Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer prior to first-line oxaliplatin-based chemotherapy
Menée à partir d'échantillons plasmatiques prélevés sur 493 patients atteints d'un cancer colorectal métastatique traité par chimiothérapie à base d'oxaliplatine, cette étude évalue l'association entre le niveau de l'ADN total libre circulant mesuré avant le traitement et la survie globale
Background : Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors.
Patients and methods : This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical endpoint was overall survival (OS).
Results : cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7,673 alleles/mL (1,050-1,645,000) for B2M and 5,959 alleles/mL (555-854,167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6 months for levels above ULN and 25.9 months for levels below ULN (HR = 1.83, 95% CI 1.51–2.21, P < 0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response (SIR) as measured by IL-6 (F(6, 357) = 62.7, P < 0.001).
Conclusion : cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC prior to first-line oxaliplatin-based chemotherapy, and may be a complex entity associated with tumor burden, liver metastases and SIR.
Trial registration : ClinicalTrials.gov, NCT00145314
Annals of Oncology , résumé, 2018