Changes in circulating tumor DNA and outcomes in solid tumors treated with immune checkpoint inhibitors: a systematic review

Abstract

BackgroundQuantification of circulating tumor DNA (ctDNA) levels is a reliable prognostic tool in several malignancies. Dynamic changes in ctDNA levels in response to treatment may also provide prognostic information. Here, we explore the value of changes in ctDNA levels in response to immune checkpoint inhibitors (ICIs).MethodsWe searched MEDLINE (host: PubMed) for trials of ICIs in advanced solid tumors in which outcomes were reported based on change in ctDNA levels. ctDNA reduction was defined as reported in individual trials. Typically, this was either >50% reduction or a reduction to undetectable levels. We extracted HRs and related 95% CIs and/or p values comparing ctDNA reduction versus no reduction for progression-free survival (PFS) and/or overall survival (OS). Data were then pooled in a meta-analysis. Variation in effect size was examined using subgroup analyses.ResultsEighteen trials were included in the meta-analysis. ctDNA levels were detectable in all participants in all studies prior to initiation of ICIs. A reduction in ctDNA measured 6–16 weeks after starting treatment was associated with significantly better PFS (HR 0.20; 95% CI, 0.14 to 0.28; p<0.001). Similarly, OS was superior in patients with reduced ctDNA levels (HR 0.18; 95% CI, 0.12 to 0.26; p<0.001). The results were consistent across all disease sites, lines of treatment, magnitude of change (to undetectable vs >50% reduction) and whether treatment exposure comprised single or combination ICIs.ConclusionsIn advanced solid tumors, a reduction in ctDNA levels in response to ICIs is associated with substantial improvements in outcome. ctDNA change is an early response biomarker which may allow for de-escalation of cross-sectional imaging in patients receiving ICIs or support treatment de-escalation strategies.

Progresses in biomarkers for cancer immunotherapy

“…It has been demonstrated that ctDNA clearance is associated with significantly better outcomes beyond 2 years after initiating ICIs 197 . Of note, early evidence did not seem to indicate a consistent association between ctDNA dynamic changes and TMB or PD‐L1 expression 194,198,199 . Compared with this, Kim et al 200 .…”

Promising and Minimally Invasive Biomarkers: Targeting Melanoma

“…Detecting circulating DNA offers multiple opportunities in (a) early cancer diagnosis (b) assessment of minimal residual disease (MRD) (c) disease tracking during anticancer treatment—“molecular response” to therapy and (d) uncovering tumour heterogeneity and novel targets conferring treatment resistance [ 57 , 58 , 59 , 60 , 61 , 62 ]. Variant allele frequency (VAF) is the most common readout for a mutation detected in ctDNA and is defined as the fraction of cfDNA molecules sequenced at a particular locus that harbours the variant of interest.…”

“…Molecular response and ctDNA kinetics refer to VAF dynamics during treatment, and it is worth mentioning that, besides tumour driver mutations, these can encompass the characterisation of neoantigens and/or chromosomal number aberrations [ 83 , 84 , 85 ]. Several studies and meta-analyses have attempted to highlight the robustness of ctDNA as a biomarker of treatment response, which can guide treatment duration or monitoring intensity in a pan-cancer fashion [ 59 , 62 , 68 , 86 , 87 , 88 ]. Across 16 tumour types, including melanoma, Zhang et al confirmed that mean VAF pre-treatment with immune checkpoint inhibition was prognostic of overall survival [OS; stratified by the median; unadjusted HR, 0.58; 95% confidence interval (CI), 0.49–0.69; p < 0.0001].…”

It is time to improve the diagnostic workup of oropharyngeal cancer with circulating tumor HPV DNA: Systematic review and meta‐analysis

“…Thus, often tissue biopsy in operation theater is required to prove the diagnosis of HPV + OPSCC, causing additional invasive procedure, diagnostic delays and cost increase 18 . Despite cell free DNA (cfDNA) is a promising biomarker for diagnosis and monitoring of cancer treatment as well as for detection of residual disease and recurrences, 19–21 its use is limited by increasing challenges linked to sensitivity (detection of somatic cfDNA alterations against a normal DNA background) and specificity (cfDNA alterations are not intrinsically specific for a given type of cancer) 22,23 . On the contrary, circulating tumor HPV DNA (ctHPVDNA), released by HPV‐related cancers, is more easily identified than altered somatic cfDNA, and is able to indicate the possible localization of primary tumors, thus improving sensitivity and specificity, respectively 24–26 .…”