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

Paolo Manca; Salvatore Corallo; Sara Lonardi; Giovanni Fucà; Adele Busico; Alberto Giovanni Leone; Francesca Corti; Carlotta Antoniotti; Letizia Procaccio; Valeria Smiroldo; Margherita Ratti; Roberto Murialdo; Patrizia Racca; Filippo Pagani; Giovanni Randon; Antonia Martinetti; Elisa Sottotetti; Michele Prisciandaro; Margherita Ambrosini; Alessandra Raimondi; Federica Morano; Filippo Pietrantonio

doi:10.1038/s41416-021-01591-8

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

Paolo Manca, Salvatore Corallo, Sara Lonardi, Giovanni Fucà, Adele Busico, Alberto Giovanni Leone, Francesca Corti, Carlotta Antoniotti, Letizia Procaccio, Valeria Smiroldo, Margherita Ratti, Roberto Murialdo, Patrizia Racca, Filippo Pagani, Giovanni Randon, Antonia Martinetti, Elisa Sottotetti, Michele Prisciandaro, Margherita Ambrosini, Alessandra RaimondiFederica Morano, Filippo Pietrantonio

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	449-455
Number of pages	7
Journal	British Journal of Cancer
Volume	126
Issue number	3
DOIs	https://doi.org/10.1038/s41416-021-01591-8
Publication status	Published - Feb 2022

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Manca, P., Corallo, S., Lonardi, S., Fucà, G., Busico, A., Leone, A. G., Corti, F., Antoniotti, C., Procaccio, L., Smiroldo, V., Ratti, M., Murialdo, R., Racca, P., Pagani, F., Randon, G., Martinetti, A., Sottotetti, E., Prisciandaro, M., Ambrosini, M., ... Pietrantonio, F. (2022). 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, 126(3), 449-455. https://doi.org/10.1038/s41416-021-01591-8

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. / Manca, Paolo; Corallo, Salvatore; Lonardi, Sara et al.

In: British Journal of Cancer, Vol. 126, No. 3, 02.2022, p. 449-455.

Research output: Contribution to journal › Article › peer-review

Manca, P, Corallo, S, Lonardi, S, Fucà, G, Busico, A, Leone, AG, Corti, F, Antoniotti, C, Procaccio, L, Smiroldo, V, Ratti, M, Murialdo, R, Racca, P, Pagani, F, Randon, G, Martinetti, A , Sottotetti, E , Prisciandaro, M, Ambrosini, M, Raimondi, A , Morano, F & Pietrantonio, F 2022, '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, vol. 126, no. 3, pp. 449-455. https://doi.org/10.1038/s41416-021-01591-8

Manca P, Corallo S, Lonardi S, Fucà G, Busico A, Leone AG 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. British Journal of Cancer. 2022 Feb;126(3):449-455. doi: 10.1038/s41416-021-01591-8

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title = "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",

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.",

author = "Paolo Manca and Salvatore Corallo and Sara Lonardi and Giovanni Fuc{\`a} and Adele Busico and Leone, {Alberto Giovanni} and Francesca Corti and Carlotta Antoniotti and Letizia Procaccio and Valeria Smiroldo and Margherita Ratti and Roberto Murialdo and Patrizia Racca and Filippo Pagani and Giovanni Randon and Antonia Martinetti and Elisa Sottotetti and Michele Prisciandaro and Margherita Ambrosini and Alessandra Raimondi and Federica Morano and Filippo Pietrantonio",

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T1 - 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

AU - Manca, Paolo

AU - Corallo, Salvatore

AU - Lonardi, Sara

AU - Fucà, Giovanni

AU - Busico, Adele

AU - Leone, Alberto Giovanni

AU - Corti, Francesca

AU - Antoniotti, Carlotta

AU - Procaccio, Letizia

AU - Smiroldo, Valeria

AU - Ratti, Margherita

AU - Murialdo, Roberto

AU - Racca, Patrizia

AU - Pagani, Filippo

AU - Randon, Giovanni

AU - Martinetti, Antonia

AU - Sottotetti, Elisa

AU - Prisciandaro, Michele

AU - Ambrosini, Margherita

AU - Raimondi, Alessandra

AU - Morano, Federica

AU - Pietrantonio, Filippo

PY - 2022/2

Y1 - 2022/2

N2 - 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.

AB - 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.

U2 - 10.1038/s41416-021-01591-8

DO - 10.1038/s41416-021-01591-8

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C2 - 34811502

SN - 0007-0920

VL - 126

SP - 449

EP - 455

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 3

ER -