The level of serum carcinoembryonic antigen is a surrogate marker for the efficacy of EGFR‑TKIs but is not an indication of acquired resistance to EGFR‑TKIs in NSCLC patients with EGFR mutations

  • Authors:
    • Jingquan Han
    • Yuzhang Li
    • Shouqiang Cao
    • Qing Dong
    • Guibin Zhao
    • Xiangyu Zhang
    • Jian Cui
  • View Affiliations

  • Published online on: May 19, 2017     https://doi.org/10.3892/br.2017.914
  • Pages: 61-66
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The aim of the present study was to define the relationship between carcinoembryonic antigen (CEA) and survival in non‑small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) and to investigate whether the level of serum CEA is related to the mechanism for acquisition of resistance to EGFR‑TKIs. A total of 100 patients with advanced NSCLC (stage IIIB or stage IV) and harboring EGFR mutations were included. All patients received erlotinib or gefitinib treatment. The correlation between CEA serum level and clinical benefit from erlotinib or gefitinib treatment was analyzed. Patients were appraised by a review of data from a prospective re‑biopsy protocol for lung cancer patients with an EGFR‑mutated phenotype with acquired resistance to EGFR‑TKI therapy. Of 100 patients, 49 and 21 patients carried high and low level of CEA, respectively; 30 carried normal CEA. Median progression‑free survival was 6.4 and 4.5 months in patients with high and low level of CEA, respectively (P=0.027). Median PFS of patients in low‑CEA group longer than that of those with normal level of tumors (3.0 months; P=0.002). The difference between groups L and N was not significant regarding objective response rate and overall survival. No significant difference was found in three groups of acquired resistance to EGFR‑TKIs. The relative CEA level could predict benefit of EGFR‑TKI therapy in advanced NSCLC, but could not predict acquired resistance to EGFR‑TKIs.

Introduction

Lung cancer has taken over from liver cancer as the leading cause of death in patients with malignant tumors in China (1). At least 30% of non-small cell lung cancer (NSCLC) patients missed the opportunity to have an operation when first visiting the doctor; therefore, their prognosis became worse, due to lack of effective therapy (2). EGFR-targeted therapy is a promising strategy for the treatment of NSCLC; some randomized trials have demonstrated a significantly higher tumor remission rate and longer progression free survival (PFS) in patients with EGFR mutation treated with first-line TKI (27). The frequency of the EGFR mutation in NSCLC in the Asian population is ~30%, while the white population is ~20% (8,9). In clinical subgroups, the frequency of mutation in Asian males and smokers is lower than that of Asian females and non-smokers (5,10).

Despite the initial success of these drugs in all patients, the median progression free survival was 12–16 months (4,7,11). Acquired resistance to EGFR-TKIs has been attributed to several molecular mechanisms, although the resistance of patients with unknown etiology is ~35% (12). The most common causes of resistance are the development of the T790M mutation (13), amplification of MET (14,15) and, in rare cases, transformation to small cell histology (16). Despite clinical evidence for progress in the treatment of EGFR-TKI, continued EGFR inhibition seems to provide sustained clinical benefit (17,18).

Carcinoembryonic antigen (CEA), recognized as a NSCLC marker, is also can be used for detecting adenocarcinoma with ~60% sensitivity and 50% specificity (19,20), whereas the sensitivity and specificity is ~25 to 40% and 25%, respectively, for squamous cell carcinoma (21,22). According to previous reports, CEA was a significant predictor of sensitivity and survival in patients treated with gefitinib (23,24) However, the CEA level as a predictive marker of response to EGFR-TKIs has not been extensively evaluated. The authors assumed that the level of CEA could predict the extent of benefit from EGFR-TKIs, and tumor patients with high serum CEA level may benefit more from EGFR-TKIs than those with low serum CEA level.

Patients and methods

Patients

Patients with the clinic diagnosis of NSCLC treated at the Department of Thoracic Surgery of the Fourth Affiliated Hospital, Harbin Medical University (Harbin, China) were recruited between February 2012 and May 2015. Inclusion criteria comprised: Patients with stages IIIB to IV NSCLC who had received palliative surgical resection were confirmed for EGFR mutations (either exon 19 deletions or L858R in exon 21) and received either erlotinib 150 mg/day or gefitinib 250 mg/day orally (clinical stage was determined by the 7th edition of tumor, node, metastasis classification) (25). The patients were enrolled for palliative care with EGFR-TKIs if they had an Eastern Cooperative Oncology Group performance status of 0–2 and life expectancy >3 months. Patients were appraised by a review of data from a prospective re-biopsy protocol of patients with acquired resistance to EGFR tyrosine kinase inhibitors. Patients with a previous history of malignancy were excluded. The study was approved by the institutional review boards of the Fourth Affiliated Hospital of Harbin Medical University (Harbin, China). Informed consent was acquired from each patient prior to the commencement of treatment.

Methods

Serum CEA was measured by an enzyme immunoassay within one week before starting the erlotinib or gefitinib treatment. Measurement was performed at the Clinical Laboratory of the Fourth Affiliated Hospital of Harbin Medical University using a sequential chemiluminescence immunoassay (Immulite 2000 Immunoassay System; Siemens Healthineers, Erlangen, Germany). The total included 100 patients were categorized into three groups according to their serum CEA level: High-CEA group (H), CEA baseline levels >10 ng/ml, normal-CEA group (N), CEA baseline levels <5.0 ng/ml and low-CEA group (L), CEA baseline levels between 5 ng/ml and 10 ng/ml. The authors analyzed the correlation between serum CEA level and clinical benefits in the patients receiving EGFR-TKI treatment.

Statistical analyses

The primary endpoint, progression-free survival was calculated from the first day of treatment to the date of the first disease progression or, under the condition without disease progression, the last follow-up or death. The overall survival (OS) rate was calculated from the first day of treatment to the date of mortality due to any cause or the date of the last follow-up. The secondary endpoints contained objective response rate (ORR), OS and safety. The PFS and OS rates were estimated using the Kaplan-Meier life-table method and the survival curves were compared using the log-rank test. Comparison of ORRs in different groups was performed using χ2 tests. Independent predictive factors associated with PFS were evaluated in multivariate analysis using a Cox regression model. All P-values were based on two-sided testing and statistical analyses were carried out using SAS statistical software (version 9.2; SAS Institute, Cary, NC, USA). P<0.05 was considered to indicate a statistically significant difference.

Results

Patient characteristics

Between February 2012 and May 2015, a total of 320 patients with the diagnosis of advanced NSCLC were screened for EGFR mutations before the start of EGFR-TKIs. A total of 100 patients were completely consistent with the inclusion criteria. Of the 100 patients, 54 were female and 46 men, with a mean age of 55 years (range, 23–84). In the 100 patients, 80 were non-smokers and 20 past or current smokers; 93 had adenocarcinoma, 6 squamous cell carcinoma and one adenosquamous carcinoma; according to TNM classification, 13 were in stage IIIB and 87 in stage IV. A total of 49 patients (49%) with a baseline CEA level (>10 ng/ml) were recruited with median CEA of 222.8 ng/ml (group H) (range, 10–6,840 ng/ml). A total of 21 patients with a baseline CEA level between 5 and 10 ng/ml were recruited with median CEA of 6.8 ng/ml (group L). A total of 30 patients with a baseline CEA level (<5.0 ng/ml) were in the normal group (group N). The characteristics of all patients are shown in Table I. Sex and smoking status were well balanced among these groups.

Table I.

Patient demographics and clinical characteristics.

Table I.

Patient demographics and clinical characteristics.

CharacteristicGroup HGroup LGroup NP-value
Age (years) 0.823
  Median54.551.556
  Range27–8437–6923–750.927
Gender
  Women291213
  Men20  917
Smoking history 0.752
  Non-smoker421820
  Smoker  7  310
ECOG 0.798
  018  9  6
  1281018
  2  3  2  6
Clinical stage 0.893
  IIIB  6  3  4
  IV431826
Histology 0.532
  Non-adenocarcinoma  2  1  3
  Adenocarcinoma472027
Site of metastatic disease 0.634
  Lung221719
  Brain  5  2  3
  Bone13  910
  Lymph node231722
  Visceral (liver, spleen)  4  2  3
Baseline CEA 0.000
  Median222.86.83.7
  Range10–6,8405–100.8–5
Oral medicine 0.758
  Gefitinib (250 mg/day)222519
  Erlotinib (150 mg/day)121111
EGFR mutation type 0.354
  Exon 19 deletion252223
  Exon 21 L858R  91110
Resistance mechanism 1.000
  T790M131210
  MET amplification  2  1  3
  Small cell histology  1  1  1
  Unknown  7  4  5

[i] ECOG, Eastern Cooperative Oncology Group; CEA, carcinoembryonic antigen; EGFR, epidermal growth factor receptor.

Efficacy and toxicities

Between February 2012 and May 2015, 100 patients commenced erlotinib or gefitinib treatment (Table II). The last follow-up was carried out on June 30, 2016, and median follow-up duration was 20.5 months (range, 2.5–48.0). Disease progression occurred in 93 patients. The median PFS indicated statistical significance among the three groups (P<0.001; Fig. 1). The median PFS was significantly longer in group H (6.4 months) than in group L (4.5 months; P=0.027). Furthermore, the median PFS was also statistically longer in group L than in group N (3.0 months; P=0.002). From the results of PFS, the authors could suggest that the patients with high serum CEA level were able to benefit more from gefitinib therapy than those with low serum CEA. In a multivariate Cox equilibrium regression model, patients were grouped by CEA level, gender, smoking status and pathology as concomitant variables, and results displayed that group H was an independent positive predictive factor for PFS [hazard ratio (HR), 1.25; 95% confidence interval (CI), 1.09–1.39].

Table II.

Efficacy of erlotinib or gefitinib treatment.

Table II.

Efficacy of erlotinib or gefitinib treatment.

EfficacyGroup HGroup LGroup NP-value
PFS (median, months)6.44.53.00.000
OS (median, months)11.99.47.80.000
Tumor response 0.010
  CR211
  PR3079
  SD14812
  PD358

[i] Group H, high-CEA group, CEA baseline levels >10 ng/ml; group L, low-CEA group, CEA baseline levels 5–10 ng/ml; group N, normal-CEA group, CEA baseline levels <5.0 ng/ml. Patients were enrolled in each group on the basis of tumor imaging changes. CEA, carcinoembryonic antigen; PFS, progression-free survival; OS, overall survival; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

The ORRs were 65.3, 38 and 33.3%, respectively, in groups H, L and N. ORR were significantly higher in group H than in groups N and L (P=0.006 and 0.035, respectively), while no statistical difference was observed between groups L and N (P=0.726). A total of 80 patients had not died at the last follow-up date. The median OS of patients were 11.9, 9.4 and 7.8 months, respectively, in groups H, L and N. Similar with ORR, the median overall survivals (OS) was significantly longer in group H than in groups N and L (P<0.001 and P=0.022, respectively; Fig. 2), while no statistical difference was observed between groups L and N (P=0.115). These results suggest that the patients with pre-therapeutic high serum CEA level have better response to gefitinib or erlotinib and longer OS than those with low or normal serum CEA level.

The most common adverse events were skin rash and anorexia (75 and 51% in the current study, respectively), and there were no significant differences in their incidences among the three groups. Most patients showed only grade 1/2 adverse events. Grade 3 rash was observed in nine patients, and no dose reduction or discontinuation was performed in any patients due to intolerable toxicities. No interstitial lung disease occurred.

Acquired resistance to EGFR-TKIs

Of 100 samples, 76 developed acquired resistance to EGFR-TKIs. A total of 60 patients were identified that received re-biopsy at the time of development of acquired resistance successfully. The resistance mechanism was similar in three groups, with the acquired T790M mutation being most common, followed by MET amplification and small cell histologic transformation.

Discussion

The role of CEA as a prognostic factor has been well established in colon cancer and is now part of the routine follow-up evaluation recommended by the current NCCN guidelines (2629). In NSCLC, a number of studies evaluating CEA and prognosis have been written with contrasting results in the perioperative setting, some showing its role as a prognostic value (30,31) and others not confirming it (22,32,33). To the best of the authors' knowledge, no serum marker for EGFR-mutated NSCLC has been reported to predict the efficacy of EGFR-TKIs; the present study may be the first to demonstrate that the pre-therapeutic serum CEA level may predict the extent of benefits from EGFR-TKIs in advanced NSCLC patients carrying the EGFR mutation. The research results revealed significantly different median PFS between these groups (P<0.001), suggesting that patients with high serum CEA level may benefit more than those with low serum CEA in spite of partial overlap of 95% CIs.

EGFR mutations occur most frequently in female, non-smoking, East Asian and adenocarcinoma patients (34). Therefore, tumor patients carrying EGFR activating mutations demonstrated a better response to EGFR-TKI treatment than those without EGFR mutations (9). However, the effectiveness of TKIs treatment is not the same in the patients carrying EGFR mutations. Some patients had dramatic response to EGFR-TKIs treatment, while others did not exhibit any response.

The predictive and prognostic value of CEA level have been assessed in advanced NSCLC patients fully treated with gefitinib and erlotinib, due to conflicting results have been reported higher levels of CEA and the response is directly related to EGFR-TKI, but its effectiveness has not yet been established (35). On the other hand, Okamoto et al (24) and Jung et al (23) reported that patients treated with EGFR-TKI with higher CEA levels had a longer survival and a better response than those with low CEA levels. Shoji et al (36) reported that the rate of EGFR gene mutation is significantly increased as the levels of CEA increases (for the levels of CEA of <5, ≥5 but <20 and ≥20 the rate of EGFR gene mutation was 35, 55 and 87.5%, respectively; P=0.040). Their study presented a significant association between EGFR gene mutations and the levels of CEA in patients with lung adenocarcinomas. To the best of the authors' knowledge, little is known about the function of CEA. Wirth et al (37) reported that CEA can inhibit the apoptosis and has prometastatic roles in colon cancer cells, and Ordonez et al (38) also reported that the overexpression of CEA can protect tumor cells from apoptosis and inhibit cell death. EGFR mutations were detected within an ATP binding pocket with catalytic domain, and the mutants also had an enhanced tyrosine kinase activity in response to the ligand. In addition, the present studies have demonstrated that such downstream molecules as Akt and STAT3 serve a crucial role in the antiapoptotic pathways of EGFR mutations in tumor cells (39). Moreover, the mutated EGFRs are autophosphorylated in the absence of interleukin-3 without EGF stimulation, and their expression leads to the STAT5 activation and the upregulation of the extracellular signal-regulated kinase 1 or 2 (Erk1 or 2), Erk5 and Akt (40). It is hypothesized that this continuous signal of the mutant EGFR can stimulate antiapoptotic activity in a ligand-independent manner. Thus, overexpression of the CEA protein as antiapoptotic may be observed in patients with EGFR mutants.

In the present study, the median OS of patients were 11.9, 9.4 and 7.8 months, respectively, in groups H, L and N. Similar to the ORR, the difference in the median OS between groups H and N and between groups H and L were significant (P<0.001 and P=0.022, respectively), whereas these between groups L and N were not (P=0.115). In addition, the multivariate analysis revealed that group H was an independent positive predictive factor for PFS (HR, 1.25; 95% CI, 1.09–1.39). Considering histologic heterogeneity in NSCLC, the authors hypothesized that the serum CEA level in patients with pretreated lung cancer partly represents the extent of the mutant EGFR component in the lung cancer. This hypothesis may partially explain why the effect durations were not as long as expected in some patients with EGFR mutations. By determining the serum CEA level, one could select the patients with high serum CEA levels for EGFR-TKIs treatment to guarantee the best therapy effect. Importantly, more attention should be paid to patients with low serum CEA levels while making therapeutic strategies, it is necessary for them to give combined strategies, rather than single administration of EGFR-TKIs.

With regard to the potential benefit of learning about a small cell histologic transformation, as well as the prognostic value of EGFR T790M mutation, the authors biopsy patients at the time of development of acquired resistance as part of routine consideration. These data demonstrate that there were no differences between the patients with low serum CEA and the patients who had high serum CEA. It is presumed that the level of CEA could not predict acquired resistance to EGFR-TKIs.

In summary, the present study suggests that the relative pre-therapeutic CEA level can predict the extent of benefits from EGFR-TKIs, but can not predict the acquired drug resistance to EGFR-TKIs therapy in patients with EGFR mutations. However, the current study is believed to possess some limitations. Firstly, the current study was the limited sample size of 100 patient cases. Secondly, it is uncertain whether the serum CEA level actually represents a rich mutant EGFR component in each patient. Further basic research is needed to clarify the possible molecular mechanisms behind this association.

References

1 

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, et al: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12:735–742. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, et al: First-SIGNAL: First-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 30:1122–1128. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, et al North-East Japan Study Group, : Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 362:2380–2388. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, et al West Japan Oncology Group, : Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol. 11:121–128. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361:947–957. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, et al Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica, : Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13:239–246. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Kawaguchi T, Matsumura A, Fukai S, Tamura A, Saito R, Zell JA, Maruyama Y, Ziogas A, Kawahara M and Ou SH Ignatius: Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: A collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and a Southern California Regional Cancer Registry databases. J Thorac Oncol. 5:1001–1010. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, et al Spanish Lung Cancer Group, : Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 361:958–967. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Saijo N, Takeuchi M and Kunitoh H: Reasons for response differences seen in the V15-32, INTEREST and IPASS trials. Nat Rev Clin Oncol. 6:287–294. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH, Yu CJ, Chang GC, Ho CL, Sequist LV, et al: Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): A phase 2 trial. Lancet Oncol. 13:539–548. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, et al: Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 3:75ra262011. View Article : Google Scholar : PubMed/NCBI

13 

Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG and Halmos B: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 352:786–792. 2005. View Article : Google Scholar : PubMed/NCBI

14 

Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, et al: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 316:1039–1043. 2007. View Article : Google Scholar : PubMed/NCBI

15 

Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, et al: MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA. 104:pp. 20932–20937. 2007; View Article : Google Scholar : PubMed/NCBI

16 

Zakowski MF, Ladanyi M and Kris MG; Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome Group, : EGFR mutations in small-cell lung cancers in patients who have never smoked. N Engl J Med. 355:213–215. 2006. View Article : Google Scholar : PubMed/NCBI

17 

Chmielecki J, Foo J, Oxnard GR, Hutchinson K, Ohashi K, Somwar R, Wang L, Amato KR, Arcila M, Sos ML, et al: Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 3:90ra592011. View Article : Google Scholar : PubMed/NCBI

18 

Chaft JE, Oxnard GR, Sima CS, Kris MG, Miller VA and Riely GJ: Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: Implications for clinical trial design. Clin Cancer Res. 17:6298–6303. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Bergman B, Brezicka FT, Engström CP and Larsson S: Clinical usefulness of serum assays of neuron-specific enolase, carcinoembryonic antigen and CA-50 antigen in the diagnosis of lung cancer. Eur J Cancer. 29A:198–202. 1993. View Article : Google Scholar : PubMed/NCBI

20 

Kleisbauer JP, Castelnau O, Thomas P, Ramirez J, Lanteaume A and Roux F: Prognostic value of pre-therapeutic levels of carcino-embryonic antigen in primary bronchial carcinoma]. Bull Cancer. 82:1019–1024. 1995.(In French). PubMed/NCBI

21 

Kulpa J, Wójcik E, Reinfuss M and Kołodziejski L: Carcinoembryonic antigen, squamous cell carcinoma antigen, CYFRA 21-1, and neuron-specific enolase in squamous cell lung cancer patients. Clin Chem. 48:1931–1937. 2002.PubMed/NCBI

22 

Nisman B, Lafair J, Heching N, Lyass O, Baras M, Peretz T and Barak V: Evaluation of tissue polypeptide specific antigen, CYFRA 21-1, and carcinoembryonic antigen in nonsmall cell lung carcinoma: Does the combined use of cytokeratin markers give any additional information? Cancer. 82:1850–1859. 1998. View Article : Google Scholar : PubMed/NCBI

23 

Jung M, Kim SH, Hong S, Kang YA, Kim SK, Chang J, Rha SY, Kim JH, Kim DJ and Cho BC: Prognostic and predictive value of carcinoembryonic antigen and cytokeratin-19 fragments levels in advanced non-small cell lung cancer patients treated with gefitinib or erlotinib. Yonsei Med J. 53:931–939. 2012. View Article : Google Scholar : PubMed/NCBI

24 

Okamoto T, Nakamura T, Ikeda J, Maruyama R, Shoji F, Miyake T, Wataya H and Ichinose Y: Serum carcinoembryonic antigen as a predictive marker for sensitivity to gefitinib in advanced non-small cell lung cancer. Eur J Cancer. 41:1286–1290. 2005. View Article : Google Scholar : PubMed/NCBI

25 

Marshall HM, Leong SC, Bowman RV, Yang IA and Fong KM: The science behind the 7th edition Tumour, Node, Metastasis staging system for lung cancer. Respirology. 17:247–260. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Brundage MD, Davies D and Mackillop WJ: Prognostic factors in non-small cell lung cancer: A decade of progress. Chest. 122:1037–1057. 2002. View Article : Google Scholar : PubMed/NCBI

27 

Desch CE, Benson AB III, Somerfield MR, Flynn PJ, Krause C, Loprinzi CL, Minsky BD, Pfister DG, Virgo KS and Petrelli NJ; American Society of Clinical Oncology, : Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 23:8512–8519. 2005. View Article : Google Scholar : PubMed/NCBI

28 

Lin JK, Lin CC, Yang SH, Wang HS, Jiang JK, Lan YT, Lin TC, Li AF, Chen WS and Chang SC: Early postoperative CEA level is a better prognostic indicator than is preoperative CEA level in predicting prognosis of patients with curable colorectal cancer. Int J Colorectal Dis. 26:1135–1141. 2011. View Article : Google Scholar : PubMed/NCBI

29 

Lee WS, Baek JH, Kim KK and Park YH: The prognostic significant of percentage drop in serum CEA post curative resection for colon cancer. Surg Oncol. 21:45–51. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Kozu Y, Maniwa T, Takahashi S, Isaka M, Ohde Y and Nakajima T: Prognostic significance of postoperative serum carcinoembryonic antigen levels in patients with completely resected pathological-stage I non-small cell lung cancer. J Cardiothorac Surg. 8:1062013. View Article : Google Scholar : PubMed/NCBI

31 

Okada M, Nishio W, Sakamoto T, Uchino K, Yuki T, Nakagawa A and Tsubota N: Prognostic significance of perioperative serum carcinoembryonic antigen in non-small cell lung cancer: Analysis of 1,000 consecutive resections for clinical stage I disease. Ann Thorac Surg. 78:216–221. 2004. View Article : Google Scholar : PubMed/NCBI

32 

Foa P, Fornier M, Miceli R, Seregni E, Santambrogio L, Nosotti M, Cataldo I, Sala M, Caldiera S and Bombardieri E: Tumour markers CEA NSE, SCC, TPA and CYFRA 21.1 in resectable non-small cell lung cancer. Anticancer Res. 19(4C): 3613–3618. 1999.PubMed/NCBI

33 

Reinmuth N, Brandt B, Semik M, Kunze WP, Achatzy R, Scheld HH, Broermann P, Berdel WE, Macha HN and Thomas M: Prognostic impact of Cyfra21-1 and other serum markers in completely resected non-small cell lung cancer. Lung Cancer. 36:265–270. 2002. View Article : Google Scholar : PubMed/NCBI

34 

Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, et al: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 97:339–346. 2005. View Article : Google Scholar : PubMed/NCBI

35 

Wu YL, Zhong WZ, Li LY, Zhang XT, Zhang L, Zhou CC, Liu W, Jiang B, Mu XL, Lin JY, et al: Epidermal growth factor receptor mutations and their correlation with gefitinib therapy in patients with non-small cell lung cancer: A meta-analysis based on updated individual patient data from six medical centers in mainland China. J Thorac Oncol. 2:430–439. 2007. View Article : Google Scholar : PubMed/NCBI

36 

Shoji F, Yoshino I, Yano T, Kometani T, Ohba T, Kouso H, Takenaka T, Miura N, Okazaki H and Maehara Y: Serum carcinoembryonic antigen level is associated with epidermal growth factor receptor mutations in recurrent lung adenocarcinomas. Cancer. 110:2793–2798. 2007. View Article : Google Scholar : PubMed/NCBI

37 

Wirth T, Soeth E, Czubayko F and Juhl H: Inhibition of endogenous carcinoembryonic antigen (CEA) increases the apoptotic rate of colon cancer cells and inhibits metastatic tumor growth. Clin Exp Metastasis. 19:155–160. 2002. View Article : Google Scholar : PubMed/NCBI

38 

Ordoñez C, Screaton RA, Ilantzis C and Stanners CP: Human carcinoembryonic antigen functions as a general inhibitor of anoikis. Cancer Res. 60:3419–3424. 2000.PubMed/NCBI

39 

Cappuzzo F, Magrini E, Ceresoli GL, Bartolini S, Rossi E, Ludovini V, Gregorc V, Ligorio C, Cancellieri A, Damiani S, et al: Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 96:1133–1141. 2004. View Article : Google Scholar : PubMed/NCBI

40 

Jiang J, Greulich H, Jänne PA, Sellers WR, Meyerson M and Griffin JD: Epidermal growth factor-independent transformation of Ba/F3 cells with cancer-derived epidermal growth factor receptor mutants induces gefitinib-sensitive cell cycle progression. Cancer Res. 65:8968–8974. 2005. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

July-2017
Volume 7 Issue 1

Print ISSN: 2049-9434
Online ISSN:2049-9442

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Han J, Li Y, Cao S, Dong Q, Zhao G, Zhang X and Cui J: The level of serum carcinoembryonic antigen is a surrogate marker for the efficacy of EGFR‑TKIs but is not an indication of acquired resistance to EGFR‑TKIs in NSCLC patients with EGFR mutations. Biomed Rep 7: 61-66, 2017
APA
Han, J., Li, Y., Cao, S., Dong, Q., Zhao, G., Zhang, X., & Cui, J. (2017). The level of serum carcinoembryonic antigen is a surrogate marker for the efficacy of EGFR‑TKIs but is not an indication of acquired resistance to EGFR‑TKIs in NSCLC patients with EGFR mutations. Biomedical Reports, 7, 61-66. https://doi.org/10.3892/br.2017.914
MLA
Han, J., Li, Y., Cao, S., Dong, Q., Zhao, G., Zhang, X., Cui, J."The level of serum carcinoembryonic antigen is a surrogate marker for the efficacy of EGFR‑TKIs but is not an indication of acquired resistance to EGFR‑TKIs in NSCLC patients with EGFR mutations". Biomedical Reports 7.1 (2017): 61-66.
Chicago
Han, J., Li, Y., Cao, S., Dong, Q., Zhao, G., Zhang, X., Cui, J."The level of serum carcinoembryonic antigen is a surrogate marker for the efficacy of EGFR‑TKIs but is not an indication of acquired resistance to EGFR‑TKIs in NSCLC patients with EGFR mutations". Biomedical Reports 7, no. 1 (2017): 61-66. https://doi.org/10.3892/br.2017.914