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Molecular Diagnostics

Variant allele frequency in baseline circulating tumour DNA to measure tumour burden and to stratify outcomes in patients with RAS wild-type metastatic colorectal cancer: a translational objective of the Valentino study

British Journal of Cancer volume 126, pages 449–455 (2022)Cite this article

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Abstract

Introduction

In patients with metastatic colorectal cancer (mCRC), baseline circulating tumour DNA (ctDNA) variant allele fraction (VAF) might serve as a surrogate of disease burden and should be evaluated in comparison with CEA and RECIST-defined sum of target lesions.

Methods

In this pre-planned analysis of the VALENTINO trial, we included patients with RAS wild-type mCRC receiving upfront FOLFOX/panitumumab with available baseline liquid biopsy. CtDNA was analysed by means of a 14-gene NGS panel. For each patient, the gene with the highest VAF in ctDNA was selected.

Results

The final cohort included 135 patients. The median VAF was 12.6% (IQR: 2.0–45.2%). Higher VAF was observed in patients with liver metastases and with synchronous metastases presentation. Patients with high VAF had poorer median OS compared to those with low VAF (21.8 vs 36.5 months; HR: 1.82, 95%CI: 1.20–2.76; p = 0.005). VAF outperformed baseline CEA and target lesion diameter in the prognostic stratification and remained significantly correlated with OS (p = 0.003) in a multivariate model. VAF was not significantly correlated with dimensional response and PFS.

Conclusion

CtDNA measured by VAF is prognostic in patients with RAS wild-type mCRC. Response and PFS after an anti-EGFR-based first-line strategy are independent from initial tumour burden.

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Fig. 1: Correlation of VAF, CEA and RECIST.
Fig. 2: Heatmap of mutations.
Fig. 3: Impact of VAF on PFS and OS.

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Code availability

Codes can be made available upon request to the corresponding author.

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Author information

Authors and Affiliations

  1. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Paolo Manca, Salvatore Corallo, Giovanni Fucà, Alberto Giovanni Leone, Francesca Corti, Filippo Pagani, Giovanni Randon, Antonia Martinetti, Elisa Sottotetti, Michele Prisciandaro, Margherita Ambrosini, Alessandra Raimondi, Federica Morano & Filippo Pietrantonio

  2. Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology - IRCCS, Padova, Italy

    Sara Lonardi & Letizia Procaccio

  3. Oncology Unit 3, Department of Oncology, Veneto Institute of Oncology - IRCCS, Padova, Italy

    Sara Lonardi

  4. Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Adele Busico

  5. Unit of Medical Oncology, Azienda Ospedaliero-Universitaria (AOU) Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy

    Carlotta Antoniotti

  6. Department of Surgery, Oncology, and Gastroenterology, University of Padova, Padova, Italy

    Letizia Procaccio

  7. Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy

    Valeria Smiroldo

  8. Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale (ASST) Ospedale di Cremona, Cremona, Italy

    Margherita Ratti

  9. Department of Internal Medicine, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy

    Roberto Murialdo

  10. ColoRectal Cancer Unit - Department of oncology, AOU Città della Salute e della Scienza, Torino, Italy

    Patrizia Racca

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  1. Paolo Manca
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  2. Salvatore Corallo
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Contributions

PM and FP designed the work, interpreted the results and drafted the original version of the manuscript. FP conceived the work. All authors acquired data, revised the manuscript, approved the final version and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Filippo Pietrantonio.

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Ethics approval and consent to participate

Institutional review board approval was obtained from all participating Centres and all patients provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki.

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The authors declare no competing interests.

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Manca, P., Corallo, S., Lonardi, S. et al. Variant allele frequency in baseline circulating tumour DNA to measure tumour burden and to stratify outcomes in patients with RAS wild-type metastatic colorectal cancer: a translational objective of the Valentino study. Br J Cancer 126, 449–455 (2022). https://doi.org/10.1038/s41416-021-01591-8

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