Lung cancer ranks second among the most common cancers worldwide and is the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC), accounting for 85% of all lung cancers, has a very low overall survival (OS) and a high postoperative recurrence rate despite improved therapeutic interventions. Surgery is the primary treatment for most cases of early-stage NSCLC, while chemotherapy, targeted therapy, and immunotherapy are principally employed to advanced NSCLC. However, new techniques are needed to identify relapsed and non-relapsed patients and individualize treatments accordingly.
MRD refers to the small number of tumor cells that are resistant to treatment and survive in the blood or bone marrow. It can be associated with the risk of relapse as it remains undetected by imaging techniques. Circulating tumor DNA in blood can effectively identify MRD.
A review conducted by Dr. Libo Tang, Dr. Chongrui Xu and Dr. Qing Zhou from Southern Medical University, and Dr. Ruiyang Li and Dr. Huahai Wen from First Affiliated Hospital of Chongqing Medical University, provides a comprehensive account of ctDNA-based MRD focusing on NSCLC and its clinical applications. It was published online on June 28, 2023 in the Chinese Medical Journal Pulmonary and Critical Care Medicine.
Sharing the significance of their study, Dr. Zhou and Dr. Xu explain, "The level of MRD can be obtained by monitoring ctDNA to provide guidance for more precise and personalized treatment, the scientific feasibility of which could dramatically modify lung cancer treatment paradigm. In this review, we provide a comprehensive description of ctDNA-based MRD and its relevant clinical applications."
Most conventional imaging techniques like positron emission tomography/computed tomography (PET/CT) and laboratory procedures cannot detect MRD and thus the risk of progression and remission. On the contrary, ctDNA can effectively measure tumor load while being non-invasive. Thus, a combination of the two would surely be a breakthrough method for the detection and prognosis of solid cancers like NSCLC. Currently there are two main methods for ctDNA-based MRD technology—tumor agnostic assays and tumor-informed assays. However, there is no universal standard for MRD detection and there are variations among different technical systems.
Postoperative adjuvant therapy is highly recommended for early to middle stage NSCLC patients to eliminate MRD and improve OS. However, it is not beneficial to patients who have already been cured and causes side effects. However, existing detection methods cannot differentiate between cured patients and those at high recurrence risk. The TRACERx project demonstrated that ctDNA-based MRD detection could predict recurrence much before imaging techniques and identified the lead cycle for tumor recurrence, the time between the detection of recurrence positivity by ctDNA and the confirmation of tumor recurrence by clinical CT imaging. There are numerous studies that have reported the competence of ctDNA-based MRD for patient risk stratification, prognostic assessment, and recurrence detection.
Various studies and expert consensus have also determined that the optimal time for MRD identification was within one week to one month after radical surgery, followed by testing at regular intervals to identify subgroups with a high risk of recurrence. Furthermore, patients with undetectable MRD at follow up could potentially be the patients who have been completely cured.
ctDNA-based MRD was found to be equally effective in guiding adjuvant therapy. They found that MRD-positive patients treated with adjuvant therapy showed improved rates of recurrence-free survival. Moreover, patients with prolonged MRD negativity maintained a very high disease-free rate and represented the cured population. Therefore, with the help of ctDNA-based MRD detection, unnecessary overmedication could be avoided. The researchers also found evidence suggesting the utility of ctDNA-based MRD for efficacy assessment of NSCLC patients after consolidation immunotherapy.
Neoadjuvant therapy has been effective in improving long-term survival in patients with NSCLC. One of the studies reported significant correlation between low ctDNA levels and MRD negativity, before and after neoadjuvant therapy, respectively. This suggests that ctDNA-based MRD could be a novel predictive biomarker for assessing neoadjuvant therapy efficacy.
ctDNA-based MRD has also been considered as a promising supplement to imaging techniques for prognosis of oligometastatic NSCLC (lung cancer with metastases in no more than three organs and ≤ 5 metastases in total). Overall, the authors found that ctDNA-based MRD can be employed as a potential biomarker for tumor monitoring, prognostic assessment, recurrence prediction, and clinical decision making.
They also addressed the limitations of this technique and found lack of sensitivity, non-uniform criteria for assessing positive ctDNA-based MRD, and the timing of detection to be the main drawbacks. Moreover, they suggested measures to overcome the drawbacks and improve the technique to gain global acceptance. Dr. Zhou and Dr. Xu conclude, "In order to build a consistent MRD assessment system and validate the clinical utility of MRD, more research is still required. Overall, using ctDNA-based MRD analysis to assist clinical decisions and increase patient survival is very advantageous in the era of precision medicine."
