Journal of Thoracic Oncology:
Cytokeratin 19 Fragment Predicts the Efficacy of Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor in Non–Small-Cell Lung Cancer Harboring EGFR Mutation
Tanaka, Kosuke MD*; Hata, Akito MD*; Kaji, Reiko MD*; Fujita, Shiro MD, PhD*; Otoshi, Takehiro MD†; Fujimoto, Daichi MD†; Kawamura, Takahisa MD†; Tamai, Koji MD*; Takeshita, Jumpei MD†; Matsumoto, Takeshi MD†; Monden, Kazuya MD†; Nagata, Kazuma MD†; Otsuka, Kyoko MD†; Nakagawa, Atsushi MD†; Tachikawa, Ryo MD†; Otsuka, Kojiro MD, PhD†; Tomii, Keisuke MD, PhD†; Katakami, Nobuyuki MD, PhD*
*Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Minatojima-Minamimachi, Chuo-Ku, Kobe, Japan; and †Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, Japan.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: Nobuyuki Katakami, MD, Division of Integrated Oncology, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan. E-mail: email@example.com
Background: EGFR gene mutation is independently associated with a favorable response in non–small-cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor -tyrosine kinase inhibitors (EGFR-TKIs), regardless of sex or smoking history. Squamous cell carcinoma patients harboring EGFR mutations show a significantly worse response to EGFR-TKIs compared with adenocarcinoma patients. We hypothesized that the serum cytokeratin 19 fragment (CYFRA 21-1) is associated with the efficacy of EGFR-TKIs in EGFR-mutated NSCLC patients.
Methods: We retrospectively screened 160 NSCLC patients harboring EGFR mutations, who had received either gefitinib, or erlotinib between 1992 and 2011. Patients were screened for clinical characteristics, the efficacy of EGFR-TKI, and tumor markers (carcinoembryonic antigen [CEA]/CYFRA 21-1) at the initial diagnosis.
Results: Of 160 eligible patients treated with EGFR-TKIs, 77 patients with high CYFRA 21-1 level (>2 ng/ml) showed significantly shorter progression-free survival (PFS) than the 83 patients with normal CYFRA 21-1 level (median PFS, 7.5 versus 13.3 months; p < 0.001). No significant difference in PFS was observed between the high-CEA group (>5 ng/ml) and the normal-CEA group (median PFS, 8.6 versus 11.2 months; p = 0.242). A multivariate analysis revealed that high CYFRA 21-1 level is independently associated with PFS (hazard ratio, 1.27; p = 0.002). No significant difference in overall survival was observed between the high- and the normal-CYFRA 21-1 groups (median overall survival, 24.8 versus 39.1 months; p = 0.104).
Conclusions: Patients with a high CYFRA 21-1 level have significantly shorter PFS. CYFRA 21-1 is not a prognostic but a predictive marker of EGFR-TKI treatment in EGFR-mutated NSCLC patients.
Lung cancer is the leading cause of cancer death worldwide. Non–small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers.1 Chemotherapy alone, or in combination with other agents, can modestly improve lung cancer outcomes, but at the cost of significant toxicity to patients. In recent years, molecular-targeted therapies, such as epidermal growth factor receptor (EGFR) inhibitors, have gained attention for their potential to improve patient survival and reduce toxic side effects.2–4 The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in the treatment of NSCLC has been proven, especially in EGFR-mutation–positive patients, and the presence of EGFR mutations is known to predict the efficacy of EGFR-TKIs.5–7
EGFR mutations are usually found in adenocarcinoma and rarely in other histologic subtypes.8–12 The incidence of EGFR mutations in squamous cell carcinoma (SCC) is reported to be approximately 5%,12–15 therefore, most SCC patients do not seem to benefit much from major advances in the development of EGFR-gene–targeted therapy. Moreover, a recent pooled analysis showed that nonadenocarcinoma patients harboring EGFR mutations have shorter progression-free survival (PFS) when treated with EGFR-TKIs compared with patients with adenocarcinoma harboring EGFR mutations.16
Cytokeratin 19 fragment (CYFRA 21-1) is both a sensitive and specific tumor marker for NSCLC, especially for SCC.17–21 Shukuya et al.16 reported that SCC patients harboring EGFR mutations exhibit lower response to EGFR-TKIs. We, therefore, hypothesized that the serum CYFRA 21-1 level is related to the efficacy of EGFR-TKIs in NSCLC patients harboring EGFR mutations. Carcinoembryonic antigen (CEA), recognized as a tumor marker for NSCLC, is also useful for the detection of adenocarcinoma, with approximately 60% sensitivity and 50% specificity for adenocarcinoma,22,23 whereas the sensitivity and specificity is approximately 25% to 40% and 25%, respectively, for squamous cell carcinoma.19,20 Moreover, the serum CEA level at diagnosis is a poor prognostic factor in lung cancer patients.23–25 The aims of our present study were: (1) to analyze the predictive and prognostic value of the serum CYFRA 21-1 level in EGFR-mutant patients treated with EGFR-TKI; (2) to compare the significance of CYFRA 21-1 with that of another tumor marker, CEA; (3) to identify the indicative factors among these tumor markers and the clinical characteristics (i.e., age, sex, smoking history, performance status [PS], and histology) associated therein.
PATIENTS AND METHODS
Patients and EGFR Mutation Analysis
In this retrospective study, we screened the cases of 160 EGFR-mutated advanced NSCLC patients treated with EGFR-TKIs at the Institute of Biomedical Research and Innovation or the Kobe City Medical Center General Hospital (Japan), between 1992 and 2011. All patients with locally advanced (stage IIIB), metastasized (stage IV), or postsurgically relapsed NSCLC were confirmed for EGFR mutations and received either gefitinib 250 mg/d or erlotinib 150 mg/d orally (clinical stage was determined by the 7th edition of tumor, node, metastasis classification). EGFR mutations were identified by the peptide nucleic acid–locked nucleic acid polymerase chain reaction clamp method. One hundred fifty-three patients harbored activated EGFR mutations (either exon 19 deletions or L858R in exon 21). The other seven patients had minor mutations (1 with L861Q in exon 21, and 6 with G719X in exon 18). Histologic subclassification was carried out according to the World Health Organization classification.26 A computed tomography scan was performed for tumor assessment within 28 days before initiating treatment, and was repeated every 2 to 3 months. All responses were defined according to Response Evaluation Criteria in Solid Tumors. Response was confirmed at least 4 weeks (for a complete or partial response) or 6 weeks (for stable disease) after the first documentation.
Measurement of Serum CEA and CYFRA 21-1 Levels
The serum CEA level was measured within 2 weeks before the initial diagnosis of NSCLC, by a commercial electrochemiluminescence immunoassay on the ARCHITECT i2000SR system (Abbott Diagnostics, Tokyo, Japan). The serum CYFRA 21-1 level was measured simultaneously, by a commercial electrochemiluminescence immunoassay on the ElecSys 2010 system (Roche Diagnostics, Indianapolis, IN). The standard cutoff values for CEA and CYFRA 21-1 at our institutions are 5.0 ng/ml and 2.0 ng/ml, respectively.
Statistical analyses were performed using the JMP statistical software program (9th version; SAS Institute Inc., Cary, NC) to compare patient characteristics and responses with EGFR-TKI treatment. Wilcoxon test was performed to compare serum CYFRA 21-1 levels between the two groups. Survival curves were estimated by the Kaplan–Meier method, and the differences between the two groups were compared with the log-rank test. Single-variable survival analyses were done by means of log-rank tests, and the multivariate regression was done with Cox’s proportional hazard regression model. The PFS was calculated from the date of initiation of EGFR-TKI treatment to, either the date of disease progression, or the date of last contact. The overall survival (OS) was defined as the interval from the date of initiation of EGFR-TKI treatment to the date of death from any cause, or the last follow-up. All tests were two-sided, and a p value of less than 0.05 was considered significant.
The clinical characteristics of the 160 patients are shown in Table 1. Ninety-one patients (57%) were women and 97 (61%) were never-smokers, with an age range of 33 to 90 years (median, 67 years). Most patients had adenocarcinoma; only eight patients had SCC, and one had large-cell carcinoma. One hundred thirty-two patients received gefitinib 250 mg/d, and 28 patients were treated with erlotinib 150 mg/d. Fifty-seven patients were treated with EGFR-TKI as a first-line therapy, 67 patients as a second-line therapy, and 36 patients as third-line or thereafter. Seventy-one patients (44%) had a PS of 0, 69 (43%) had a PS of 1, 16 (10%) had a PS of 2, and four (3%) had a PS of 3 to 4.
Serum CYFRA 21-1/CEA Levels and PFS
Of 160 eligible patients treated with EGFR-TKIs, 83 patients showed serum CYFRA 21-1 level above the normal upper limit of 2.0 ng/ml at initial diagnosis. The serum CEA level in 89 patients at initial diagnosis was elevated (> 5.0 ng/ml). At the time of analysis, the median follow-up time was 32.5 months (range, 23.3–44.6 months). The median duration of PFS in patients with high- and normal-serum CYFRA 21-1 level was 7.5 months (95% confidence interval [CI], 6.2–9.1 months) and 13.3 months (95% CI, 10.6–18.2 months), respectively (p < 0.001; Fig. 1A). In addition, there was no significant difference in tumor responses between high- and normal-CYFRA 21-1 groups (response rate, 48.1% versus 42.2%; p = 0.818). The median durations of PFS in the two groups of patients with high- and normal-serum CEA levels were 8.6 months (95% CI, 7.6–11.9 months) and 11.2 months (95% CI, 7.1–16.6 months), respectively (p = 0.242; Fig. 1B).
Serum CYFRA 21-1/CEA Levels and OS
As shown in Figure 2A, the median duration of OS in the patients with high- and normal-serum CYFRA 21-1 levels were 24.8 months (95% CI, 20.3–36.5 months) and 37.8 months (95% CI, 26.4–52.7 months), respectively (p = 0.104). The median duration of OS in patients with high- and normal-serum CEA level was 26.0 months (95% CI, 20.3–36.5 months) and 39.0 months (95% CI, 26.5–61.3 months), respectively (p = 0.163; Fig. 2B). There was no significant difference in OS between the high-CYFRA 21-1 group and the normal-CYFRA 21-1 group (median OS, 24.8 versus 37.8 months; p = 0.104; Fig. 2A). Moreover, postprogression survival ([PPS], calculated as OS minus PFS) was almost the same between the two groups (median PPS, 14.7 versus 18.0 months; p = 0.655; Fig. 2C). As for CEA, no significant difference in PPS was shown between the high-CEA group and the normal-CEA group (median OS, 26.0 versus 39.0 months; p = 0.163; Fig. 2B).
Impact of Serum CYFRA21-1/CEA Levels on the Efficacy of EGFR-TKI
To determine the predictive importance of clinical characteristics and the serum CYFRA 21-1/CEA level in the EGFR-mutant NSCLC patients treated with EGFR-TKIs, we performed a Cox proportional hazard regression analysis on the parameters listed in Table 2. The univariate analyses revealed that high-serum CYFRA 21-1 level (p < 0.001), SCC (p = 0.002), and poor PS (p = 0.001) were significant negative predictive factors for PFS. In addition, the multivariate analyses (Table 3) demonstrated that high-serum CYFRA 21-1 level (hazard ratio [HR], 1.27; 95% CI, 1.11–1.40; p = 0.002) was independently a significant predictive factor for PFS.
Impact of Serum CYFRA21-1/CEA Levels on Survival
To determine prognostic variant factors, we also performed a Cox proportional hazard regression analysis on the parameters listed in Table 2. The univariate analyses showed that SCC (p = 0.002) and poor PS (p < 0.001) were significantly associated with shorter OS. The multivariate analyses (Table 3) demonstrated that PS (HR, 1.62; 95% CI, 1.14–2.22; p = 0.009) alone was a prognostic factor for OS.
Eight SCC Patients Harboring EGFR Mutations
As shown in Table 2, the eight SCC patients harboring EGFR mutations had significantly shorter PFS than the non-SCC patients harboring EGFR mutations (median PFS, 4.0 months versus 10.2 months; p = 0.002). We compared serum CYFRA 21-1 levels between 151 adenocarcinoma patients and eight SCC patients. CYFRA 21-1 level was significantly higher in SCC patients (median, 5.6 ng/ml; 95% CI, 1.7–8.3) compared with adenocarcinoma patients (median, 2.1 ng/ml; 95% CI, 1.7–2.4; p = 0.014). The four patients with highest CYFRA 21-1 levels did not respond to EGFR-TKIs (disease progression was confirmed within 2 months), whereas the remaining four patients with lower serum CYFRA 21-1 levels had much longer PFS (median PFS, 1.0 months versus 7.0 months; p = 0.007; Table 4).
Our findings revealed that high-serum CYFRA 21-1 level at initial diagnosis was related to shorter PFS of EGFR-TKIs in patients with EGFR-mutated NSCLC. Several reports have demonstrated that high levels of CEA and CYFRA 21-1 at baseline are correlated with worse OS in advanced NSCLC patients.27,28 In the previous study, CYFRA 21-1 was shown to be significantly more sensitive than CEA for predicting clinical outcome of NSCLC patients (HR, 1.3; p = 0.01).27 Recently, it was found that the factors CYFRA 21-1 and change in CYFRA 21-1 were reliable markers for response to chemotherapy for NSCLC patients.29 To the best of our knowledge, no serum marker for EGFR-mutated NSCLC has been reported to predict the efficacy of EGFR-TKIs, and ours may be the first report that focused on predicting PFS and OS of EGFR-TKI treatment in NSCLC patients harboring EGFR mutations.
EGFR mutations occur most frequently in female, nonsmoking, East-Asian, and adenocarcinoma patients.30 Several reports have suggested that tumor molecular profiling may supersede these clinical selection factors for EGFR-TKI treatment in NSCLC patients. EGFR mutation was reported to be independently associated with a favorable prognosis in gefitinib-treated patients, regardless of sex or smoking history.31 However, in a pooled analysis,16 gefitinib was less effective in nonadenocarcinoma NSCLC harboring EGFR mutations, than in adenocarcinoma harboring EGFR mutations.
Distinguishing adenocarcinoma from SCC has recently provided clinical benefits for treatment decisions, however, the histologic classification is solely based on small biopsy or cytologic specimens in most cases. Travis et al.32 mentioned the considerable limitation of the diagnosis based on a small biopsy sample, which occasionally leads to controversial diagnosis in NSCLC. They indicated that one major underlying problem is the inherent histologic heterogeneity that exists in a subset of NSCLC. Because of this inherent histologic heterogeneity in NSCLC, and because the structural features of SCC or adenocarcinoma differentiation are focal or not distinguishable in small biopsy or cytologic specimens, 10% of SCCs, 14% of adenocarcinomas, and 50% of large-cell carcinomas were misclassified on the basis of bronchial biopsies.33
CYFRA 21-1 is 40 kD acidic protein that is part of the cytoskeleton of epithelial cells.34 Increased CYFRA 21-1 is the result of not only cytokeratin release as a consequence of cell lysis, or necrosis, but also the generation of cytokeratin filament by activated protease in tumor cells.35 Some studies have shown that CYFRA 21-1 is both a sensitive and specific tumor marker for NSCLC, and especially for SCC.17–21 The sensitivity and specificity of CYFRA 21-1 for SCC were reported to be 66.5% and 95%, respectively, making CYFRA 21-1 a much better diagnostic marker than CEA, for SCC.20 It was reported that the serum CYFRA 21-1 level is associated with the efficacy of pemetrexed in nonsquamous NSCLC and may be a predictive marker for pemetrexed use.36 Considering histologic heterogeneity in NSCLC, we speculated that the serum CYFRA 21-1 level in pretreatment lung cancer patients proportionately represents the extent of the squamous component in the lung tumor. This hypothesis can explain the difference in pemetrexed’s efficacy in nonsquamous NSCLC between normal- and high-CYFRA 21-1 groups, because SCC patients have been reported to respond more poorly to pemetrexed therapy compared with adenocarcinoma patients.37–39 Our study demonstrated the difference in EGFR-TKI treatment efficacy in NSCLC harboring EGFR mutations between normal- and high-CYFRA 21-1 groups. In addition, our multivariate analysis revealed that high CYFRA 21-1 level was an independent negative predictive factor for PFS in the EGFR-mutant NSCLC patients (HR, 1.27; 95% CI, 1.11–1.40), conforming to our speculation that the serum CYFRA 21-1 level is associated with the proportion of the squamous component in NSCLC. As the frequency of SCC is low in EGFR-mutated NSCLC, CYFRA 21-1 is a more valuable predictive marker for EGFR-TKI treatment than squamous histology.
Similar to the Shukuya et al.16 report the eight SCC patients harboring EGFR mutations in our study also had shorter PFS (median PFS, 4.0 months) than the adenocarcinoma patients harboring EGFR mutations. The interesting point is that higher CYFRA 21-1 level was closely related to the worse efficacy of EGFR-TKI even among the SCC patients. The four patients with highest CYFRA 21-1 levels did not respond to EGFR-TKIs (disease progression was confirmed within 2 months), whereas the remaining four patients with lower serum CYFRA 21-1 levels had much longer PFS (Table 4). We observed a strong trend, in which high CYFRA 21-1 level patients with SCC harboring EGFR mutations had significantly worse responses to EGFR-TKI (median PFS, 1.0 months versus 7.0 months; p = 0.007).
In our data, longer PFS in the normal-CYFRA 21-1 group did not directly translate into longer OS compared with the high-CYFRA 21-1 group. The reason may be that the PPS, after EGFR-TKI failure, was almost equal between the high- and normal-CYFRA 21-1 groups (shown in Fig. 2C). This indicates that the serum CYFRA 21-1 level is not a surrogate marker for the efficacy of systemic cytotoxic chemotherapies other than EGFR-TKIs in NSCLC patients harboring EGFR mutations.
Our study has some limitations. First, we retrospectively screened 195 consecutive EGFR-mutated NSCLC patients treated with EGFR-TKIs, and 35 patients were excluded from our study because their serum CYFRA 21-1 was not examined at the initial diagnosis. This may have led to selection bias. Second, the data for OS were premature, with approximately 50% of the patients still alive, when reported. Third, it is uncertain whether the serum CYFRA 21-1 level actually represents a rich squamous component in each patient. At least, in the literature with which we are familiar, it has not been proven molecularly that serum circulating CYFRA 21-1 is associated with the existence and progression of lung SCC component. We demonstrated, as a whole, a significant trend in which the efficacy of EGFR-TKIs in patients harboring EGFR mutations depends on the initial serum CYFRA 21-1 level, which may represent the presence of a squamous-rich component in NSCLC.
In conclusion, CYFRA 21-1 is a predictive, not a prognostic, marker of PFS in NSCLC patients harboring EGFR mutations when treated with EGFR-TKIs. An NSCLC patient’s circulating CYFRA 21-1 level should be measured before EGFR-TKI treatment, and this level could be used as a clinically relevant marker in NSCLC patients with EGFR mutations. A prospective clinical trial is needed to test our present findings.
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Cytokeratin 19 fragment; Epidermal growth factor receptor-tyrosine kinase inhibitor; Non–small-cell lung cancer
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