Elsevier

Lung Cancer

Volume 59, Issue 1, January 2008, Pages 81-87
Lung Cancer

Elevated serum level of sialylated glycoprotein KL-6 predicts a poor prognosis in patients with non-small cell lung cancer treated with gefitinib

https://doi.org/10.1016/j.lungcan.2007.07.018Get rights and content

Summary

Purpose

The factors affecting survival after gefitinib treatment in patients with non-small cell lung cancer (NSCLC) remain to be fully elucidated, although epidermal growth factor receptor (EGFR) mutation is a substantial prognostic factor. KL-6 has been studied as a useful indicator for interstitial lung diseases; however, it was first discovered as a lung cancer-related antigen. The aim of this study was to investigate the prognostic value of the serum KL-6 levels in advanced NSCLC patients treated with gefitinib and thus determine its association with the EGFR mutation status.

Patients and methods

Between September 2002 and September 2005, 41 patients with NSCLC were treated with gefitinib after having their serum KL-6 levels measured at Okayama University Hospital. EGFR mutations were analyzed by direct sequence methods.

Results

The serum KL-6 levels ranged from 199 to 9080 U/ml (median, 550 U/ml), and 54% of 41 patients showed a level higher than the cut-off level of 500 U/ml. The median progression-free survival (PFS) time and the median overall survival (OS) time were 4.7 months and 13.9 months, respectively. Multivariate analyses revealed that the elevated KL-6 level was an independent adverse prognostic factor for PFS (hazard ratio: 2.278, p = 0.040) as well as OS (hazard ratio: 4.858, p = 0.002) in NSCLC patients treated with gefitinib. The EGFR mutation status was analyzed in 22 patients (54%). Among those with wild-type EGFR, the patients with high serum KL-6 levels also had a worse survival than those within normal serum KL-6 levels (6.5 months versus 13.3 months, p = 0.0194).

Conclusion

Our data suggest that NSCLC patients with high serum KL-6 levels tended to have a poor clinical outcome when 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.

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