Reply to Fujimoto et al.: The Need for a CYFRA 21-1 Cutoff Value to Predict Clinical Progression of IPF in Clinical Practice

From the Authors:

We are grateful to Fujimoto and colleagues for their interest in our work (1). As they note, there remains an unmet need in clinical practice for biomarkers to aid in the diagnosis, prognostic assessment, and treatment of patients with idiopathic pulmonary fibrosis (IPF) and other forms of interstitial lung disease. We believe that CYFRA 21–1 has the potential to fulfill some of these roles (1, 2).

In interpreting our work, it is important to note that the assay used for measuring CYFRA 21–1 was a commercially available research ELISA and not a GLP standard bioanalytical assay. For this reason, we observed batch-by-batch variation in readings; this can be appreciated when comparing the median values obtained in our discovery and validation cohorts. Although within-batch comparison of CYFRA 21–1 values is valid, between-batch comparisons cannot easily be made. Thus, there is limited utility in providing absolute thresholds of CYFRA 21–1 for distinguishing either IPF from healthy controls or stable from progressive disease.

However, as suggested by Fujimoto and colleagues, receiver operator curve analysis gives some indication of the potential biomarker value of CYFRA 21–1. The c-statistic for distinguishing cases of IPF from healthy control subjects was 0.81 (95% confidence interval [CI], 0.74–0.88; P < 0.0001) in our discovery cohort and 0.77 (95% CI, 0.71–0.84; P < 0.0001) in our validation cohort. The capacity for CYFRA 21–1 to distinguish progressive from stable cases of IPF was 0.70 (95% CI, 0.61–0.79; P < 0.0001) in the discovery cohort and 0.65 (95% CI, 0.59–0.71; P < 0.0001) in the validation cohort.

Several important steps are required before recently reported biomarkers of IPF progression (1, 3, 4) and treatment response can be effectively used in the clinic (5). One of these is assay development and validation; to this end, we are pleased to note that CYFRA 21–1 is now available as a high-sensitivity, high-throughput, clinic-ready assay (Roche Diagnostics). Another important step is the replication of our findings in separate IPF populations and the rigorous defining of clinically useable thresholds. To this end, we hope that ongoing biomarker discovery studies will build on our findings and allow the integration of molecular data into routine practice to improve the care of patients with IPF.