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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 254-258

Serum carcinoembryonic antigen levels predicts the efficacy of EGFR-TKI in non-small cell lung cancer harboring EGFR mutations


Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic China

Date of Web Publication13-Apr-2016

Correspondence Address:
Han Baohui
Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huai Hai Road, Shanghai
People's Republic China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.153666

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 > Abstract 


Objectives: Not all the patients harboring epidermal growth factor receptor (EGFR) mutations have a clinical response after the treatment of EGFR-tyrosine kinase inhibitor (TKI). The purpose of the present study was to find whether the baseline carcinoembryonic antigen (CEA) levels were associated with the efficacy of EGFR-TKI in patients harboring EGFR mutations.
Materials and Methods: Clinical features, serum tumor marker levels, and survival time were analyzed, retrospectively, in 200 non-small cell lung cancer (NSCLC) patients harboring EGFR mutations treated with EGFR-TKI.
Results: The total objective response rate (ORR) is 44.0% and disease control rate is 84.5%. The disease control rate in the patients with high CEA levels was significantly higher than that with low CEA levels (88.3 vs 74.5%, P = 0.029). There was no significant difference in progression-free survival (PFS) between high (≥5 ng/ml) and normal CEA groups (< ng/ml; 12.0 vs 8.3m, and P = 0.055). The PFS in patients with higher CEA levels (≥ 20 ng/ml) was longer than in patients with lower CEA levels (< ng/ml; 12.8 vs 8.7m, P = 0.016). Multivariate analysis shows that high CEA level (> ng/ml) were independent predictive factors for PFS (HR = 1.412, 93% CI: 1.042–1.913, P = 0.026).
Conclusions: Baseline serum CEA levels can serve as predictive factors for the treatment of EGFR-TKI in NSCLC patients harboring EGFR mutations.

Keywords: Carcinoembryonic antigen, epidermal growth factor receptor mutations, epidermal growth factor receptor-tyrosine kinase inhibitors, lung cancer


How to cite this article:
Yanwei Z, Bo J, Yuqing L, Rong L, Xueyan Z, Song H, Baohui H. Serum carcinoembryonic antigen levels predicts the efficacy of EGFR-TKI in non-small cell lung cancer harboring EGFR mutations. J Can Res Ther 2016;12:254-8

How to cite this URL:
Yanwei Z, Bo J, Yuqing L, Rong L, Xueyan Z, Song H, Baohui H. Serum carcinoembryonic antigen levels predicts the efficacy of EGFR-TKI in non-small cell lung cancer harboring EGFR mutations. J Can Res Ther [serial online] 2016 [cited 2021 Jan 23];12:254-8. Available from: https://www.cancerjournal.net/text.asp?2016/12/1/254/153666




 > Introduction Top


Lung cancer is the leading cause of cancer-related mortality worldwide, and most of the patients have advanced disease at the time of diagnosis.[1] Chemotherapy with the angiogenesis inhibitor bevacizumab can modestly improve lung cancer outcomes, but at the cost of significant toxicity to patients. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have proven their efficacy in the treatment of non-small cell lung cancer (NSCLC), and EGFR sensitive mutations were found to be the most important predictive factors for the response to the treatment of EGFR-TKI.[2],[3],[4],[5],[6] Unfortunately, acquiring sufficient amounts of tissue for EGFR mutational analysis is often not feasible, and not all the patients harboring EGFR sensitive mutations can benefit from EGFR-TKI treatment. So surrogate markers of EGFR-TKI activity in NSCLC patients remain to be identified.

Carcinoembryonic antigen (CEA) has been thought sensitive and valuable for diagnosis, prognosis, and therapy monitoring; especially for adenocarcinoma.[7],[8],[9] Some studies [10],[11],[12],[13] have stated the relationships between CEA levels, EGFR mutations, and efficacy of EGFR-TKI treatments. One of our previous study [14] also found that the incident rate of EGFR gene mutations significantly increased with the elevation of serum CEA levels and the variation types of CEA level after EGFR-TKI treatment could predict the efficacy of EGFR-TKI in patients harboring EGFR mutation for a short time. The aim of the present study was to find whether the baseline CEA levels were associated with the efficacy of EGFR-TKI in patients harboring EGFR mutations.


 > Materials and Methods Top


Patients

From September 2010 to February 2014, totally 200 cases of EGFR mutated advanced NSCLC patients treated with EGFR-TKI in pulmonary medicine department of our hospital were retrospectively screened. Clinicopathological variables recorded were as follows: Gender, age, stage, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status (PS), histological type, number of prior chemotherapy regimens, CEA level, CYFRA21-1 level, and CA125 level. All patients received gefitinib 250 mg/day, erlotinib 150 mg/day, or icotinib 125 mg q8h/day orally. Clinical stage was determined by the International Association for the Study of Lung Cancer (IASLC) TNM (tumor-node-metastasis) classification, 7th edition.[15] The histological diagnoses were performed according to the WorldHealth Organization (WHO) classification criteria.[16] All responses were defined according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor response was assessed every 6–8 weeks until disease progression. The study was approved by the Institutional Review Board of our hospital.

Analysis of egfr mutation by ARMS

The ADx EGFR Mutations Detection Kit (Amoy Diagnostics, Xiamen, China) was used to detect the mutation. The kit used the principle of Amplified Refractory Mutation System (ARMS) and covered the 29 EGFR mutation hotspots from exon 18 to 21. The assay was carried out according to the manufacturer's protocol with the MX3005P (Stratagene, La Jolla, USA) real-time polymerase chain reaction (PCR) system. A positive or negative result could be reached if it met the criterion that was defined by the manufacturer's instruction.

Measurement of serum tumor markers

The serum CEA level was measured by a commercial electrochemiluminescence immunoassay on the ARCHITECT i2000SR system (Abbott Diagnostics, Tokyo, Japan). The serum CYFRA21-1 level was measured by an electrochemiluminescence immunoassay on an automatic analyzer (Elecsys 200; Roche Diagnostics Corp, Indianapolis, IN, USA). The serum CA125 was measured by third generation enzyme-linked immunosorbent assay (ELISA) kits (Can Ag, Canada). The cutoff values for CEA, CYFRA 21-1, and CA125 at our institutions are 5.0 ng/ml, 3.3 ng/ml, and 35 U/ml, respectively.

Statistical analysis

Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) statistical software (version 13.0). The primary end point, progression-free survival (PFS), was defined as the time from commencement of treatment to disease progression according to RECIST criteria or death resulting from any cause. Comparison of ORRs in different groups was performed using χ2 tests. Survival curves were estimated by the Kaplan–Meier method. Single-variable analyses were done by means of log-rank tests, and the multivariate regression was done with Coxmencement of treatment to dession model. A two-sided P <</i> 0.05 was considered statistically significant.


 > Results Top


Patient characteristics

The clinical characteristics of the 200 patients are shown in [Table 1]. Eighty-four (42.0%) patients were men and 116 (58.0%) patients were women, with a mean age of 60.5 years. One hundred and eighty patients had adenocarcinoma, 19 patients had squamous cell cancer, and only one patients had large cell cancer.
Table 1: Relevance between clinical characteristics and efficacy of EGFR-TKI

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Relationship between baseline CEA levels and efficacy of EGFR-TKIs

Of all the 200 patients, 109 patients were treated with gifitinib 250 mg/day, 11 patients were treated with erlotinib 150 mg/day, and nine patients were treated with icotinib 125 mg q8h/day. One patient had complete response (CR, 0.5%), 87had partial response (PR, 43.5%), 81had stable disease (SD, 40.5%), and 31 had progressive disease (PD, 15.5%). The total objective response rate (ORR) is 44.0% and disease control rate (DCR) is 84.5%. The response rate to EGFR-TKI was significantly higher in patients with adenocarcinoma, high CEA levels and low CYFRA21-1 levels [Table 1]. The disease control rate in the patients with high CEA levels was significantly higher than that with normal CEA levels (88.3 vs 74.5%, P = 0.029) [Table 1]. The patients with normal CYFRA21-1 levels also have a higher disease control rate than patients with high CYFRA21-1 levels (90.0 vs 80.0%, P = 0.030) [Table 1].

Univariate analysis showed that patients with adenocarcinoma have a longer PFS than patients with non-adenocarcinoma (11.0 vs 3.5 m, P < 0.001) [Table 2]. There was no significant difference in PFS between high and normal CEA groups (5 ng/ml; 12.0 vs 8.3m, P = 0.055) [Figure 1]a and [Table 2]. Then the patients were grouped according to different CEA cutoff values (10, 20, 40, 60, 80, and 100 ng/ml). The PFS in patients with higher CEA levels (> ng/ml) was longer than in patients with lower CEA levels (< ng/ml; 12.8 vs 8.7m, P = 0.016) [Figure 1]c and [Table 2]. Other CEA cutoff values (10, 40, 60, 80, and 100 ng/ml) did not show significant differences between higher and lower CEA groups [Figure 1]b and [Figure 1]d. The patients with normal CYFRA21-1 levels did not have a longer PFS than patients with high CYFRA21-1 level (12.5 vs 9.2m, P = 0.086) [Table 2]. Multivariate cox proportional hazards model analyses of various factors affecting PFS shows that adenocarcinoma and high CEA level (> ng/ml) were independent predictive factors for PFS [Table 3].
Table 2: Univariate analysis of EGFR-TKI treatment

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Figure 1: Progression-free survival (PFS) for epidermal growth factor receptor-tyrosine kinase inhibitor treatment (EGFR-TKI). (a) The PFS curves of EGFR-TKI treated patients with different carcinoembryonic antigen levels (5 ng/ml). (b) The PFS curves of EGFR-TKI treated patients with different carcinoembryonic antigen levels (10 ng/ml). (c) The PFS curves of EGFR-TKI treated patients with different carcinoembryonic antigen levels (20 ng/ml). (d) The PFS curves of EGFR-TKI treated patients with different carcinoembryonic antigen levels (100 ng/ml)

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Table 3: Multivariate analysis of EGFR-TKI treatment

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 > Discussion Top


To the best of our knowledge, the present study may be the first to investigate the value of CEA in predicting the efficacy of EGFR-TKI in such a large amount of NSCLC patients harboring EGFR mutations. Our study demonstrated that patients with high CEA level (≥20 ng/ml) could benefit from the treatment of EGFR-TKI (hazard ratio (HR) =1.412, P = 0.026).

EGFR mutations were more frequent in patients with lung adenocarcinoma [17] and EGFR mutations were considered to be independently associated with a better prognosis in EGFR-TKI treated patients, regardless of sex or smoking history.[18] A study conducted by Toyooka et al.,[19] found that gefitinib is less effective in non-adenocarcinoma NSCLC harboring EGFR mutations than adenocarcinoma harboring EGFR mutations. In the present study, 180 patients were diagnosed as adenocarcinoma, 20 patients were diagnosed as non-adenocarcinoma. Patients with adenocarcinoma have a longer PFS than patients with non-adenocarcinoma (11.0 vs 3.5 m, P < 0.001). This is similar to the study of Shukuya.

The over expression of CEA has been found in many types of carcinomas and is thought to be related to tumorigenesis.[20] Elevated CEA levels were reported in 30–70% of patients with NSCLC and were most frequently observed in patients with adenocarcinoma and advanced stage carcinoma.[21] Some recent studies have found the relevance between CEA level and the efficacy of EGFR-TKI. Pan et al.,[22] reported that patients with a higher level of serum CEA had a higher disease control rate and longer survival time (P < 0.05). Okamoto et al.,[11] also reportedthat patients with an elevated serum CEA level (≥5 ng/ml) have a significantly better prognosis for gefitinib treatment than those with normal CEA level (P = 0.0027). But there are a few studies which focus on whether CEA levels are related to the efficacy of EGFR-TKI of patients harboring EGFR-sensitive mutations. In the present study, patients with high CEA level (≥5 ng/ml) had a better DCR than the patients with normal CEA levels (88.3 vs 74.5%, P = 0.029). But the univariate analysis showed that there was no significant difference between the two groups (12.0 vs 8.3 m, P = 0.055). Then we used different CEA cutoff value to evaluate the relationship between CEA levels and efficacy of EGFR-TKI. The results showed that patients with higher CEA level (≥20 ng/ml) had a longer PFS than the patients with lower CEA level (< ng/ml; 12.8 vs 8.7 m, P = 0.016). The same result was found in the multivariate cox proportional hazards model analyses of various factors affecting PFS (HR = 9.148, P < 0.001). Therefore, high CEA level (≥20 ng/ml) seems to be an independent positive predictive factor for PFS in NSCLC patients harboring EGFR sensitive mutations.

CYFRA 21-1, a fragment of cytokeratin subunit 19, was reported as a prognostic factor in patients with a variety of cancer types.[23],[24],[25] A study conducted by Tanaka et al.,[26] found that CYFRA 21-1 is a predictive marker of PFS in NSCLC patients harboring EGFR mutations when treated with EGFR-TKIs. Ono et al.,[27] also stated that mutant EGFR patients with serum CYFRA21-1 <2.2 ng/ml have a better prognosis than the mutant EGFR patients with higher CYFRA21-1 level. In our study, patients with normal CYFRA21-1 level had a better DCR than the patients with higher CYFRA21-1 level (90.0 vs 80.0%, P = 0.030). The patients with normal CYFRA21-1 level had a better PFS (12.5 vs 9.2 m), but the difference did not show statistical significance (P = 0.086).

According to our latest follow-up, most patients enrolled in this study still received EGFR-TKI treatment or second-line chemotherapy. So we cannot report overall survival data of the patients.

There are some limitations of the study. Firstly, according to our latest follow-up, most patients enrolled in this study still received EGFR-TKI treatment or second-line chemotherapy. So we cannot report the patientsng from any cause. Comparison now. Secondly, we did not collect enough amount of blood samples to compare the EGFR mutation status with tissue since it is a retrospective study.

In conclusion, high CEA level (≥20 ng/ml) is an independent positive predictive factor for PFS in NSCLC patients harboring EGFR sensitive mutations.


 > Acknowledgments Top


This study was supported by Grant No. 81172104 from the National Science Foundation of China (NSFC).

 
 > References Top

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