Utility of serum CYFRA 21-1 as a prognostic biomarker in ALK-positive non-small cell lung cancer treated with ALK-TKIs: a retrospective cohort study

Introduction

Background

Lung cancer is the leading cause of cancer-related death (1). Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases (2). Anaplastic lymphoma kinase (ALK)-positive NSCLC is a common driver of mutation-positive lung cancer resulting from genetic alterations in the ALK gene, often leading to the production of the EML4-ALK fusion protein, which drives cancer cell growth. This form of NSCLC is more frequently diagnosed in younger non-smokers and is commonly associated with adenocarcinoma (3). Globally, ALK-positive NSCLC accounts for approximately 5% of all NSCLCs (4).

Compared with systemic chemotherapy, treatment with targeted ALK tyrosine kinase inhibitors (ALK-TKIs) significantly enhances survival and prognosis (5). The median overall survival (OS) exceeds 6 years in patients with stage IV NSCLC after treatment with ALK-TKIs (6). Several ALK-TKIs, including alectinib, brigatinib, and lorlatinib, were initially introduced for treating progressive or recurrent ALK-positive NSCLC (7). Subsequent treatments, including the potential use of other ALK-TKIs, chemotherapy, or chemoimmunotherapy, are recommended when disease progression occurs during the first ALK-TKI therapy. Developing treatment strategies to address resistance mechanisms to molecularly targeted agents is crucial in driver mutation-positive NSCLC. Notably, previous studies on epidermal growth factor receptor (EGFR)-positive NSCLC have revealed that activation of bypass pathways and tumor heterogeneity because of concurrent mutations correlated with poorer outcomes in EGFR-TKI monotherapy (8-10). Similar mechanisms have been reported in ALK-positive NSCLC (11,12). However, as confirming these resistance mechanisms in routine clinical practice is often challenging, predicting the prognosis of driver mutation-positive NSCLC and the efficacy of TKIs using easily measurable parameters is necessary.

Rationale and knowledge gap

Tumor markers, such as carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1 and CYFRA), have been investigated as prognostic or predictive factors for chemotherapy outcomes (13). Moreover, elevated CYFRA levels have been associated with poorer chemotherapy outcomes (14). CEA and CYFRA are useful predictors of chemotherapy and immunotherapy outcomes (14-16).

Additionally, serum CYFRA has been identified as a prognostic factor for EGFR-positive NSCLC (17,18). In ALK-positive NSCLC, high CYFRA levels have been reported to correlate with liver metastasis and multi-organ metastases (19). However, its utility as a predictive or prognostic factor for the efficacy of ALK-TKIs has not been reported to date, and its role in ALK-positive NSCLC remains unclear.

Objective

This study aimed to retrospectively evaluate the utility of serum tumor markers CEA and CYFRA as predictive biomarkers for clinical outcomes in patients with advanced, recurrent ALK-positive NSCLC treated with ALK-TKIs. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1180/rc).

Methods

Patients

This study enrolled 197 patients. The eligibility criteria were as follows: (I) patients who started treatment with the first ALK-TKI as systemic therapy between July 1, 2014 and December 31, 2022, at 13 facilities in Japan; (II) patients with measurable lesions based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and (III) patients diagnosed with advanced or recurrent NSCLC with ALK fusion genes. ALK fusion genes were detected using immunohistochemistry, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, or next-generation sequencing. Patients with pretreatment serum CEA data were included in the CEA cohort, and those with pretreatment serum CYFRA data were included in the CYFRA cohort. Patients with pretreatment serum CEA and CYFRA data were included in the respective cohorts, while those with missing data were excluded. Serum levels were measured using commercially available immunoassays per standard protocols at each institution. All participating centers were informed and agreed on the study. The study was conducted in accordance with the Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of Kyoto Prefectural University of Medicine for all centers under a centralized collective review (No. ERB-C-3010). Informed consent for the use of personal medical data was obtained through an opt-out method, as outlined in the disclosure document.

Data collection and follow-up

Clinical data, including age, sex, Eastern Cooperative Oncology Group performance status (ECOG-PS), smoking history, histology type, ALK rearrangement status, pretreatment serum CYFRA and CEA levels, progression-free survival (PFS) and maximal tumor reduction (MTR) rate of the first ALK-TKI, and OS of the enrolled patients were obtained from medical records. Follow-up was performed through medical record reviews. The first ALK-TKI was defined as the initial ALK-TKI administered among those given to the enrolled patients. PFS of the first ALK-TKI (hereafter referred to as PFS) was defined as the period between the initiation of the first ALK-TKI treatment to disease progression, treatment discontinuation, or death. OS was defined as the period between the first-line treatment initiation (including ALK-TKIs and chemotherapy) and death. PFS and OS were censored for final survival analysis in patients whose disease did not progress or who survived.

Evaluation of treatment efficacy and statistical analysis

The primary endpoint was PFS. The secondary endpoints were OS and the objective response rate (ORR) of the first ALK-TKI. Patients were classified into two groups based on their serum CYFRA level [normal (≤3.5 ng/mL) or elevated (>3.5 ng/mL)]. The cut-off values of serum CYFRA and CEA [normal (≤5 ng/mL) or elevated (>5 ng/mL)] were based on the upper limit of the normal range and those reported in previous studies (17,20-22). To compare factors between groups, Fisher’s exact, Chi-squared, and Mann-Whitney U tests were used. PFS and OS were calculated using the Kaplan-Meier method, and the differences were verified using the log-rank test. Student’s t-test was used to compare age (<75 or ≥75 years), sex, ECOG-PS (0–1 or 2–4), smoking status (never or past/current), histological status, clinical stage (III/IV or recurrence), the regimen of the first ALK-TKI, existence of metastatic sites (including brain, liver, and bone), and serum CEA and CYFRA levels (normal or elevated). For survival analyses, we employed a Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The covariates used in the univariate and multivariate Cox regression analyses were selected based on previous reports, including age (≥75 years), sex, ECOG-PS (PS ≥2), stage (III/IV or recurrence), presence of brain metastasis, and serum CYFRA level (normal or elevated). Schoenfeld residual tests were performed to assess the Cox proportional hazards. Tumor response was evaluated using RECIST version 1.1. All statistical tests were two-sided, and statistical significance was set at P<0.05. All statistical analyses were performed using EZR statistical software, version 1.54.

Results

Patient characteristics

Table 1 shows the characteristics of the 197 enrolled patients. Five of these patients were excluded owing to missing data on serum CEA level, leaving 192 patients in the CEA cohort. Moreover, 45 patients were excluded for missing data on serum CYFRA level, resulting in 152 patients in the CYFRA cohort. Figure S1 presents the CONSORT diagram of this study.

In the CEA cohort, the median age was 62.0 years. Of these patients, 53.1% were men, 93.8% had ECOG-PS of 0/1, 84.9%/15.1% were in clinical stage III, IVA, or IVB/recurrence, 36.5% were current or former smokers, and 98.4% had histologically confirmed adenocarcinoma. No association was observed between patients with normal and elevated serum CEA levels, except for bone metastasis status (Table S1).

The median age of all patients in the CYFRA cohort was 60.8 years. Of these patients, 54.6% were men, 94.7% had ECOG-PS of 0/1, 86.2%/13.8% were in clinical stage III, IVA, or IVB/recurrence, 36.8% were current or former smokers, and 99.3% had histologically confirmed adenocarcinoma. No association was observed between patients with normal and elevated serum CYFRA levels, except for brain metastasis status (Table S2).

Treatment efficacy of the first ALK-TKI

Of the 197 patients, 124 experienced disease progression, and 73 either died or missed the cut-off date. The median follow-up durations of all enrolled patients, those in the CEA cohort, and those in the CYFRA cohort were 34.1 months (95% CI: 30.5–40.0), 33.8 months (95% CI: 30.4–40.0), and 34.3 months (95% CI: 29.1–43.6), respectively.

The ORR for patients with normal serum CEA levels (normal CEA group, n=84) was 79.8% (95% CI: 69.6–87.7%) and that of patients with elevated serum CEA levels (high CEA group, n=108) was 78.7% (95% CI: 69.8–86.0%), with no significant difference between the two groups (P>0.99).

The ORR for patients with normal serum CYFRA (normal CYFRA group, n=91) was 85.7% (95% CI: 76.8–92.2%). In contrast, the ORR of patients with elevated serum CYFRA (high CYFRA group, n=61) was 70.5% (95% CI: 57.4–81.5%). The high CYFRA group had a significantly lower ORR than did the normal CYFRA group (P=0.03). According to the RECIST criteria, the best responses in the normal CYFRA group were as follows: complete response (CR) 30.77%, partial response (PR) 54.95%, stable disease (SD) 8.79%, progressive disease (PD) 3.30%, and not evaluable (NE) 2.20%. In contrast, the high CYFRA group showed CR 11.48%, PR 59.02%, SD 8.20%, PD 14.75%, and NE 6.56% (Figure 1).

Figure 1 ORR of the first ALK-TKI, stratified by serum CEA and CYFRA levels. *, P<0.05; ns, not statistically significant. ALK, anaplastic lymphoma kinase; CEA, carcinoembryonic antigen; CR, complete response; CYFRA, cytokeratin 19 fragment; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor.

The difference observed in median PFS between the normal CEA group (25.6 months, 95% CI: 14.2–35.0) and high CEA group (26.5 months, 95% CI: 18.6–54.2) was insignificant (HR: 0.85, 95% CI: 0.59–1.24, log-rank test P=0.41). In contrast, the median PFS of the high CYFRA group was 9.27 months (95% CI: 7.7–23.1), whereas that of the normal CYFRA group was 42.0 months (95% CI: 26.5–61.3) (Figure 2A). Similar trend was observed in OS analysis (Figure 2B), with detailed analysis provided in the “Prognosis” section. These findings were consistent in subgroup analyses for patients treated with alectinib or brigatinib, but not for those treated with crizotinib as the initial TKI (Figure S2A for PFS, Figure S2B for OS). Therefore, further analyses were conducted within the CYFRA cohort. The univariate analysis showed that the high CYFRA group had a significantly shorter PFS (HR: 2.35, 95% CI: 1.54–3.58, log-rank test P<0.001) than the normal CYFRA group (Table 2), which was confirmed in the multivariate analysis.

Figure 2 Kaplan-Meier curves for patients with NSCLC, based on the serum CEA and CYFRA levels. (A) PFS with the first ALK-TKI (PFS); (B) OS. ALK, anaplastic lymphoma kinase; CEA, carcinoembryonic antigen; CI, confidence interval; CYFRA, cytokeratin 19 fragment; HR, hazard ratio; NA, not available; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

The median MTR rate of the high CYFRA group was −55.4% (interquartile range, −76.2% to −33.2%), which was significantly lower than that of the normal CYFRA group (−74.8%, interquartile range, −100% to −48.0%) (P=0.002). Figure 3 shows the waterfall and scatter plots.

Figure 3 Waterfall plot (A) and scatter plot (B) showing the MTR rate of the first ALK-TKI. **, P<0.01. ALK, anaplastic lymphoma kinase; CYFRA, cytokeratin 19 fragment; MTR, maximal tumor reduction; TKI, tyrosine kinase inhibitor.

Then, defining CYFRA >10 ng/mL as CYFRA super-high, we analyzed PFS across three groups: normal CYFRA group (≤3.5 ng/mL), high CYFRA group (>3.5–10 ng/mL, except for super high), and super high CYFRA group (>10 ng/mL). The super-high CYFRA group had a significantly shorter PFS than did the other two groups (Figure S3).

Status after discontinuation of first ALK-TKI

In the normal CYFRA group, 29 (31.9%) patients completely responded to the first ALK-TKI with 100% MTR, and only 3 (3.3%) did not respond to the treatment. Thirty-five (38.5%) patients continued with the same ALK-TKI regimen beyond the data cut-off point. Among those who discontinued the first ALK-TKI, 29 (31.9%) patients switched to another ALK-TKI, and 15 (16.5%) patients switched to other chemotherapies, allowing them to continue treatment. The number of patients who could not continue treatment and died was 9 (9.9%). In contrast, only 11 (18.0%) patients in the high CYFRA group could continue the first ALK-TKI treatment, and 13 (21.3%) patients could not initiate subsequent treatment.

Prognosis

The median OS in the high CYFRA group [28.8 months, 95% CI: 20.1 months–not available (NA)] was significantly worse than that in the normal CYFRA group (143.3 months, 95% CI: 94.8 months–NA) (Figure 2B). Univariate analysis identified high serum CYFRA as a poor prognostic factor, with an HR of 3.28 (95% CI: 1.89–5.70, log-rank test P<0.001). Multivariate analysis confirmed these results (Table 3).

Safety profile

CTCAE grade 3 or higher adverse events (AEs) occurred during administration of the first ALK-TKI in 8 out of 91 patients (8.8%, 95% CI: 3.9–16.6%) in the normal CYFRA group and 13 out of 61 patients (21.3%, 95% CI: 12.0–33.7%) in the high CYFRA group. The first ALK-TKI was discontinued because AEs occurred in 6 (6.6%, 95% CI: 2.5–13.8%) and 8 patients (13.1%, 95% CI: 5.8–24.2%) in the normal CYFRA and high CYFRA groups, respectively. No treatment-related deaths occurred in either group. As the incidence of grade 3 or higher AEs was higher in the high CYFRA group, we excluded these patients and compared PFS and OS between the normal CYFRA group without AE (n=83) and the high CYFRA group without AE (n=48). The median PFS and OS were significantly shorter in the high CYFRA group without AE, confirming the results observed in the overall population (Figure S4).

CEA and CYFRA

Furthermore, when patients were divided into four groups based on serum CEA and CYFRA levels, no significant differences in PFS and OS were observed between groups 1 (CEA normal/CYFRA normal) and 2 (CEA high/CYFRA normal), and between groups 3 (CEA normal/CYFRA high) and 4 (CEA high/CYFRA high) (Figure 4).

Figure 4 Kaplan-Meier curves for (A) PFS with the first ALK-TKI and (B) OS in patients with NSCLC based on CYFRA and CEA levels. *, P<0.05; **, P<0.01; ns, not statistically significant. Group 1: CEA normal/CYFRA normal; group 2: CEA high/CYFRA normal; group 3: CEA normal/CYFRA high; group 4: CEA high/CYFRA high. ALK, anaplastic lymphoma kinase; CEA, carcinoembryonic antigen; CI, confidence interval; CYFRA, cytokeratin 19 fragment; HR, hazard ratio; NA, not available; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

Discussion

Key findings

Recent clinical developments in molecular-targeted therapies have led to significant breakthroughs in treating advanced NSCLC. However, developing reliable predictive biomarkers for these therapies remains a critical challenge. Serum CEA and CYFRA are commonly used as tumor markers in NSCLC treatment. In this study, we investigated the relationship between baseline serum CEA and CYFRA levels and the therapeutic effects of ALK-TKIs, demonstrating that CYFRA could serve as a clinical biomarker for predicting the therapeutic efficacy of ALK-TKI treatment and prognosis in ALK-positive NSCLC.

Strengths and limitations

To our knowledge, this study is the first to demonstrate that serum CYFRA, when using the upper limit of normal as a cut-off, is a negative predictor of prognosis in ALK-positive NSCLC in a large cohort of over 100 cases.

This study has some limitations. First, this was a retrospective study. Second, 45 cases in which CYFRA was not measured were excluded from this study, which could introduce bias. Third, the analysis was conducted only on a Japanese population; therefore, differences across ethnicities remain unclear. Fourth, while CYFRA has been suggested as a prognostic factor for ALK-positive lung cancer, the results of this study do not allow us to determine its predictive value for the therapeutic effect of ALK-TKIs.

Comparison with similar researches

CEA inhibits anoikis in tumor cells, blocks cell differentiation, and accelerates cellular transformation via apoptosis-related proteins such as Myc and Bcl-2 (23,24). In EGFR-positive and ALK-positive NSCLC, activation of EGFR and ALK signaling leads to activation of the PI3K/AKT and JAK/STAT pathways, which promote cell survival and inhibit apoptosis (25-27). Notably, activation of these pathways has been associated with increased expression of CEA in EGFR-positive NSCLC (25), suggesting that a comparable mechanism may also operate in ALK-positive NSCLC. Therefore, high serum CEA levels may suggest high ALK signaling activity, and tumor components with high CEA expression may respond well to ALK-TKI treatment. Conversely, the therapeutic effect of ALK-TKIs is poor in ALK-positive squamous cell carcinoma. CYFRA is more broadly expressed in poorly differentiated squamous cell carcinomas (28), and higher levels of CYFRA indicate the presence of a squamous cell cancer component (29). Therefore, tumors with a high squamous cell component, reflected by high CYFRA levels, may have inadequate treatment effects (Figure 5). Particularly, tumors with super-high CYFRA levels showed early disease progression, confirming this observation. Furthermore, we attributed the early decline observed in the Kaplan-Meier curve of the high CYFRA group to this population.

Figure 5 Differences between CEA-high and CYFRA-high ALK-positive NSCLC. Created in BioRender. Sawada, R. [2025] https://BioRender.com/fjqpeod. ALK, anaplastic lymphoma kinase; CEA, carcinoembryonic antigen; CYFRA, cytokeratin 19 fragment; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

The incidence of brain metastases was significantly higher in the high CYFRA group. To minimize bias from the treatment selectivity and adverse effects, we performed analyses excluding cases treated with crizotinib, which has poor efficacy against brain metastases (30). Similarly, we also excluded cases with grade 3 or higher AEs from ALK-TKIs to minimize bias related to these events. These analyses yielded poor prognostic outcomes in the high CYFRA level group, consistent with the results observed in the overall population.

Explanations of findings

This study analyzed MTR rates of the first ALK-TKI regimen based on CYFRA levels and found significantly lower MTR rates in the high CYFRA group. This observation suggests that CYFRA expression may predict the proportion of ALK-TKI-sensitive cells in ALK-positive NSCLC. In other words, high CYFRA levels could serve as an alternative marker for tumor heterogeneity in ALK-positive NSCLC and may be useful for predicting early drug tolerance.

Implications and actions needed

In routine clinical practice, measuring CYFRA as a tumor marker has limited significance in lung adenocarcinoma with driver gene mutations. However, the results of this study highlight the importance of pretreatment CYFRA measurements in predicting the clinical outcomes for ALK-positive NSCLC treated with ALK-TKIs. Prospective studies and further research are needed to confirm whether serum CYFRA levels are predictive factors for the therapeutic effect of ALK-TKIs in ALK-positive NSCLC and strengthen the findings of this study.

Conclusions

In conclusion, our study demonstrates that high serum CYFRA level (>3.5 ng/mL) is associated with poor efficacy of ALK-TKIs and affects OS in patients with ALK-positive NSCLC, indicating its potential utility as a prognostic biomarker. CYFRA elevation may reflect underlying tumor heterogeneity, which has been linked to decreased efficacy of ALK-TKI therapy. Therefore, assessing CYFRA levels prior to treatment could help identify patients at higher risk of unfavorable outcomes and support more individualized treatment planning. Prospective studies are warranted to verify and further establish the prognostic value of CYFRA in this setting.

Acknowledgments

We would like to thank the Editage (www.editage.jp) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1180/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1180/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1180/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1180/coif). Tadaaki Yamada serves as an unpaid editorial board member of Translational Lung Cancer Research from October 2023 to September 2025. Tadaaki Yamada reports receiving grants from Ono Pharmaceutical Co. Ltd., Janssen Pharmaceuticals Inc., and Takeda Pharmaceutical Company Limited; speaking and lecture fees from Eli Lilly and Chugai Pharmaceutical Co. Ltd., outside the submitted work. S.W. reports receiving speaking and lecture fees from Chugai Pharmaceutical Co. Ltd. T.K. reports receiving grants from Chugai Pharmaceutical Co. Ltd., outside the submitted work. K.T. reports receiving grants from Taiho Pharmaceutical Co. Ltd.; speaking and lecture fees from Chugai Pharmaceutical, Merck Sharp and Dohme Pharmaceuticals, Ono Pharmaceutical Co. Ltd., Daiichi Sankyo Inc., and AstraZeneca, outside the submitted work. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of Kyoto Prefectural University of Medicine for all centers under a centralized collective review (No. ERB-C-3010). Informed consent for the use of personal medical data was obtained through an opt-out method, as outlined in the disclosure document.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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