Molecular Diagnostics

Early assessment of KRAS mutation in cfDNA correlates with risk of progression and death in advanced non-small-cell lung cancer

Abstract

Background

Liquid biopsy has the potential to monitor biological effects of treatment. KRAS represents the most commonly mutated oncogene in Caucasian non-small-cell lung cancer (NSCLC). The aim of this study was to explore association of dynamic plasma KRAS genotyping with outcome in advanced NSCLC patients.

Methods

Advanced NSCLC patients were prospectively enrolled. Plasma samples were collected at baseline (T1), after 3 or 4 weeks, according to treatment schedule (T2) and at first radiological restaging (T3). Patients carrying KRAS mutation in tissue were analysed in plasma with droplet digital PCR. Semi-quantitative index of fractional abundance of mutated allele (MAFA) was used.

Results

KRAS-mutated cohort included 58 patients, and overall 73 treatments (N = 39 chemotherapy and N = 34 immune checkpoint inhibitors) were followed with longitudinal liquid biopsy. Sensitivity of KRAS detection in plasma at baseline was 48.3% (95% confidence interval (CI): 35.0–61.8). KRAS mutation at T2 was associated with increased probability of experiencing progressive disease as best radiological response (adjusted odds ratio: 7.3; 95% CI: 2.1–25.0, p = 0.0016). Increased MAFA (T1–T2) predicted shorter progression-free survival (adjusted hazard ratio (HR): 2.1; 95% CI: 1.2–3.8, p = 0.0142) and overall survival (adjusted HR: 3.2; 95% CI: 1.2–8.4, p = 0.0168).

Conclusions

Longitudinal analysis of plasma KRAS mutations correlated with outcome: its early assessment during treatment has great potentialities for monitoring treatment outcome in NSCLC patients.

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Fig. 1: Association of liquid biopsy results and progression-free survival (PFS).
Fig. 2: Association of liquid biopsy results and overall survival (OS).
Fig. 3: Clinical benefit according to longitudinal liquid biopsy analysis in patients treated with chemotherapy (CT) or immune checkpoint inhibitors (ICIs).
Fig. 4: Specific pattern of response according to longitudinal liquid biopsy analysis in patients treated with immune checkpoint inhibitors (ICIs).

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Acknowledgements

We thank Dr. Rafael Rosell for his critical review of the manuscript. This work was partially presented at the ESMO Congress in 2018.31

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Affiliations

Authors

Contributions

L.B. and S.I. conceived and designed the study; E.Z., G.N, M.V., A.B.B. and L.P. performed molecular analyses, I.A., A.P. and L.B. collected clinical data, reviewed radiological imaging and organised plasma samples collection, L.B. and G.P. were responsible for patients’ treatment and care; M.F. and F.C. provided tissue samples; P.D.B. performed statistical analyses; E.Z., L.B. and S.I. analysed and interpreted data; E.Z., L.B. and S.I. wrote the manuscript; A.A., P.F.C. and S.I. edited the manuscript; P.F.C., V.G., A.A. and S.I. performed critical review to the analyses of data and manuscript writing; all the authors read and approved the manuscript.

Corresponding author

Correspondence to Stefano Indraccolo.

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Ethics approval and consent to participate

The ethics committee of Istituto Oncologico Veneto evaluated and approved study design and informed consent (2016/82, 12 December 2016). Written informed consent was obtained from all patients before study entry. The study was conducted in accordance with the precepts of the Declaration of Helsinki.

Consent to publish

The property of data belongs to the sponsor, IOV, and the authors have the right to publish the data.

Data availability

The data generated and analysed during this study are included in this published article and its additional files. Further raw data might be asked to the authors.

Competing interests

The authors declare no competing interests.

Funding information

This work was funded by IOV intramural research grant 2017 – SINERGIA (to S.I. and L.B.). The QX200 ddPCR system (Bio-Rad Laboratories) was purchased through a grant provided by Università degli Studi di Padova, Padova, Italy (2015).

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Zulato, E., Attili, I., Pavan, A. et al. Early assessment of KRAS mutation in cfDNA correlates with risk of progression and death in advanced non-small-cell lung cancer. Br J Cancer 123, 81–91 (2020). https://doi.org/10.1038/s41416-020-0833-7

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