New strategy for antimetastatic treatment of lung cancer: a hypothesis based on circulating tumour cells

Metastasis is a major factor contributing to the high mortality of lung cancer, and effective antimetastatic drugs are lacking [1]. The primary reason is that the current therapeutic drugs and strategies are based on the molecular or pathological diagnosis results of the primary tumour tissue [2]. However, the benefit for patients with early-stage lung cancer is very limited [3]. Considerable heterogeneity exists between the primary tumour and different metastatic lesions [4]. One tissue biopsy cannot accurately capture the complete genome of the patient’s cancer, and the phenotype and gene of cancer cells will change after treatment, bringing challenges to individualized and precise medication [5]. Additionally, after surgery in patients with early-stage lung cancer, distinguishing between the occurrence and location of metastases is difficult. However, circulating tumour cells (CTCs), as the link between the primary tumour and metastasis, play a crucial role in the precise treatment of lung cancer metastasis [6].

The metastatic cascade of tumours begins before the first diagnosis [7]. Circulating tumour cells (CTCs), shed from primary tumours and circulation in peripheral blood, are considered a precursor of metastasis [8]. CTC counts can be used not only to diagnose lung cancer early but also to assess metastatic risk and prognosis [9, 10]. Multiple lines of evidence have indicated that the metastatic potential of CTCs is significantly enhanced when they form cell clusters with CTCs, neutrophils, and platelets [11], and lung cancer patients with detectable CTC clusters had shorter progression-free survival (PFS) and overall survival (OS) [12]. Additionally, analysing CTCs can reflect not only the primary tumour but also information on undiscovered micrometastasis [13]. Exome sequencing of lung cancer CTCs can identify mutations associated with metastatic cancer [14]. Therefore, analysing ALK, EGFR and other gene mutations and PD-L1 protein expression in CTCs can help clinicians guide medication [15, 16]. Additionally, CTCs can be cultured ex vivo to identify new mutations and perform individualized testing of drug susceptibility [17]. Notably, multiple lines of evidence have indicated that the increased number of CTCs in postoperative patients was consistent with the imaging results of computed tomography (CT) scans and was associated with shorter PFS and OS, suggesting that the existing treatment failed to improve patient survival [18]. Additionally, although no change was found in the number of CTCs, its phenotype changed, leading to treatment resistance and disease progression [19]. In this setting, the formulation of antimetastatic therapeutic strategies based on CTCs may break through the curative effect of lung cancer.

In summary, the primary tumour represents the visible battlefield, and the prevention and treatment of tumour metastasis represent the invisible battlefield. CTCs are associated with distant metastasis and are alternative markers of invisible micrometastases, which, like a beacon in navigation, can dynamically reflect the state of metastases in real time and point out the direction for metastasis prevention and treatment. In the case of tumours in patients with CTCs after surgery, treatment should be adjusted, and multimodal treatment based on the molecular pathological information of CTCs should be considered. CTCs counts are now gradually entering the clinical staging system. Because the analysis and detection standards of CTCs are not unified and the existing clinical treatment guidelines do not allow the primary tumour to guide anti-lung cancer metastasis treatment, clinical trials have not yet been performed. However, lung cancer metastasis may be prevented and the survival of patients may be prolonged. Overall, this hypothesis provides a new strategy for treating lung cancer metastasis and may be of great significance in improving the survival of lung cancer patients.