Circulating cell-free DNA as a prognostic and predictive biomarker in non-small cell lung cancer

Abstract

Circulating cell-free DNA (cfDNA), which can be obtained from plasma or serum by non-invasive procedures, has showed great potential to predict treatment response and survival for cancer patients. Several studies have assessed the prognostic and predictive value of cfDNA in non-small cell lung cancer (NSCLC). However, these studies were often small and reported varying results. To address this issue, a meta-analysis was carried out. A total of 22 studies involving 2518 patients were subjected to the final analysis. Our results indicated that NSCLC patients with higher cfDNA concentration had shorter median progression-free survival (PFS) and overall survival (OS) time. In addition, high levels of cfDNA were significantly associated with poor PFS (hazard ratio or HR, 1.32; 95% CI, 1.02-1.71) and OS (HR, 1.64; 95% CI, 1.26-2.15). With respect to tumor specific mutations, we failed to reveal significant differences for PFS (HR, 1.30; 95% CI, 0.66-2.56) and OS (HR, 1.05; 95% CI, 0.49-2.25) when NSCLC patients were grouped according to KRAS genotype detected in cfDNA. However, NSCLC patients which harbored EGFR activating mutation in cfDNA had a greater chance of response to EGFR-TKIs (odds ratio or OR, 1.96; 95% CI, 1.59-2.42). No significant publication bias was detected in this study. In conclusion, cfDNA could act as a prognostic and predictive biomarker for patients with NSCLC.

Circulating DNA in EGFR-mutated lung cancer

“…Median OS was found to be shorter in patients with the L858R mutation in ctDNA than in those with the exon 19 deletion (13.7 vs. 30.0 months) and patients with L858R mutations detected in both ctDNA as well as tumor had shorter survival compared to patients with the mutation detected only in tumor tissue (13.7 vs. 27.7 months). The mean level of circulating free DNA (cfDNA) has also been shown to predict OS in NSCLC patients, with higher levels correlating with worse survival (38). Levels >3 ng/μL were associated with a median OS of 24 vs. 46 months in one prospective study (7).…”

KRAS mutations in the circulating free DNA (cfDNA) of non-small cell lung cancer (NSCLC) patients

“…However, when EGFR mutant patients were excluded, there were no statistical differences between progression-free survival (PFS) to chemotherapy and response rates to EGFR-TKIs or chemotherapy. One explanation might be that KRAS and EGFR mutations are generally mutually exclusive in NSCLC and, consequently, the vast majority of EGFR mutations are present in KRAS wild-type patients (15,16). Therefore, the absence of EGFR alterations, rather than the presence of KRAS mutation, can be a negative predictor of response to EGFR-TKIs (8).…”

“…Three were performed using plasma samples and showed worse PFS and OS in KRAS mutated patients (31,33,35) while a study performed in serum did not show any significant differences (30). However, a meta-analysis incorporating data from all the studies concluded that KRAS mutations in cfDNA may not be useful to predict response to chemotherapy (16).…”

Possible application of circulating free tumor DNA in non-small cell lung cancer patients

“…The data until now from several studies as well as a metaanalysis indicate that KRAS mutations in cfDNA may not be useful to predict response to chemotherapy (49)(50)(51). However, our everyday clinical experience allows us to say that in KRAS mutant NSCLC patients, when the mutation is also detected in the cfDNA the prognosis of the patients is detrimental.…”