During the proliferation and development of malignant tumors, tumor cells change their cell phenotype through epithelial-mesenchymal transition, fall off from the primary tumor or metastasis, and invade the peripheral circulation to form metastatic CTCs(13).In this study, we used five CTCs per sample as a threshold, and there were fewer patients with CTCs-d0 < 5 compared to those with CTCs-d0 ≥ 5. In 2012, Krebs et al.(14) used cell search technology to release CTCs from 101 patients with stage III-IV NSCLC, and reported that the number of CTCs in stage IV patients was higher than that in stage III patients. The cut-off value of CTCs ≥ 5 is associated with shorter PFS and OS. In addition, a decrease in the number of CTCs after a cycle of standard chemotherapy may correlate with better PFS and OS. Another study conducted by Tanaka et al. found that patients with metastatic NSCLC had a higher number of CTCs than that non-metastatic patients. These findings indicate that the number of CTCs may be related to cancer stage in NSCLC patients(15). First-generation EGFR-TKIs are the first-line treatment for advanced NSCLC patients with EGFR mutations. However, drug resistance limits the use of first-generation EGFR-TKIs. Studies have shown that CTC count is negatively correlated with the efficacy of EGFR-TKI treatment. With the launch of the next-generation sequencing platform, studies have shown that TP53 mutations in EGFR-mutated NSCLC range from 30% to 60% prevalence(9). When treated with a first-generation EGFR-TKI, patients with EGFR/TP53 double mutations, especially those with missense mutations, exhibit a lower effective rate and PFS compared to advanced NSCLC patients without TP53 mutations(8, 16). Predicting efficacy of first-generation EGFR-TKIs is crucial for the treatment and prognosis of NSCLC patients with EGFR/TP53 co-mutations.
In recent years, CTC count and peripheral blood gene expression data have been used to guide the clinical treatment of NSCLC. Punnoose et al.(17) reported that in EGFR-TKI-treated NSCLC patients, the genome expression of CTCs was highly consistent with that of the primary tumor tissue. Maheswaran et al.(18, 19) reported that EGFR, EGFR T790M, MET, and other gene mutations in CTCs can be used to evaluate the treatment effect and prognosis of NSCLC patients.
Common CTC detection methods include the isolation by size of tumor cells (ISET) method, the Cell SearchTM system, reverse transcription polymerase chain reaction, CTC-chip, and more. These technologies can significantly improve the sensitivity and specificity of CTC detection. ISET is a high-speed cell analysis and sorting technique. Because it is simple, reliable and fast, ISET has been selected as the main method for detecting CTCs(20).
In this study, ISET was used to count CTCs in the peripheral blood of patients with advanced NSCLC. For the first time, this study demonstrated that in NSCLC patients with EGFR/TP53 mutations, low CTC count was correlated with better PFS after first-line treatment with first-generation EGFR-TKIs. The improved PFS was most obvious in patients with reduced CTC count after treatment.
The median PFS of the low CTC group was significantly higher than that of the high CTC group both before and after treatment with a first-generation EGFR-TKI (P<0.01). These data indicate that CTC count is closely related to prognosis of advanced NSCLC in patients with EGFR/TP53 mutations following treatment with a first-generation EGFR-TKI. This study is not without shortcomings; the small sample size must be expanded to further confirm these findings.