通过超灵敏ctDNA检测增强MRD检出：来自真实世界临床数据的见解

There is a need for more sensitive circulating tumor DNA (ctDNA) tests that can achieve earlier detection of disease. The NeXT Personal Dx (NPDx) ctDNA MRD test utilizes a bespoke panel of up to ~1800 variants to achieve ultrasensitive detection down to ~1 part per million (PPM) of ctDNA with high analytical specificity (>99.9%). Here, we describe the real world performance from more than 5,000 patients profiled using NPDx. In this analysis we examined performance in a variety of real world testing situations and in the ultrasensitive range below 100PPM and 10 PPM, the latter of which has not been previously characterized. Overall, the median limit of detection (LOD) across all timepoints was 1.90 PPM (IQR:1.53-2.70 PPM) across 15 different cancer types. This performance was achieved with a relatively low median cell free DNA (cfDNA) input of 12ng (range 2-30 ng). 45.3% of tests were ctDNA positive overall. The NPDx tests performed well with challenging FFPE tumor samples (low tumor DIN <=3.4 or tumor fraction <=20%), achieving low LODs (median = 2.38 and 2.33 PPM, respectively). NPDx also achieved a median LOD of 3.78 PPM on low TMB tumors (<=0.98 mutation/MB). With ultra-low cfDNA inputs (<=5ng, 11.98% of cohort), NPDx achieved a median LOD of 2.31 PPM. Next we looked at performance in the ultrasensitive ranges below 100 PPM and 10 PPM. 40.2% of detections were in the ultrasensitive range below 100 PPM. Notably, 36.6% of all ultrasensitive detections were found to be <10 PPM (14.7% of detections overall), which aligned well with data from published NeXT Personal clinical studies (Lung - 42.5% in RWD, 40.5% in Black et. al 2025; Breast - 37.5% in RWD, 42.2% in Garcia-Murrillas et. al 2025). Detection rates <10 PPM were consistent across cfDNA input amounts down to 2 ng. For those patients who had sustained ctDNA positivity after a ctDNA negative timepoint, 49% had their first MRD+ detection <10 PPM. Two case studies demonstrate the clinical value of detections below 10 PPM in patient management. A 68-year-old female with squamous NSCLC underwent left upper lobectomy and MRD monitoring with NPDx. After three negative results, two low-level positives (6.2 and 9 PPM) prompted PET imaging that revealed a surgical-site recurrence. ctDNA rose to 80 PPM on the day of imaging, and radiation therapy led to ctDNA clearance. A 67-year-old female with colorectal cancer treated with FOLFOX + Avastin achieved ctDNA clearance and remained negative for over a year. Following a treatment break, low-level ctDNA positivity (1 and 3 PPM) preceded imaging-confirmed recurrence and chemotherapy was resumed. These cases highlight how NeXT Personal detections <10 PPM can guide earlier clinical interventions in real-world practice. These data demonstrate the consistent performance of NPDx in challenging real world conditions with limited inputs. The data also indicate the importance of detections below both 100 PPM and 10 PPM in the clinical setting.