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Clinical Trial
. 2026 Jan;56(1):e70103.
doi: 10.1111/eci.70103. Epub 2025 Aug 1.

Circulating hsa-miR-29c-3p and VEGF-A levels predict the response to FOLFIRI plus aflibercept in elderly metastatic colorectal cancer patients

Marta Toledano-Fonseca  1   2 , María Teresa Cano-Osuna  1   2 , Elena Élez  3 , Javier Soto-Alsar  4 , David Páez  5 , Ana Fernández-Montes  6 , Begoña Graña  7 , Antonieta Salud  8 , Alfonso Yubero  9 , Ismael Macías  10 , Guillermo Quintero  11 , Carlos López-López  12 , Teresa Fernández-Rodríguez  13 , María Victoria García-Ortiz  1   2 , Javier Sastre  14 , Pilar García-Alfonso  4 , Antonio Rodríguez-Ariza  1   2 , Enrique Aranda  1   2 ; Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)
Affiliations
Clinical Trial

Circulating hsa-miR-29c-3p and VEGF-A levels predict the response to FOLFIRI plus aflibercept in elderly metastatic colorectal cancer patients

Marta Toledano-Fonseca et al. Eur J Clin Invest. 2026 Jan.

Abstract

Background: Metastatic colorectal cancer (mCRC) patients who progress on oxaliplatin-based chemotherapy benefit from second-line treatment with FOLFIRI plus the antiangiogenic drug aflibercept. However, the absence of validated biomarkers for antiangiogenic therapies remains a challenge. In this context, we previously reported that combining plasma VEGF-A levels, a circulating microRNA profile, and patient clinical characteristics predicts outcomes in FOLFIRI plus aflibercept treatment. In the present study, we now report biomarkers of response to FOLFIRI plus aflibercept in elderly mCRC patients who progressed after first-line oxaliplatin-based chemotherapy.

Methods: The study included 154 mCRC patients over 70 years of age enrolled in the clinical phase II trial AFEMA. Plasma samples were obtained before FOLFIRI plus aflibercept treatment, and circulating levels of VEGF-A and 13 miRNAs were analysed.

Results: The levels of VEGF-A and five of these 13 miRNAs (miR-193-3b, miR-432-5p, miR-29c-3p, miR-93-5p, miR-30a-3p) enabled the stratification of patients based on progression-free survival and time-to-treatment failure. Specifically, combining miR-29c-3p with VEGF-A improved prognostic accuracy.

Conclusion: Our study underscores the value of integrating miR-29c-3p analysis with VEGF-A as a biomarker strategy to advance the management of elderly mCRC patients receiving FOLFIRI plus aflibercept, improving outcome predictions and enabling more personalised therapeutic strategies.

Keywords: FOLFIRI; VEGF‐A; aflibercept; antiangiogenic therapy; circulating miRNAs; metastatic colorectal cancer.

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Conflict of interest statement

M. Toledano‐Fonseca reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from SYSMEX and support for attending meetings and/or travel from MERCK. E. Élez reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AGENUS, AMGEN, BAYER, BMS, BOEHRINGER INGELHEIM, CURE TEQ AG, GLAXOSMITHKLINE, ROCHE, JANSSEN, LILLY, MEDSCAPE, MERCK, MSD, NOVARTIS, ORGANON, PFIZER, PIERRE FABRE, REPARE THERAPEUTICS INC., RIN INSTITUTE INC., SANOFI, SEAGEN INTERNATIONAL GMBH, SERVIER, TAKEDA, and consulting fees from AGENUS, AMGEN, BAYER, BMS, BOEHRINGER INGELHEIM, CURE TEQ AG, GLAXOSMITHKLINE, ROCHE, JANSSEN, LILLY, MEDSCAPE, MERCK, MSD, NOVARTIS, ORGANON, PFIZER, PIERRE FABRE, REPARE THERAPEUTICS INC., RIN INSTITUTE INC., SANOFI, SEAGEN INTERNATIONAL GMBH, SERVIER, TAKEDA. J. Soto‐Alsar reports grants or contracts from SANOFI, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MERCK, IPSEN, PFIZER, RECORDATI, SERVIER, LEO PHARMA, ASTRAZENECA, MSD, support for attending meetings and/or travel from MSD, ANGELINI, VIFOR PHARMA, ROVI, AMGEN, PFIZER, ROCHE. D. Páez reports consulting fees from AMGEN, TAKEDA, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, MSD, NOVARTIS and support for attending meetings and/or travel from AMGEN, ESTEVE, MERCK, IPSEN, SERVIER. A. Fernández‐Montes reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from SERVIER, MSD, ROCHE, BMS, PIERRE FABRE, ASTRA ZEENECA, ASTELLAS, MERCK, consulting fees from MSD, AMGEN, TAKEDA, ARIXTO and support for attending meetings and/or travel from ROCHE, ASTRA ZENECA. B. Graña reports consulting fees from SERVIER, grants or contracts from AMGEN, BMS, and support for attending meetings and/or travel from AMGEN, ASTRA ZENECA, MERCK, ROCHE, SERVIER. C. López‐López reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from ROCHE, MERCK, EISAI, IPSEN, ASTRA ZENECA, SERVIER, BMS, MSD, ADVANCED ACCELERATOR APPLICATIONS, GLAXOSMITHKLIME, consulting fees from AMGEN, ROCHE, MERCK, SERVIER, IPSEN, BAYER, EISAI, ASTRA ZENECA, TAKEDA, grants or contracts from AMGEN, ROCHE, MERCK, MSD, ASTRA ZENECA, IPSEN, EISAI, BMS, GLAXOSMITHKLIME and support for attending meetings and/or travel from ROCHE, MERCK, SERVIER, AMGEN, IPSEN, ADVANCED ACCELERATOR APPLICATIONS. M.V. García‐Ortiz reports support for attending meetings and/or travel from MERCK. J. Sastre reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from ROCHE, LILLY, SERVIER, MSD, AMGEN, EISAI, BMS, PIERRE‐FABRE, ASTELLAS, consulting fees from ROCHE, SERVIER, BMS, ASTELLAS, LILLY, ASTRA‐ZENECA, PIERRE‐FABRE, BOEHRINGER INGELHEIM, and support for attending meetings and/or travel from MERCK, ROCHE, SERVIER, ASTELLAS. A. Rodríguez‐Ariza reports consulting fees from SYSMEX and support for attending meetings and/or travel from MERCK. E. Aranda reports consulting fees from AMGEN, BAYER, BRISTOL MYERS SQUIBB, MERCK, ROCHE, SANOFI, SERVIER, grants or contracts from ROCHE. The other authors have stated that they have no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
VEGF‐A as biomarker of response to FOLFIRI plus aflibercept treatment. (A) Higher basal levels of plasma VEGF‐A were significantly associated with worse progression‐free survival (PFS) in the AFEMA cohort. (B) Patients who responded to FOLFIRI plus aflibercept according to RECIST 1.1 criteria showed lower levels of VEGF‐A. PROG, Progressive disease; SD, Stable disease; R, Response. (C) Lower VEGF‐A levels were associated with patients with longer time‐to‐treatment failure (TTF).
FIGURE 2
FIGURE 2
Association of plasma miRNA levels with progression free survival. Plasma levels of five miRNAs (miR‐193b‐3p, miR‐29c‐3p, miR‐30a‐3p, miR‐432‐3p and miR‐93‐5p) significantly stratify patients receiving FOLFIRI plus aflibercept based on PFS.
FIGURE 3
FIGURE 3
miRNAs targeting VEGF‐A. The bioinformatic tool miRTargetLink 2.0 was used to identify highly validated miRNAs targeting VEGF‐A, including miR‐29c‐3p and miR‐93‐5p.
FIGURE 4
FIGURE 4
Association between miR‐29c‐3p levels and response to FOLFIRI plus aflibercept treatment according to RECIST 1.1 criteria. (A) miR‐29c‐3p was differentially expressed depending on response according to RECIST 1.1 criteria showing lower levels in those patients whose best response was progression. (B) Patients whose best response was disease control (complete or partial response and stable disease) showed significantly higher levels of miR‐29c‐3p.
FIGURE 5
FIGURE 5
Association between miR‐29c‐3p and time‐to‐treatment failure. (A) Higher levels of miR‐29c‐3p were significantly associated with response when patients were classified into responders or non‐responders using the median of TTF. (B) miR‐29c‐3p levels efficiently stratified patients according to TTF.
FIGURE 6
FIGURE 6
Association between miRNAs levels and time‐to‐treatment failure. Plasma levels of miR‐193b‐3p, miR‐30a‐3p, miR‐432‐3p and miR‐93‐5p efficiently stratified patients according to TTF.
FIGURE 7
FIGURE 7
Combination of VEGF‐A and miR‐29c‐3p improves patient stratification. (A) PFS according to VEGF‐A and miR‐29c‐3p combination (both biomarkers compared to none biomarker: p = .0102; both biomarkers compared to one bimarker: p = .0144; one biomarker compared to none biomarker: p = .2726). (B) TTF according to VEGF‐A and miR‐29c‐3p combination (both biomarkers compared to none biomarker: p = .0320 and both biomarkers compared to none biomarker p = .0023). (C) Number of patients with none, one or both positive markers according to RECIST 1.1 criteria (both biomarkers versus one biomarker, p = .0010; and both biomarkers versus none biomarker, p = .0212). R, Response; SD, Stable disease; PROG, Progressive disease.
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