# KRAS Mutations in Circulating Tumor DNA for Lung Cancer Diagnosis: A Comprehensive Meta-Analysis

## TL;DR

This study finds that detecting KRAS mutations in blood-based tumor DNA is highly specific but moderately sensitive for diagnosing lung cancer, suggesting it could be a useful complementary tool.

## Contribution

The study provides a meta-analysis of ctDNA-based KRAS mutation detection accuracy in lung cancer diagnosis, highlighting its high specificity and moderate sensitivity.

## Key findings

- KRAS ctDNA testing showed a pooled specificity of 93.7% and sensitivity of 65.2% for lung cancer diagnosis.
- High positive likelihood ratio (10.35) indicates strong rule-in capability for lung cancer.
- KRAS liquid biopsy could complement traditional diagnostics, especially when tissue biopsies are not feasible.

## Abstract

KRAS mutations are among the most common genetic alterations in lung cancer and can now be detected in circulating tumor DNA (ctDNA) via a straightforward blood test. These liquid biopsy approaches are appealing because they are minimally invasive and can provide genetic information when a tissue biopsy is not possible. However, the diagnostic accuracy of ctDNA in identifying KRAS mutations remains unclear. In this study, we conducted a systematic review of the available evidence and performed a meta-analysis of nine clinical studies involving 691 patients. Our findings suggested that the detection of KRAS mutations in ctDNA demonstrates very high specificity, meaning a positive result strongly indicates the presence of lung cancer. However, sensitivity was moderate and varied across studies. Overall, our findings suggest that KRAS ctDNA testing could support the decision-making process in diagnosis, but should complement, rather than replace, standard diagnostic procedures.

Background: Mutations in the KRAS gene play a pivotal role in lung cancer development and progression and are becoming increasingly important in therapeutic decision-making. The detection of these mutations in circulating tumor DNA (ctDNA) has attracted attention as a minimally invasive diagnostic approach. However, the accuracy reported in different studies varies widely. Methods: We conducted a systematic review and meta-analysis in accordance with the PRISMA-DTA guidelines. Eligible studies evaluated the detection of KRAS mutations in ctDNA in plasma or serum for lung cancer diagnosis and reported sufficient data to construct 2 × 2 contingency tables. Primary pooled estimates of sensitivity, specificity and likelihood ratios were calculated using aggregated 2 × 2 contingency tables. Additionally, a bivariate random-effects model was applied in a secondary analysis to investigate between-study heterogeneity. Results: Nine diagnostic study arms comprising 691 patients met the inclusion criteria. Across all datasets, there were 255 true positives, 19 false positives, 136 false negatives, and 281 true negatives. The pooled sensitivity was 65.2%, while the pooled specificity was 93.7%. The positive likelihood ratio was 10.35, and the negative likelihood ratio was 0.37, resulting in a diagnostic odds ratio of 28.0, which indicates strong rule-in capability. Sensitivity showed moderate heterogeneity across studies. In contrast, specificity demonstrated minimal heterogeneity. Conclusions: ctDNA-based detection of KRAS mutations demonstrates high specificity but moderate sensitivity for diagnosing lung cancer. These findings suggest that a KRAS liquid biopsy could be a valuable complementary diagnostic tool, particularly when a tissue biopsy is not possible or is inadequate, and it could support more personalized decision-making as analytical technologies continue to advance.