Unraveling the potential clinical utility of circulating tumor DNA detection in colorectal cancer-evaluation in a nationwide Danish cohort.

BACKGROUND: Increasingly, circulating tumor DNA (ctDNA) is proposed as a tool for minimal residual disease (MRD) assessment. Digital PCR (dPCR) offers low analysis costs and turnaround times of less than a day, making it ripe for clinical implementation. Here, we used tumor-informed dPCR for ctDNA detection in a large colorectal cancer (CRC) cohort to evaluate the potential for post-operative risk assessment and serial monitoring, and how the metastatic site may impact ctDNA detection. Additionally, we assessed how altering the ctDNA-calling algorithm could customize performance for different clinical settings. PATIENTS AND METHODS: Stage II-III CRC patients (N = 851) treated with a curative intent were recruited. Based on whole-exome sequencing on matched tumor and germline DNA, a mutational target was selected for dPCR analysis. Plasma samples (8 ml) were collected within 60 days after operation and-for a patient subset (n = 246)-every 3-4 months for up to 36 months. Single-target dPCR was used for ctDNA detection. RESULTS: Both post-operative and serial ctDNA detection were prognostic of recurrence [hazard ratio (HR) = 11.3, 95% confidence interval (CI) 7.8-16.4, P < 0.001; HR = 30.7, 95% CI 20.2-46.7, P < 0.001], with a cumulative ctDNA detection rate of 87% at the end of sample collection in recurrence patients. The ctDNA growth rate was prognostic of survival (HR = 2.6, 95% CI 1.5-4.4, P = 0.001). In recurrence patients, post-operative ctDNA detection was challenging for lung metastases (4/21 detected) and peritoneal metastases (2/10 detected). By modifying the cut-off for calling a sample ctDNA positive, we were able to adjust the sensitivity and specificity of our test for different clinical contexts. CONCLUSIONS: The presented results from 851 stage II-III CRC patients demonstrate that our personalized dPCR approach effectively detects MRD after operation and shows promise for serial ctDNA detection for recurrence surveillance. The ability to adjust sensitivity and specificity shows exciting potential to customize the ctDNA caller for specific clinical settings.

Strain Elastography Evaluation of Rectal Tumors: Inter- and Intraobserver Reproducibility.

PURPOSE: Elastography is a promising method for the identification and differentiation of malignant tissue in several organ systems. The primary aim was to evaluate the inter- and intraobserver reproducibility of endorectal strain elastography differentiation of adenomas and adenocarcinomas. The secondary aim was to compare the performance of strain elastography to endorectal ultrasonography (ERUS) examinations. MATERIALS AND METHODS: Consecutive inclusion of 95 ERUS examinations and 110 elastography video loops with ERUS overlay mode. Video loops were randomized and evaluated by eight observers on two separate occasions. Observers were blinded to all clinical information except the circumferential location of the tumor. A continuous visual analog scale (VAS) and a categorical scale (W-score) were used for elastography evaluation. ERUS loops were T-staged according to the TNM classification system. Histopathological evaluation of surgical resection specimen was used as the reference standard. RESULTS: Strain elastography visual evaluation yielded intraobserver variability from 0.86 to 0.97 and interobserver variability of 0.99. VAS strain elastography differentiation of adenomas (pT0) and adenocarcinomas (pT1 - 4) yielded sensitivity, specificity, accuracy, positive and negative predictive values of 0.94, 0.71, 0.89, 0.92 and 0.78, respectively. The corresponding ERUS values were 0.83, 0.64, 0.79, 0.88 and 0.54, respectively. CONCLUSION: Visual evaluation of elastography loops is highly reproducible in an offline setting with blinded observers, and correlates significantly with pT-stages. Strain elastography performs better than ERUS and might consequently improve staging.