It is well known that lung cancer is a multi-factorial and highly aggressive cancer, and is the common cause of cancer-related death worldwide[22].The etiology of lung cancer is still unknown, but cancer and chronic respiratory disease are both linked to tobacco use[23].Smoking is recognized as the leading risk factor for lung cancer, but there are other risk factors such as air pollution, biomass burning, and occupational exposure (asbestos) also play an important role in the development of lung cancer[24].Lung cancer is generally divided into non-small cell lung cancer(includes lung adenocarcinoma, lung squamous cell carcinoma and large cell lung cancer) and small cell lung cancer according to pathological types, accounting for 85% and 15% of all lung cancers respectively. Significant survival differences between patients with different T and M stages of lung cancer have been reported, including differences in survival among patients with single-site or multi-site metastases involving the brain or other sites[25, 26].Therefore, in order to effectively prevent the occurrence of death from lung cancer, in addition to avoiding or reducing the exposure of risk factors as much as possible, appropriate early diagnosis is particularly important.
Low-dose computed tomography (LDCT) screening significantly reduces lung cancer mortality in high-risk populations by detecting early-stage disease, according to the results of a large randomized controlled trial published in the August 2011 issue of the New England Journal of Medicine[27]. Based on this, the American Cancer Society (ACS), American College of Chest Physicians (ACCP) and other lung cancer screening guidelines have the same inclusion criteria for the target population: annual LDCT screening for people aged 55 to 74 years, who had a smoking index of ≥30 pack years, are actively smoking or have quit smoking within the past 15 years and have no other life-limiting comorbidity[28-30].However, with the improvement of people's awareness of health examination and the popularization of LDCT application, due to the high sensitivity and lack of specificity of CT, the detection rate of clinical pulmonary nodules is getting higher, which may lead to the increase of invasive treatment, and has potential harm risk[31].Currently, pulmonary nodules are defined as focal, quasi-round, dense solid or subsolid pulmonary opacity ≤3 cm in diameter, which can be solitary or multiple pulmonary nodule, and can be benign or malignant, among which malignant nodules are lung cancer[32].The diagnosis of pulmonary nodules is mainly evaluated by clinical informational, imaging techniques, surgical and non-surgical biopsy. For low-risk patients, LDCT scan should be repeated in long-term follow-up to compare the external structure (nodule size, shape, edge, etc.) and internal characteristics (nodule density, structure, etc.) to help distinguish benign and malignant pulmonary nodules[32].Correct differentiation of benign and malignant pulmonary nodules is helpful for early surgical treatment of malignant nodules and improvement of patient prognosis.
Dr. Ruth L. Katz of the M.D. Anderson Cancer Center, as the technical inventor of the MDA Test, developed a four-color FISH technique to identify cytogenetic changes, and proposed the concept of circulating genetically abnormal cell (CAC) as a distinct cell from circulating tumor cell (CTC)[19].This advance suggests that there are genetic abnormalities in patients with lung non-small cell carcinoma that are similar to those in the primary tumor and are strongly associated with the presence and early development the cancer, and because it is antigen-independent expression, it may show more CAC if it is not restricted by antigen detection of epithelial cell differentiation. In recent years, there has also been research data to demonstrate that, including in 2020, Katz et al. [33]used a novel antigen-independent method of 4-color FISH to detect circulating tumor cells with abnormal copy number mononuclear cells in peripheral blood of patients with lung cancer (n = 107) and non-lung cancer (n = 100), and obtained results with an accuracy of 94.2%, sensitivity of 89%, and specificity of 100%.And Wei-ran Liu et al. [34]analyzed 261 lung cancer patients, 78 healthy participants in 2020 , concluded that the number of CAC in early-stage NSCLC patients was significantly higher than the latter, and the sensitivity of CAC detection in the identification of NSCLC was 67.2%(higher than tumor markers), and the specificity was 80.8%.These studies all prompt that CAC may be an effective, specific biomarker for the diagnosis of tumor , with high potential in accurate.
In this topic, we counted the number of peripheral blood CAC of 63 patients in two groups. After excluding statistical differences in gender, age and smoking history of the two groups of patients, the results showed that the lung cancer group of CAC positive rate (90%) is significantly higher than the lung benign disease group (23.1%), the difference was statistically significant, which corresponds to the previous research suggesting that CAC may be a potential biomarker for early diagnosis of lung cancer. Since it has been previously reported that different nodular features are helpful to the diagnosis of lung cancer[35, 36], we added such indicators as density, size and special signs of nodules in this study. Through further analysis ,we found that the CAC positive rate of solid nodules (95%) was significantly higher than pure ground glass nodules (52.9%), and there was a statistically significant difference in the course of disease between CAC positive and CAC negative. Therefore, we conducted correlation analysis, found that the correlation coefficient between CAC positive rate and course of disease was 0.045, and the density of nodules was -0.430, both of which were not significantly correlated. After that ,we also made a comparison in diagnostic efficacy of CAC and tumor markers and special appearance of nodules on CT. The AUC of CAC count was 0.837(P < 0.001), higher than that of combined or single tumor marker test. The sensitivity (90%) and accuracy (87.3%) of CAC in the diagnosis of lung cancer were higher than other detection methods, including tumor biomarker combination detection (37.1% sensitivity, 46.5% accuracy) and nodular special signs, such as vessel convergence sign had the highest sensitivity (56%)and accuracy (54%) of the diagnosis of lung cancer, and signs of vacuolar in the diagnosis of lung cancer has the highest specificity (92.3%).It indicates that CAC detection has a high sensitivity and specificity in the early-stage diagnosis of lung cancer, which is basically consistent with the results of the research by the experts mentioned previously.
As a result, we can conclude that non-invasive CAC detection may have a higher detection rate than tumor markers and chest CT in the diagnosis of early-stage lung cancer. Although the tumor markers have certain reference significance for the diagnosis of lung cancer, traditional serum tumor markers are mostly related to the pathological types of lung cancer, such as CYFRA21-1[37], often used as a serum tumor marker of non-small cell lung cancer;NSE[38] is often used as a serum tumor marker for small cell lung cancer. However, when we analyzed the relationship between CAC positive expression and pathological types of lung cancer, it was found that the positive expression of CAC in lung cancer was not affected by pathological types of lung cancer patients. Therefore, it has more advantages when applied in the diagnosis of lung cancer. Of course, if it is used for the early diagnosis of lung cancer, it has to be considered that its price is almost 10 times that of LDCT, which increases the economic burden of patients. And this study shows that CAC has some false positive or false negative results, but it is undeniable the clinical application value. However, due to the limited number of samples included in this study, such as only 1 case was positive for CEA and CA125,0 cases were positive for SCC, there may be some statistical errors, and further verification of the accuracy of the results of this study is needed in a large sample population. At present, led by Professor Chunxue Bai, the Chinese Alliance for Lung Cancer Prevention and Treatment and SANMED BIOTECH jointly launched Bai-DX & MDA TEST malignancy auxiliary diagnosis of pulmonary nodules of national multicenter clinical study has fully developed. A total of 13 regional key tertiary class A hospitals participated in the study and planned to include more than 1,000 patients with pulmonary nodules. The MDA TEST technology was combined with artificial intelligence imaging analysis to conduct a prospective validation study on the benign and malignant pulmonary nodules. We believe that there will be a large sample data of MDA TEST in China to share with you soon, in order to provide a basis for improving the early-stage detection rate of lung cancer and the prognosis of patients.