Quantification of Cell-Free mSHOX2 Plasma DNA for Therapy Monitoring in Advanced Stage Non-Small Cell (NSCLC) and Small-Cell Lung Cancer (SCLC) Patients

Abstract

PurposeMost patients suffering from advanced lung cancer die within a few months. To exploit new therapy regimens we need better methods for the assessment of a therapy response.Material and MethodsIn a pilot study we prospectively enrolled 36 patients with advanced NSCLC and SCLC (34 stage IV, 2 stage IIIB) of whom 34 received standard platinum-based chemo/radiotherapy and two were treated with a tyrosine kinase inhibitor. We measured the levels of extracellular methylated SHOX2 DNA (mSHOX2) in plasma before and during therapy until re-staging. The mSHOX2 analysis was blinded with respect to the clinical data making it an observational study.ResultsAccording to the re-staging of 31 first-line patients, 19 patients were classified as non-responders while 12 patients were in the responder group. We observed a tight correlation between radiological data and the change of plasma mSHOX2 level as the equivalent for a therapy response. A ROC analysis showed a high discriminatory power for both patient groups already one week after therapy start (AUC 0.844). Additionally, a Kaplan-Meier and Cox Proportional Hazards analyses revealed a strong relationship between survival and plasma mSHOX2 value p≤0.001 (hazard ratio 11.08) providing some evidence for mSHOX2 also being a predictive marker.ConclusionThe longitudinal measurement of extracellular plasma mSHOX2 DNA yields information about the response to cytotoxic treatment and allows an early assessment of treatment response for lung cancer patients. If confirmed in a larger study this would be a valuable tool for selecting and guiding a cytotoxic treatment.

WT1 Expression in Circulating RNA as a Minimal Residual Disease Marker for AML Patients After Stem-Cell Transplantation

“…We assume that even extramedullary leukemic cells may provide nucleic acids that can be detected in the analysis of CRNA. Data from studies of solid tumors also support the concept that plasma/serum samples have a tendency to be enriched with tumor-specific CRNA [33][34][35]. This enrichment is perhaps due to the high turnover of the tumor cells, compared with nonmalignant cells.…”

Methylation analyses in liquid biopsy

“…Wang and colleagues reported an elevated level of adenomatous polyposis coli (APC) and RASSF1A promoter methylation in ctDNA within 24 h after cisplatin-based therapy, consistent with chemotherapyinduced cell death (52). Methylation of SHOX2, RASSF1A and RARB2 has shown potential to monitor disease recurrence after surgery and chemotherapy (49,53). The value of methylated ctDNA to predict response to therapy has also been investigated.…”

Current status and future perspectives of circulating cell-free DNA methylation in clinical diagnostics

“…release of tumor DNA from responding tumor cells. Accordingly, a proof-of-concept study showed that the longitudinal measurement of SHOX2 ccfDNA methylation allowed for the assessment of the response to cytotoxic treatment of patients with advanced lung cancers [22].…”