KRAS ctDNA Detection in Patients With Resectable Lung Adenocarcinoma
Meghan L De Meo1, Joseph Seitlinger2, Roni F Rayes3
1Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, Canada; Department of Experimental Surgery, McGill University, Montreal, Canada; Department of Surgery, Division of Thoracic Surgery, McGill University, Montreal, Canada.
Introduction/Background:
Clinical trials are assessing the suitability of KRASG12C inhibitors in the neoadjuvant setting. Appropriate patient selection is paramount to ensure therapeutic efficacy. Here we sought to investigate the clinical utility of ctDNA to identify resectable lung adenocarcinoma (LUAD) patients with KRAS-driven disease.
Materials & Patients:
From our institution's clinical database and biobank, we identified 47 patients based on our inclusion criteria: research-consented, treatment-naïve, NGS-confirmed KRAS-mutated resectable stage IA-IIIB LUAD with available pre-operative blood. cfDNA was isolated from 700-2000µL plasma and was preamplified. In a tumour-informed approach, digital droplet polymerase chain reaction (ddPCR) was performed to identify hotspot KRASG12C & KRASG12V ctDNA and wild-type KRAS cfDNA in the same reaction based on prior tumor tissue profiling.
Results:
In overall clinical staging, KRASG12C ctDNA was detected in liquid biopsies of stage II (1/7, 14%) and III (2/5, 40%) patients. In overall pathological staging, KRASG12C ctDNA was detected exclusively in liquid biopsies of stage III patients (4/11, 36%). KRASG12V ctDNA was detected in liquid biopsies of overall clinical stage I (1/3, 33%) and III (1/1, 100%) patients and in pathological stage II (1/3, 33%) and III (1/2, 50%) patients. KRAS ctDNA positivity was associated with shorter overall survival (median OS 21 months vs. 41 months, P < .05). KRASG12C ctDNA positivity was associated with larger tumour size, presence of nodal involvement, and higher overall pathological stage.
Conclusion:
ctDNA positivity from liquid biopsy is a low-cost and accessible method for triaging patients with LUAD towards trials evaluating KRAS inhibitors in the neoadjuvant setting.
Insights
Liquid biopsy detecting KRAS ctDNA can identify patients with lung adenocarcinoma for KRAS inhibitor trials. This accessible method aids in selecting patients for neoadjuvant therapy, improving treatment efficacy.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genetics
Background:
- Clinical trials are evaluating KRAS G12C inhibitors for neoadjuvant treatment in lung adenocarcinoma (LUAD).
- Accurate patient selection is crucial for the efficacy of these targeted therapies.
- Investigating the utility of circulating tumor DNA (ctDNA) for identifying suitable LUAD patients is essential.
Purpose of the Study:
- To assess the clinical utility of ctDNA for identifying resectable LUAD patients with KRAS-driven disease.
- To determine if ctDNA detection can aid in patient selection for neoadjuvant KRAS inhibitor trials.
Main Methods:
- Retrospective analysis of 47 treatment-naïve, resectable LUAD patients with KRAS mutations.
- Isolation of cell-free DNA (cfDNA) from plasma and preamplification.
- Tumor-informed digital droplet PCR (ddPCR) to detect KRAS G12C, KRAS G12V, and wild-type KRAS ctDNA.
Main Results:
- KRAS G12C ctDNA was detected in 14% of clinical stage II and 36% of pathological stage III LUAD patients.
- KRAS G12V ctDNA was detected in various stages, including 100% of clinical stage III patients.
- KRAS ctDNA positivity correlated with shorter overall survival and advanced pathological stage, including nodal involvement.
Conclusions:
- ctDNA detection via liquid biopsy is a cost-effective and accessible method for patient triage.
- This approach can facilitate patient selection for clinical trials involving neoadjuvant KRAS inhibitors in LUAD.
- ctDNA analysis offers a valuable tool for optimizing targeted therapy in lung cancer.
