What are the tumor markers for lung cancer?

Lung cancer is one of the malignant tumors with the highest morbidity and mortality, and has become a public health problem that seriously endangers human health. Since the clinical symptoms of early lung cancer are not obvious, most patients are already in the middle and late stages when they seek medical treatment. Therefore, early diagnosis of lung cancer has become a major problem facing us today. At present, the clinical diagnosis of lung cancer mainly relies on imaging and pathology. The National Lung Cancer Screening Trial in the United States recommends annual low-dose spiral CT examinations for asymptomatic high-risk patients with lung cancer. However, CT screening sometimes fails to detect smaller lung tumors, and it is difficult to effectively differentiate some lung nodules from lung cancer. Pathological diagnosis is invasive and has limitations in specimen collection. The detection of serological tumor markers has the advantages of rapid, accurate, non-invasive, and repeatable measurements, so it has been widely used in the clinical auxiliary diagnosis of tumors.

The following section summarizes some important tumor markers for lung cancer.

1. NSE

It is composed of two almost identical polypeptide chains (a/y or y/y), both with a molecular weight of 39 kDa. NSE is a glycolytic enzyme enolase, which is secreted by central or peripheral neurons and neuroectodermal tumors. When histological results cannot confirm the diagnosis, NSE can assist in supporting the diagnosis of SCLC; hemolysis will significantly affect the NSE test results, and it should be separated from red blood cells within 60 minutes to prevent false elevation. The release of NSE can occur in red blood cells and platelets, and changes in its concentration are unrelated to age, gender, and smoking. NSE is a highly specific marker for neural and peripheral neuroendocrine cells, and is elevated in the serum of patients with neuroblastoma, melanoma, and seminoma. NSE has significant sensitivity and specificity for the diagnosis and treatment of SCLC, and also has clinical value for NSCLC.

2. ProGRP

As a single marker, its specificity for SCLC diagnosis is better than other markers, and it is positively correlated with SCLC staging, which helps to distinguish SCLC from benign lung diseases. Elevated ProGRP concentrations also occur in patients with renal insufficiency, and its levels are related to serum creatinine. Therefore, when ProGRP levels are elevated but inconsistent with the patient's clinical symptoms, the patient's serum creatinine level should be evaluated first. Human gastrin-releasing peptide (GRP) is mainly expressed in the gastrointestinal tract, respiratory tract, and central nervous system. Several studies have confirmed that SCLC tumor cells release GRP, and GRP may stimulate SCLC cell growth. ProGRP is a precursor of GRP and is widely used in the diagnosis, prognosis assessment, and efficacy monitoring of clinical SCLC. Current studies have reported that the diagnostic sensitivity of ProGRP for SCLC is 47%-86%, and the specificity is close to 100%. As a single TM, its diagnostic specificity for SCLC is better than CEA, NSE, and CYFRA21-1.

3.CEA

It is a cell membrane-associated glycoprotein group with a molecular weight of approximately 180kDa. It is most significantly elevated in lung adenocarcinoma and large cell lung cancer, and has a high sensitivity. However, it should be noted that elevated CEA can also be seen in gastrointestinal tumors and pulmonary interstitial fibrosis. The diagnosis of lung malignancies often involves combined testing of CEA and CYFRA21-1. Long-term smokers may have slightly higher CEA levels than healthy people. The serum CEA level of NSCLC patients is significantly higher than that of healthy people and patients with benign lung diseases, and when the doubled CEA cutoff is used as the positive standard, the possibility of lung cancer is greatest. The specificity and sensitivity of CEA in diagnosing lung cancer are not high, but studies have shown that with the increase in the clinical stage of lung cancer, the CEA level also tends to increase, and the long-term survival rate of CEA-positive patients is significantly lower than that of CEA-negative patients.

4.CYFRA 21-1

It is a 36 kDa fragment of cytokeratin 19 and is a tumor marker for detecting NSCLC, especially squamous cell carcinoma of the lung. It is mainly present in the cytoplasm of monolayer and pseudostratified epithelial cells and is the only source of CYFRA21-1 with high specificity. CYFRA21-1 has been shown to be expressed only in lung tissue and is currently the most sensitive tumor marker for NSCLC (especially squamous cell carcinoma)2.

5.SCCA

It is a 48-kDa protein that belongs to the family of serine protease inhibitors. SCCA is present in squamous cells and is considered to be a structural protein that reflects the differentiation stage of squamous cell carcinoma. Changes in its levels are closely related to the different stages of lung cancer. However, a single marker cannot distinguish SCLC from NSCLC. About 10% of NSCLCs have an immune response to at least one of the neuroendocrine markers. If NSE, ProGRP, CYFRA21-1, CEA and SCCA are detected together, the accuracy of identification can be improved.

6.TPA

It is a cytoskeletal protein with a molecular weight of 20 kDa, released by proliferating cells (derived from the endoplasmic reticulum and cell membrane). TPA is a sensitive but low-specificity tumor marker used to evaluate lung cancer and breast cancer. In addition, TPA can show an independent good prognosis for lung cancer.

Biomarkers can predict the efficacy of immunotherapy and screen patients who will truly benefit. However, no single biomarker is currently sufficient to achieve this goal. Therefore, as long as it is not truly equivalent to complete ineffectiveness, it is difficult to conclude that patients cannot try immunotherapy, an important treatment mode and opportunity. At the same time, due to the complexity of the immune microenvironment, the interactive effects of multiple medical factors, and the current limitations of cognition, the predictive role of many markers is not absolute. It is hoped that in the near future, with the advancement of scientific and technological means, the continuous discovery of new biomarkers, and the establishment of more effective multi-omics and multi-parameter prediction models, clinical physicians will be able to achieve more optimized and accurate predictions and program formulation for immunotherapy.