Value of concentration and gene methylation analyses of circulating cell-free DNA as diagnostic method for breast cancer: a systematic review

Background and aims: Many studies focus attention on circulating cell-free DNA (cfDNA) concentration and methylation as means for early detection of breast cancer. However, the results of existing studies are different and it remains difficult to determine the diagnostic role of circulating cfDNA in breast cancer. Therefore, this study performed a meta-analysis to integrate the findings of these published studies and establish the diagnostic value of circulating cfDNA in diagnosis of breast cancer. Methods: A total of 19 studies were included and divided into three subgroups. Sensitivity, specificity, and other important measures of cfDNA accuracy for breast cancer diagnosis were pooled using random-effects models. Summary receiver operating characteristic curve analysis techniques were used to summarize overall accuracy. Results: Summary estimates for cfDNA concentration and gene methylation in diagnosis of breast cancer were as follows: in the subgroup of quantitative analysis, sensitivity and specificity were 0.889 (95%CI = 0.858-0.915) and 0.806 (95%CI = 0.767-0.841); PLR was 5.058 (95%Cl = 2.723-9.392); NLR was 0.150 (95% CI = 0.090-0.251) and DOR value was 42.156 (95% CI = 19.364-91.774). In the subgroup of single-gene indicators, sensitivity and specificity were 0.406 (95%CI = 0.390-0.421) and 0.848 (95% CI = 0.836-0.860); PLR was 4.569 (95% CI = 3.329-6.270); NLR was 0.643 (95% CI = 0.588-0.704) and DOR value was 8.608 (95% CI = 5.679-13.046). In the subgroup of multiple-gene panel, sensitivity and specificity were 0.778 (95% CI = 0.760-0.796) and 0.835 (95% CI = 0.819-0.850); PLR was 6.158 (95% CI = 4.432-8.556); NLR was 0.194 (95% CI = 0.139-0.272) and DOR value was 39.353 (95% CI = 21.139-73.260). Conclusion: Circulating cfDNA concentration and gene methylation analysis might be applied in breast cancer detection since the test has a relatively high level of diagnostic accuracy. If only the single-gene methylation detection assay is used for breast cancer diagnosis, extra caution should be applied. Evaluation of circulating cfDNA concentration and multiple-gene methylation analyses might improve breast cancer early diagnosis.