Cyfra 21-1 as a Biologic Marker of Non-small Cell Lung Cancer: Evaluation of Sensitivity, Specificity, and Prognostic Role

doi:10.1378/chest.108.1.163

Chest

Volume 108, Issue 1, July 1995, Pages 163-169

https://doi.org/10.1378/chest.108.1.163 Get rights and content

Background: Cytokeratins are epithelial markers whose expression is not lost during malignant transformation. Cyfra 21-1 is a cytokeratin-19 fragment that is soluble in serum and may be a useful circulating tumor marker.

Study objective: The aims of this study were (1) to confirm sensitivity and specificity of Cyfra 21-1 in detecting non-small cell lung cancer (NSCLC) and especially the squamous cell subtype, (2) to assess the potential relationship between Cyfra 21-1 and disease stage of the disease in NSCLC, and (3) to evaluate prognostic effect of Cyfra 21-1 in NSCLC.

Methods: An immunoradiometric assay of serum Cyfra 21-1 was performed in 161 patients with lung cancers and 71 others with benign lung diseases. The ability of Cyfra 21-1 to detect different histologic subtypes of lung cancer vs benign lung diseases was assessed through receiver operating characteristic (ROC) curves and comparisons with other tumor markers such as carcinoembryonic antigen, neuron-specific enolase, and squamous cell carcinoma antigen. Comparisons of Cyfra 21-1 levels according to histologic subtype and disease stage were done using Kruskal-Wallis test. Independent prognostic value of Cyfra 21-1 was studied with a multivariate analysis of survival (Cox's model).

Results: Using a threshold of 3.3 ng/mL for Cyfra 21-1, sensitivity and specificity were, respectively, 0.59 and 0.94 in NSCLC, 0.68 and 0.94 in the subgroup of the squamous cell carcinoma, and 0.19 and 0.94 in small cell lung cancer. Cyfra 21-1 levels were significantly higher in advanced NSCLC than in early-stage disease. All 29 patients with serum concentrations >32 ng/mL had stage IIIB-IV and only one of 14 patients with stage I-II disease had Cyfra 21-1 level >18 ng/mL. In the multivariate analysis of survival, Cyfra 21-1 was an independent prognostic factor along with performance status and disease stage in NSCLC.

Conclusions: Cyfra 21-1 is a sensitive and specific tumor marker of NSCLC, especially of squamous cell subtype. It also reflects the extent of the disease and has an independent prognostic role along with performance status and disease stage in NSCLC.

Implications: A high level of Cyfra 21-1 in apparently early-stage NSCLC should be an indication for more extensive workup before thoracotomy. The independent prognostic role of Cyfra 21-1 level may be useful in stratifying populations with advanced NSCLC or early-stage resected NSCLC as elevated Cyfra 21-1 levels might identify those patients at high risk for treatment failure.

Section snippets

Patients

One hundred sixty-one patients with lung cancer admitted to the Department of Chest Disease (University Hospital, Strasbourg, France) between March 1989 and June 1993 were prospectively entered in the study (Table 1). All had histologically and/or cytologically confirmed lung cancer. There were 72 with squamous cell carcinomas, 29 with adenocarcinomas, 15 with large cell carcinomas, and 45 with SCLC. Karnofsky performance status was noted and staging³ of NSCLC was done by clinical examination;

Reproductibility of Cyfra 21-1 Radiometric Assay

Reproductibility of determination of serume centrations was examined by measuring a control serum control in 13 different assays (interassay). The mean ± standard deviation and coefficient of variation was 3.67 ng/mL ± 0.41 and4.6%, respectively.

Cyfra 21-1 and Histology

The median (interquartile) serum Cyfra 21-1 in all NSCLC, squamous cell carcinoma, NSCLC other than squamous cell, and SCLC were 4.3 (2.05 to 16), 6.0 (2.55 to 19), 2.6 (1.25 to 9.75), and 1.7 (0.98 to 2.4) ng/mL, respectively. The median

Discussion

Our study confirms that Cyfra 21-1 is a both sensitive and specific tumor marker for NSCLC and especially for squamous cell carcinoma. It appears more sensitive and more specific than other tumor markers such as CEA, NSE, and slightly better than SCC in squamous cell carcinoma. The inability of Cyfra 21-1 to detect SCLC was also confirmed. The Cyfra 21-1 level in NSCLC correlates with the stage and, moreover, it appears as an independent prognostic factor along with performance status and stage.

Acknowledgments

We are grateful to Yolande Ledermann for excellent technical assistance.

References (26)

AlbainKS et al.
Long-term survival and toxicity in small cell lung cancer: expanded Southwest Oncology Group experience
Chest
(1991)
BonomiP et al.
Pre-treatment prognostic factors in stage III non-small cell lung cancer patients receiving combined modality treatment
Int J Radiat Oncol Phys
(1991)
MüllerLC et al.
Neuro-specific-enolase in small cell lung cancer: longitudinal tumors marker evaluation
Lung Cancer
(1992)
MollR et al.
The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells
Cell
(1982)
KasperM et al.
Histological evaluation or three new monoclonal anti-cytokeratin antibodies
Eur J Cancer Clin Oncol
(1987)
SculierJP et al.
Value of CEA determination in biological fluids and tissues
Eur J Cancer Clin Oncol
(1987)
CarrDT
Histopathology of lung cancer
Int J Epid
(1990)
HansenH
Histopathological typing of lung cancer: etiologic and epidemiologic features
Mc Vie JS, ed. Clinical and experimental pathology of lung cancer, developments in oncology 39. Boston: Martinus Nijhoff
(1986)
MountainCF
A new international staging system for lung cancer
Chest
(1986)
SpiegelmanD et al.
Prognostic factors in small-cell carcinoma of the lung: an analysis of 1,521 patients
J Clin Oncol
(1989)

SunN et al.

Immunohistochemical localization of carcinoembryonic antigen, CEA-S, and nonspecific cross-reacting antigen in carcinomas of lung

Cancer

(1983)

AkounGM et al.

Serum neuron-specific enolase: a marker for disease extent and response to therapy for small cell lung cancer

Chest

(1985)

MinoN et al.

Availability of tumor-antigen as a marker of squamous cell carcinoma of the lung and other organs

Cancer

(1988)

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Cytokeratin 19 fragment (CYFRA21-1) serves as a crucial tumor marker in the context of lung cancer patients, playing a pivotal role as a calibrator in the realm of in vitro diagnostics. Nevertheless, during practical application, it has come to light that the recombinantly synthesized full-length CYFRA21-1 antigen exhibits suboptimal stability at the requisite concentration, while the utilization of natural antigens incurs a substantial cost. To address this issue, our investigation harnessed a strategic approach whereby the soluble fragment of cytokeratin 19 (Aa244-400) was integrated into the pET32a vector, subsequently being expressed within E. coli through a fusion with the TrxA protein. This process involved induction of protein expression through 0.2 mM IPTG at 16 °C for a duration of 16 h. After induction, the target protein was purified through Ni affinity and ion exchange chromatography. Subsequent characterization of the targeted protein was executed through the SEC-HPLC technique. The attained CYFRA21-1 antigen, as generated within this study, was effectively incorporated into a chemiluminescence-based in vitro diagnostic detection kit. The results indicate that the fusion protein exhibited commendable reactivity and stability, manifesting a deviation of less than 10 % following incubation at 37 °C for 7 days. Importantly, the production yield achieved a notable magnitude of 300 mg/L, thus rendering it a cost-effective and scalable alternative to natural antigens for clinical diagnostic applications.
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Non-small cell lung cancer (NSCLC) has a long history of defying traditional cytotoxic treatment. Significant advancements in biotechnology, cancer biology, and immunotherapy have provided new insights that have altered the landscape for the management of NSCLC, clearing the way for a new era of pharmaceuticals in the form of monoclonal antibodies and their fragments. Antibody fragments are superior to monoclonal antibodies because of their small size, which allows them to penetrate cells and tissues effectively. When combined with functional nanocarriers, antibody fragments can target cancer cells while offering improved efficacy and fewer off-target effects. We discuss current topics of interest including anti-CTLA-4 mAbs, Talactoferrin alfa (TLF), and the CYFRA 21-1 biomarker, with brief insights into its novel detection system.
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Citation Excerpt :
In this case, less than half of the analyzed studies provided a direct comparison with a gold standard (ELISA). CYFRA-21-1 is a cancer marker of new conception, found to be particularly useful in the detection of non-small cell lung cancer (Stieber et al., 1993; Wieskopf et al., 1995). Kumar and coworkers realized an electrochemical biosensor for the detection of CYFRA 21–1 using DPV (Kumar et al., 2016).
As biosensing research is rapidly advancing due to significant developments in materials, chemistry, and electronics, researchers strive to build cutting-edge biomedical devices capable of detecting health-monitoring biomarkers with high sensitivity and specificity. Biosensors using nanomaterials are highly promising because of the wide detection range, fast response time, system miniaturization, and enhanced sensitivity. In the recent development of biosensors and electronics, graphene has rapidly gained popularity due to its superior electrical, biochemical, and mechanical properties. For biomarker detection, human saliva offers easy access with a large variety of analytes, making it a promising candidate for its use in point-of-care (POC) devices. Here, we report a comprehensive review that summarizes the most recent graphene-based nanobiosensors and oral bioelectronics for salivary biomarker detection. We discuss the details of structural designs of graphene electronics, use cases of salivary biomarkers, the performance of existing sensors, and applications in health monitoring. This review also describes current challenges in materials and systems and future directions of the graphene bioelectronics for clinical POC applications. Collectively, the main contribution of this paper is to deliver an extensive review of the graphene-enabled biosensors and oral electronics and their successful applications in human salivary biomarker detection.
Cytokeratin 19 as a biomarker of highly invasive oral squamous cell carcinoma with metastatic potential
2020, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology
Citation Excerpt :
Over 20 different CKs have been identified, of which CK19 is the smallest member of the acidic type I CK family proteins [10,12]. Soluble CK19 fragments in circulation are widely used as a tumor marker in non-small cell lung cancer (NSCLC) [13–15]. Recent studies have shown that CK19 is expressed in various tumor tissues, including breast cancer, colon cancer, lung cancer, head and neck cancer (HNC) and hepatocellular carcinoma (HCC) [16–20].
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A total of 100 patients who had been diagnosed with OSCC at our department between January 2011 and December 2016 was included. The patients were divided into three groups based on an optimal cut-off points (5% and 77%) of the labeling index (LI) as follows: group A; LI < 5%, group B; 5%≤ LI < 77%, group C; LI ≥ 77%. Then, clinicopathological features and survival rates were compared among the groups.
Histologically high-grade tumors were significantly more common in group C than in groups A and B. Furthermore, the incidence of nodal metastasis was significantly higher in group C than in other groups. Intense CK19 immunoreactivity was detected in metastatic lymph nodes of groups B and C, but not from group A. Moreover, patients with advanced pN stage and extranodal extension were more common in groups B and C than group A. Disease-specific survival curves revealed poorer prognoses in group C.
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Early diagnosis and histological subtyping are important issues in the management of patients with lung cancer (LC). The aim of this study is to investigate the diagnostic value of a panel of serum tumor markers in newly diagnosed patients with LC.
Venous blood samples were collected from 99 patients with LC (42 adenocarcinoma, 35 squamous, and 22 small cell carcinoma) and 30 patients with benign lung disease. Progastrin releasing peptide (ProGRP), squamous cell carcinoma antigen (SCCAg), cytokeratin 19-fragments (CYFRA 21.1), human epididymis protein 4 (HE4), Chromogranin A (CgA) and neuron specific enolase (NSE) levels were measured. The diagnostic value of the biomarkers was assessed with ROC curve analyses; the area under the curve (AUC) was calculated.
Serum CYFRA 21.1, ProGRP, SCCAg, NSE levels were significantly higher in LC patients. While ProGRP levels were higher (p = 0.009) in SCLC; CYFRA 21.1 and SCCAg levels were higher in NSCLC (p = 0.019 and p = 0.001, respectively). The sensitivity and specificity of tumor markers were 72%, 83% for CYFRA 21.1; 70%, 57% for HE4; 18%, 93% for ProGRP; 43%, 77% for SCCAg; 54%, 53% for CgA; 73%, 50% for NSE. CYFRA 21.1 (p < 0.001, r = 0.394), HE4 (p = 0.014, r = 0.279) and CgA (p = 0.023, r = 0.259) levels were positively correlated with tumor stage in NSCLC. CgA levels were significantly higher in extensive stage SCLC (p = 0.004). CYFRA 21.1 had the highest diagnostic value for LC (AUC = 0.865). When it is combined with HE4, diagnostic value increased (AUC = 0.899). ProGRP had the highest diagnostic value (AUC = 0.875, p < 0.001) for discriminating SCLC from NSCLC.
A panel of three tumor markers CYFRA 21.1, HE4 and ProGRP may play a role for discriminating LC from benign lung disease and subtyping as SCLC.

View all citing articles on Scopus

: Manuscript revision accepted November 4.

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Chest

Clinical InvestigationsCyfra 21-1 as a Biologic Marker of Non-small Cell Lung Cancer: Evaluation of Sensitivity, Specificity, and Prognostic Role

Section snippets

Patients

Reproductibility of Cyfra 21-1 Radiometric Assay

Cyfra 21-1 and Histology

Discussion

Acknowledgments

Chest

Int J Radiat Oncol Phys

Lung Cancer

Cell

Eur J Cancer Clin Oncol

Eur J Cancer Clin Oncol

Histopathology of lung cancer

Int J Epid

Histopathological typing of lung cancer: etiologic and epidemiologic features

Mc Vie JS, ed. Clinical and experimental pathology of lung cancer, developments in oncology 39. Boston: Martinus Nijhoff

A new international staging system for lung cancer

Chest

Prognostic factors in small-cell carcinoma of the lung: an analysis of 1,521 patients

J Clin Oncol

Immunohistochemical localization of carcinoembryonic antigen, CEA-S, and nonspecific cross-reacting antigen in carcinomas of lung

Cancer

Serum neuron-specific enolase: a marker for disease extent and response to therapy for small cell lung cancer

Chest

Availability of tumor-antigen as a marker of squamous cell carcinoma of the lung and other organs

Cancer

Clinical Investigations
Cyfra 21-1 as a Biologic Marker of Non-small Cell Lung Cancer: Evaluation of Sensitivity, Specificity, and Prognostic Role