Elevated serum level of sialylated glycoprotein KL-6 predicts a poor prognosis in patients with non-small cell lung cancer treated with gefitinib
Introduction
Epidermal growth factor receptor (EGFR) is a promising target for cancer therapy, because its signaling drives the proliferation and survival of cancer cells and it has been shown to be frequently overexpressed in various tumor types including non-small cell lung cancer (NSCLC). In fact, gefitinib, an EGFR tyrosine kinase inhibitor, has shown substantial antitumor activity in early phase II clinical trials for patients with advanced NSCLC who had previously received platinum-based chemotherapy [1], [2]. Although a subsequent large randomized phase III trial for pretreated NSCLC failed to demonstrate a significant survival advantage of gefitinib over a placebo in the entire cohort, a subgroup analysis revealed the superiority of gefitinib over a placebo in patients of Asian origin [3]. Recent prospective studies of NSCLC also demonstrated that gefitinib is highly effective in female patients, those with an adenocarcinoma histology, and those without a smoking history [4], [5]. All of these findings suggest the importance of predictors for selecting patients who are most likely to benefit from gefitinib.
Recently, mutations of EGFR tyrosine kinase domain have been identified as a molecular predictor for the treatment outcome of gefitinib [6], [7], [8], [9]. Approximately 90% of EGFR mutations are either in-frame deletion mutations in exon 19 or point mutations in exon 21, and they are closely related to known clinical predictors as well as to the response to gefitinib [10]. Research from other groups has identified candidate gene alternations other than EGFR mutations that may be involved in determining the response to gefitinib, including an increased EGFR gene copy number and K-ras mutations [11], [12], [13]. However, these genetic markers seem to be somewhat inconvenient to use in daily practice; not all NSCLC patients are always able to undergo a routine assessment of their gene status in their tumors before starting gefitinib treatment due to technical or financial restraints. Moreover, there can be some interinstitutional variances in the accuracy of the assays [14]. Therefore, new biomarkers appear to be needed that are more readily available in daily clinical practice with the development of the specificity and sensitivity of EGFR mutations.
KL-6 is a high molecular weight sialylated glycoprotein that is predominantly expressed on pulmonary epithelial cells [15]. Although KL-6 has been studied as a useful indicator for interstitial lung diseases, it was originally discovered as a lung cancer-related antigen [16]. In addition, the biochemical properties of KL-6 are similar to those of other MUC1 mucins that have been reported to be associated with a poor prognosis in NSCLC [17], [18]. Taken together, the serum KL-6 levels might thus be able to provide predictive information about the survival in the treatment of NSCLC by gefitinib. However, this issue remains to be fully evaluated. In this study, we investigated whether pretreatment serum KL-6 levels could predict the survival in NSCLC patients treated with gefitinib, while also determining its association with the EGFR mutation status.
Section snippets
Patients
We retrospectively reviewed the medical records of 41 NSCLC patients who underwent gefitinib monotherapy at Okayama University Hospital between September 2002 and September 2005. All patients fulfilled the following eligibility criteria enrolled consecutively in this study: (1) NSCLC patients who underwent gefitinib monotherapy after failure of at least one prior cytotoxic chemotherapy, (2) those whose serum KL-6 level was measured within 1 month before the initiation of gefitinib treatment.
Patient characteristics
Table 1 summarizes the characteristics of the 41 NSCLC patients analyzed. The median age was 67 years (range, 34–82 years), and the majority of patients were male (61%), with a history of smoking (71%), and had an adenocarcinoma histology (85%). Approximately half of all patients (54%) received two or more prior types of chemotherapy before starting the gefitinib treatment. According to the TNM staging system, these recurrent cases were regarded as the following stages at the time of gefitinib
Discussion
In this study, we found a close relationship between the serum levels of KL-6 and the survival time in NSCLC patients treated with gefitinib. Patients with high serum KL-6 levels showed a significantly shorter progression-free survival time than those with normal serum KL-6 levels. These results held true for the overall survival even when EGFR mutations are taken into account. This easily assessable and serological biomarker might therefore provide additional valuable information for
Conflict of interest
None.
References (28)
- et al.
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer)
Lancet
(2005) - et al.
The role of gefitinib treatment for Korean never-smokers with advanced or metastatic adenocarcinoma of the lung: a prospective study
J Thorac Oncol
(2006) - et al.
Clinical significance of epidermal growth factor receptor gene mutations on treatment outcome after first-line cytotoxic chemotherapy in Japanese patients with non-small cell lung cancer
J Thorac Oncol
(2007) - et al.
EGFR mutations do not accurately predict response to erlotinib in first-line monotherapy treatment of advanced non-small-cell lung cancer
Lung Cancer
(2005) - et al.
Detection of serum and intrahepatic KL-6 in anti-HCV positive patients with hepatocellular carcinoma
Hepatol Res
(2004) - et al.
Continued gefitinib treatment after disease stabilisation prolongs survival of Japanese patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience
Ann Oncol
(2005) - et al.
Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial)
J Clin Oncol
(2003) - et al.
Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial
JAMA
(2003) - et al.
A phase II study of gefitinib as first line treatment for good performance advanced or metastatic non-small cell lung cancer in East Asian patients
Proc Am Soc Clin Oncol
(2006) - et al.
Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence
J Clin Oncol
(2005)
The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers
Clin Cancer Res
The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer
Int J Cancer
Epidermal growth factor receptor mutations in patients with non-small cell lung cancer
Cancer Res
Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer
J Natl Cancer Inst
Cited by (16)
A straightforward protocol for the preparation of high performance microarray displaying synthetic MUC1 glycopeptides
2014, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :However, 5 out of 6 donors (except donor 2) exhibited the circulation of IgG autoantibodies to 49 (GSTA) and 58 (VTSA) involving sialyl-T antigen, suggesting that the antibody might have an anti-carbohydrate reactivity rather than against “glycopeptides”. It was also revealed that only 2–4 out of 6 donors had IgG autoantibodies to MUC1 glycopeptides having Tn or T antigen [42–46,53] as well as naked MUC1 peptides 41 or 51. There might be a considerable difference in the serum levels of the MUC1 autoantibodies between healthy human subjects.
Dephosphorylation of intact glycoprotein to greatly improve digestion efficiency coupled with matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometric analysis
2013, Analytica Chimica ActaCitation Excerpt :Previous studies have reported that different physiological conditions generated different glycans and glycan diversification at one glycosylation site of one protein may show distinct functions [5,6]. Previous studies have also shown that aberrant sialylations of proteins are significantly associated with diseases [5,7–11]. Traditional methods for the characterization of the sialylated glycans involve proteolysis of glycoproteins with several enzymes.
KL-6 and poor prognosis in NSCLC patients treated with gefitinib
2008, Lung CancerClinical significance of KL-6 in immune-checkpoint inhibitor treatment for non-small cell lung cancer
2023, Cancer Chemotherapy and PharmacologyThe role of mucin 1 in respiratory diseases
2021, European Respiratory ReviewNovel perspectives regarding the pathology, inflammation, and biomarkers of acute respiratory distress syndrome
2021, International Journal of Molecular Sciences