Circulating tumour DNA (ctDNA) in metastatic melanoma, a systematic review and meta-analysis

Lara Gracie; Yi Pan; Eshetu G Atenafu; Douglas G Ward; Mabel Teng; Lallit Pallan; Neil M Stevens; Leila Khoja

doi:10.1016/j.ejca.2021.09.019

Circulating tumour DNA (ctDNA) in metastatic melanoma, a systematic review and meta-analysis

Eur J Cancer. 2021 Oct 30:158:191-207. doi: 10.1016/j.ejca.2021.09.019. Online ahead of print.

Authors

Lara Gracie¹, Yi Pan², Eshetu G Atenafu³, Douglas G Ward⁴, Mabel Teng⁵, Lallit Pallan⁵, Neil M Stevens⁶, Leila Khoja⁷

Affiliations

¹ College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
² Centre for Computational Biology and Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
³ Biostatistics Department, Princess Margaret Cancer Center, University Health Network, University Way, Toronto, Ontario, Canada.
⁴ Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
⁵ University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Department of Oncology, Birmingham B15 2TH, UK.
⁶ Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
⁷ Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: l.khoja@bham.ac.uk.

PMID: 34757258
DOI: 10.1016/j.ejca.2021.09.019

Abstract

Introduction: Circulating tumour DNA (ctDNA) is an emerging biomarker in melanoma. We performed a systematic review and meta-analysis to explore its clinical utility as a prognostic, pharmacodynamic (PD) and predictive biomarker.

Methods: A systematic search was conducted from Jan 2015 to April 2021, of the electronic databases PubMed, Cochrane Library and Ovid MEDLINE to identify studies. Studies were restricted to those published in English within the last 5 years, evaluating ctDNA in humans in ≥10 patients. Survival data were extracted for meta-analysis using pooled treatment effect (TE), i.e. log hazard ratios (HRs) and corresponding standard error of TE for progression-free survival or overall survival differences in patients who were ctDNA positive or negative. PRISMA statement guidelines were followed.

Results: A meta-analysis of 19 studies grouped according to methodology of ctDNA detection, revealed a combined estimate for HR of progression-free survival (13 studies using droplet digital Polymerase Chain Reaction (ddPCR) methodology (N = 1002) of 2.10 (95% CI: 1.71-2.59) revealing a poorer prognosis when ctDNA was detected. This result was confirmed in the smaller analysis of (non-ddPCR, N = 347) five studies: HR = 2.45 (95% CI: 1.29-4.63). Similar findings were found in the overall survival analysis of nine studies (ddPCR methodology, N = 841) where the combined HR was 2.78 (95% CI: 2.21-3.49) and of the five studies (non-ddPCR methodology, N = 326) where the combined HR was 2.58 (95% CI: 1.74-3.84). Serial ctDNA levels on treatment showed a pharmacodynamic role reflecting response or resistance earlier than radiological assessment.

Conclusions: Circulating tumour DNA is a predictive, prognostic and PD biomarker in melanoma. Technical standardisation of assays is required before clinical adoption.

Keywords: Biomarker; Melanoma; Meta-analysis; ctDNA.

Publication types

Review