KRAS ctDNA Detection in Patients With Resectable Lung Adenocarcinoma

Meghan L De Meo; Joseph Seitlinger; Roni F Rayes; Lyndon C Walsh; Muhammad H Shahzad; Thupten Tsering; Ramy Saleh; Nicole Ezer; Benjamin Shieh; Annick Wong; Scott Owen; Logan Walsh; Pierre-Olivier Fiset; Julia V Burnier; Jonathan D Spicer

doi:10.1016/j.cllc.2025.05.006

KRAS ctDNA Detection in Patients With Resectable Lung Adenocarcinoma

Clin Lung Cancer. 2025 May 29:S1525-7304(25)00104-4. doi: 10.1016/j.cllc.2025.05.006. Online ahead of print.

Authors

Affiliations

¹ Cancer 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.
² Department of Surgery, Division of Thoracic Surgery, McGill University, Montreal, Canada.
³ Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, Canada; Department of Surgery, Division of Thoracic Surgery, McGill University, Montreal, Canada.
⁴ Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, Canada.
⁵ Department of Medicine, Division of Respiratory Medicine, McGill University, Montreal, Canada.
⁶ Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada.
⁷ Goodman Cancer Institute, McGill University, Montreal, Canada.
⁸ Department of Pathology, McGill University, Montreal, Canada.
⁹ Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada; Department of Pathology, McGill University, Montreal, Canada.
¹⁰ Cancer 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. Electronic address: jonathan.spicer@mcgill.ca.

PMID: 40634198
DOI: 10.1016/j.cllc.2025.05.006

Abstract

Introduction/background: Clinical trials are assessing the suitability of KRAS^G12C 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 KRAS^G12C & KRAS^G12V ctDNA and wild-type KRAS cfDNA in the same reaction based on prior tumor tissue profiling.

Results: In overall clinical staging, KRAS^G12C ctDNA was detected in liquid biopsies of stage II (1/7, 14%) and III (2/5, 40%) patients. In overall pathological staging, KRAS^G12C ctDNA was detected exclusively in liquid biopsies of stage III patients (4/11, 36%). KRAS^G12V 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). KRAS^G12C 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.

Keywords: Biomarker; Liquid biopsy; Non-Small Cell Lung Cancer; Targeted therapy; ddPCR.