Minimal Residual Disease Monitoring in Radically Treated Non-Small Cell Lung Cancer: Challenges and Future Directions

Abstract

Circulating tumor DNA (ctDNA) analysis can identify patients with residual disease before it is clinically or radiologically evident. Minimal residual disease (MRD) is an advancing area in the management of radically treated solid tumors. Which MRD assay is optimum and when it should be used is still not defined. Whilst promising, the clinical utility of this technology to guide patient care is still investigational in non-small cell lung cancer (NSCLC) and has not entered routine care. Once technically and clinically optimized, MRD may be utilized to personalize adjuvant therapy, detect disease relapse earlier and improve cure rates. In this review, we discuss the current status of MRD monitoring in NSCLC by summarizing frequently used MRD assays and their associated evidence in NSCLC. We discuss the potential applications of these technologies and the challenge of demonstrating MRD clinical utility in trials.

Technical Advances in Circulating Cell-Free DNA Detection and Analysis for Personalized Medicine in Patients’ Care

“…In oncology, the presence of the circulating tumor cfDNA (ctDNA) and the analysis of its genetic alterations allows the detection of cancer disease, the monitoring of treatment response, and the detection of minimal residual disease, enabling personalized treatment strategies [17,18]. Currently, the most common use of ctDNA analysis is therapy selection and stratification of patients based on the likelihood of response to targeted therapies [19][20][21][22] by searching for specific mutation markers for resistance or sensitivity, such as tyrosine kinase inhibitors, programmed death inhibitors-1 [23], programmed death ligand-1 [24], and cytotoxic T lymphocyte-associated protein 4 [25].…”

Liquid Biopsy in Lung Cancer: Biomarkers for the Management of Recurrence and Metastasis

“…Liquid biopsy tests for MRD can be divided into tumor-informed (requires knowledge of the tumor's genetic profile beforehand by examining a sample of the tumor or analyzing preoperative cell-free DNA) and tumor-uninformed (intended to identify the existence of MRD without any prior knowledge of the specific molecular alterations that may be present in the tumor of an individual patient) assays [163]. Assays that use the tumor-informed approach, such as RaDaR [164], Signatera [165], and the recently tested HIFI platform [47], are personalized using the baseline genotype of the patient's primary tumor or preoperative cfDNA and require longitudinal follow-up to probe for emergent mutations.…”

“…With this approach, the same assay is used for each patient, which leads to a shorter turnaround but diminished specificity and sensitivity. Trials of liquid biopsy assays for MRD detection in NSCLC patients are currently underway [163].…”