzing S, Pietrantonio F, Montagut C, Safont Aguilera MJ, Maurel J, González Flores E, Vidal J, Formica V, Sabaté-Pina M, Alfonso-González V, Prat-Llorens G. Association of ctDNA RAS mutational status and clinical benefits in first-line metastatic colorectal cancer therapy with chemotherapy plus anti-EGFR (overall response rate and progression-free survival): a brief report of systematic review and meta-analysis. J Gastrointest Oncol 2026;17(4):271. doi: 10.21037/jgo-2025-1-879

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