Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Subjects

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.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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

Code availability

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

References

  1. 1.

    Antoniotti C, Pietrantonio F, Corallo S, De Braud F, Falcone A, Cremolini C. Circulating tumor DNA analysis in colorectal cancer: from dream to reality. JCO Precis Oncol. 2019;3:1–14.

    Google Scholar 

  2. 2.

    Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra24.

    Article  Google Scholar 

  3. 3.

    Manca P, Corallo S, Busico A, Lonardi S, Corti F, Antoniotti C, et al. The added value of baseline circulating tumor DNA profiling in patients with molecularly hyperselected, left-sided metastatic colorectal cancer. Clin Cancer Res. 2021;27:2505–14.

    CAS  Article  Google Scholar 

  4. 4.

    Randon G, Yaeger R, Hechtman JF, Manca P, Fucà G, Walch H, et al. EGFR amplification in metastatic colorectal cancer. J Natl Cancer Inst. 2021:djab069.

  5. 5.

    Normanno N, Esposito Abate R, Lambiase M, Forgione L, Cardone C, Iannaccone A, et al. 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. 2018;29:112–8.

    CAS  Article  Google Scholar 

  6. 6.

    Siravegna G, Lazzari L, Crisafulli G, Sartore-Bianchi A, Mussolin B, Cassingena A, et al. Radiologic and genomic evolution of individual metastases during HER2 blockade in colorectal cancer. Cancer Cell. 2018;34:148.e7–62.e7.

    Article  Google Scholar 

  7. 7.

    Cremolini C, Rossini D, Dell’Aquila E, Lonardi S, Conca E, Del Re M, et al. Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan: a phase 2 single-arm clinical trial. JAMA Oncol. 2019;5:343–50.

    Article  Google Scholar 

  8. 8.

    Janku F, Zhang S, Waters J, Liu L, Huang HJ, Subbiah V, et al. Development and validation of an ultradeep next-generation sequencing assay for testing of plasma cell-free DNA from patients with advanced cancer. Clin Cancer Res. 2017;23:5648–56.

    CAS  Article  Google Scholar 

  9. 9.

    Hsu HC, Lapke N, Wang CW, Lin PY, You JF, Yeh CY, et al. Targeted sequencing of circulating tumor DNA to monitor genetic variants and therapeutic response in metastatic colorectal cancer. Mol Cancer Ther. 2018;17:2238–47.

  10. 10.

    Tie J, Kinde I, Wang Y, Wong HL, Roebert J, Christie M, et al. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol. 2015;26:1715–22.

    CAS  Article  Google Scholar 

  11. 11.

    Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR, et al. Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000;124:979–94.

    CAS  Article  Google Scholar 

  12. 12.

    Pietrantonio F, Morano F, Corallo S, Miceli R, Lonardi S, Raimondi A, et al. Maintenance therapy with panitumumab alone vs panitumumab plus fluorouracil-leucovorin in patients with RAS wild-type metastatic colorectal cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5:1268–75.

    Article  Google Scholar 

  13. 13.

    Manca P, Corallo S, Randon G, Lonardi S, Cremolini C, Rimassa L, et al. Impact of early tumor shrinkage and depth of response on the outcomes of panitumumab-based maintenance in patients with RAS wild-type metastatic colorectal cancer. Eur J Cancer. 2021;144:31–40.

    CAS  Article  Google Scholar 

  14. 14.

    Morano F, Corallo S, Lonardi S, Raimondi A, Cremolini C, Rimassa L, et al. Negative hyperselection of patients with RAS and BRAF wild-type metastatic colorectal cancer who received panitumumab-based maintenance therapy. J Clin Oncol. 2019;37:3099–110.

    CAS  Article  Google Scholar 

  15. 15.

    R Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing, 2019.

  16. 16.

    Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N. Engl J Med. 2019;381:1632–43.

    CAS  Article  Google Scholar 

  17. 17.

    El Messaoudi S, Mouliere F, Du Manoir S, Bascoul-Mollevi C, Gillet B, Nouaille M, et al. Circulating DNA as a strong multimarker prognostic tool for metastatic colorectal cancer patient management care. Clin Cancer Res. 2016;22:3067–77.

    CAS  Article  Google Scholar 

  18. 18.

    Elez E, Chianese C, Sanz-García E, Martinelli E, Noguerido A, Mancuso FM, et al. Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer. Mol Oncol. 2019;13:1827–35.

    CAS  Article  Google Scholar 

  19. 19.

    Peeters M, Price T, Boedigheimer M, Kim TW, Ruff P, Gibbs P, et al. Evaluation of emergent mutations in circulating cell-free DNA and clinical outcomes in patients with metastatic colorectal cancer treated with panitumumab in the ASPECCT Study. Clin Cancer Res. 2019;25:1216–25.

    CAS  Article  Google Scholar 

  20. 20.

    Spindler KG, Appelt AL, Pallisgaard N, Andersen RF, Jakobsen A. KRAS-mutated plasma DNA as predictor of outcome from irinotecan monotherapy in metastatic colorectal cancer. Br J Cancer. 2013;109:3067–72.

    CAS  Article  Google Scholar 

  21. 21.

    Bidard FC, Kiavue N, Ychou M, Cabel L, Stern MH, Madic J, et al. Circulating tumor cells and circulating tumor DNA detection in potentially resectable metastatic colorectal cancer: a prospective ancillary study to the Unicancer Prodige-14 Trial. Cells. 2019;8:516.

    CAS  Article  Google Scholar 

  22. 22.

    Sefrioui D, Beaussire L, Gillibert A, Blanchard F, Toure E, Bazille C, et al. CEA, CA19-9, circulating DNA and circulating tumour cell kinetics in patients treated for metastatic colorectal cancer (mCRC). Br J Cancer. 2021;125:725–33.

  23. 23.

    Tie J, Cohen JD, Wang Y, Christie M, Simons K, Lee M, et al. Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer. JAMA Oncol. 2019;5:1710–7.

    Article  Google Scholar 

  24. 24.

    Lin JK, Lin PC, Lin CH, Jiang JK, Yang SH, Liang WY, et al. Clinical relevance of alterations in quantity and quality of plasma DNA in colorectal cancer patients: based on the mutation spectra detected in primary tumors. Ann Surg Oncol. 2014;21:S680–6.

    Article  Google Scholar 

  25. 25.

    Jones RP, Pugh SA, Graham J, Primrose JN, Barriuso J. Circulating tumour DNA as a biomarker in resectable and irresectable stage IV colorectal cancer; a systematic review and meta-analysis. Eur J Cancer. 2021;144:368–81.

    CAS  Article  Google Scholar 

  26. 26.

    Parikh AR, Mojtahed A, Schneider JL, Kanter K, Van Seventer EE, Isobel J Fetter, et al. Serial ctDNA monitoring to predict response to systemic therapy in metastatic gastrointestinal cancers. Clin Cancer Res. 2020;26:1877–85.

    CAS  Article  Google Scholar 

  27. 27.

    Aranda E, Viéitez JM, Gómez-España A, Gil Calle S, Salud-Salvia A, Begoña Graña, et al. FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: the randomised phase III VISNÚ-1 trial. ESMO Open. 2020;5:e000944.

    Article  Google Scholar 

  28. 28.

    Borelli B, Moretto R, Lonardi S, Bonetti A, Antoniotti C, Pietrantonio F, et al. TRIPLETE: a randomised phase III study of modified FOLFOXIRI plus panitumumab versus mFOLFOX6 plus panitumumab as initial therapy for patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer. ESMO Open. 2018;3:e000403.

    Article  Google Scholar 

  29. 29.

    Cremolini C, Antoniotti C, Rossini D, Lonardi S, Loupakis F, Pietrantonio F, et al. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21:497–507.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

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.

Ethics declarations

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.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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 (2021). https://doi.org/10.1038/s41416-021-01591-8

Download citation

Search

Quick links