Nucleosomes and CYFRA 21-1 indicate tumor response after one cycle of chemotherapy in recurrent non-small cell lung cancer

Summary

The increasing panel of systemic therapies enables the individual management of cancer patients, even in advanced stages. However, diagnostic tools indicating early the efficacy of therapy are still needed. In prospectively collected sera of 161 patients with recurrent non-small cell lung cancer (NSCLC) receiving second-line chemotherapy, the courses of nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and progastrin-releasing peptide (ProGRP) were investigated and correlated with therapy response. At high specificity for detection of progressive disease, most sensitive biomarkers were identified and included in a combination model. High levels and insufficient decreases of nucleosomes and CYFRA 21-1 during the first cycle of therapy indicated poor outcome. Combination of nucleosome concentrations at day 8 and CYFRA 21-1 before start of the second cycle enabled the early detection of progressive disease with a sensitivity of 34.4% at 95% specificity (AUC 0.79) prior to imaging techniques. When cutoffs were fixed at the 90th percentile of responding patients, the combination model achieved sensitivities of 19% at 100% specificity and of 52% at 88% specificity. Thus, nucleosomes and CYFRA 21-1 showed to be valuable for the individual management of patients with recurrent NSCLC.

Introduction

Lung cancer is one of the most life threatening cancer diseases and shows high incidences in both men and women worldwide [1]. About 80% of lung cancer patients suffer from non-small cell subtype which can be removed by surgery if detected in early stages. However, more than 80% of the patients are only diagnosed at time of advanced stages when therapeutic options are restricted to systemic chemo- and radiotherapy [1], [2]. Although these therapies often have limited success, recent developments in drug research offer a variety of therapeutic possibilities even for the second and third line treatment [3], [4], [5], [6], [7], [8]. On the other side, diagnostic tools are challenged to indicate as early as possible whether patients will benefit from a specific therapy or not in order to optimize the individual management of the disease. The early modification of the treatment strategy would save time and costs and avoid unnecessary side effects. Recently, various techniques such as positron-emission tomography (PET), alone and in combination with computed tomography (PET-CT; [9], [10], [11], [12], [13]) as well as algorithms of biomarker kinetics [14], [15], [16] have demonstrated their power to early indicate insufficient response to therapy sensitively and specifically. Because both approaches mirror the cancer activity and metabolism, they may have advantages in comparison with imaging techniques which only monitor macroscopic changes of the tumor mass. Those imaging techniques are further limited as they cannot take into account the heterogeneity of the tumor tissue containing active, silent, apoptotic and necrotic parts [10], [11], [12], [13], [14], [15], [16], [17]. In addition, changes of tumor size often are detected only after several cycles of chemotherapy, while biochemical tumor response may already be estimated by biomarkers during the initial treatment phase [12], [15], [17].

In non-small cell lung cancer (NSCLC), carcinoembryonic antigen (CEA) and cytokeratin-19 fragments (CYFRA 21-1) proved to be sensitive and valuable biomarkers for estimation of diagnosis, prognosis and therapy monitoring [14], [15], [16], [18], [19], [20], [21], [22], [23]. In small cell lung cancer (SCLC), neuron-specific enolase (NSE) and progastrin-releasing peptide (ProGRP) revealed high diagnostic sensitivity and specificity [22], [23], [24], [25], [26]. Very recently we could demonstrate in a study with 311 NSCLC patients receiving first-line chemotherapy that the combination of nucleosomes and CYFRA 21-1 was able to discriminate between those patients responsive and non-responsive to first-line chemotherapy [14], [15]. Based on these promising results, we analyzed in the present study patients with recurrent NSCLC during second-line chemotherapy using the same setting of biomarkers to validate the model of the recent study. If the earlier results were confirmed in this independent and less homogeneous patient group, this would be an important step to generalize the model for all patients with advanced NSCLC and recommend it for external validation studies.