Utility of tumor-informed circulating tumor DNA in the clinical management of gastrointestinal malignancies

Abstract

Background: Gastrointestinal (GI) malignancies represent a heterogeneous group of diseases. Traditional tumor markers, though part of standard-of-care, lack sensitivity and specificity. Tumor-informed circulating tumor DNA (ctDNA) assay-based molecular residual disease assessment as well as recurrence and treatment response monitoring can serve as a robust tool in patients with wide range of GI malignancies and ethnicities.Methods: A personalized, tumor-informed multiplex PCR-NGS assay (Signatera TM ) was used for the detection and quantification of ctDNA in 258 plasma samples from 198 patients with GI cancers at two institutions. Serial time-points were collected on a subset of patients (n=64) to monitor their ctDNA levels in response to treatment. Chi-square test was used to compare ctDNA-positivity rates in different cohorts. Results:The study included stage I-IV patients with a median age of 62 years (61% females and 49% ethnic minorities); 92% had surgical resection, 83% received systemic treatment. ctDNA-positivity was significantly associated with advanced stage (P=0.004), and presence/extent of metastases (P<0.00003). Serial time-point analysis showed that 22% (14/64) patients cleared ctDNA following treatment. ctDNA was detected in all patients who recurred (4/4; 100% sensitivity).Conclusions: Serial monitoring of ctDNA using a tumor-informed ctDNA assay can be prognostic and predictive in advanced GI malignancies in adjuvant setting.

Circulating Tumor DNA is Unreliable to Detect Somatic Gene Alterations in Gastrointestinal Peritoneal Carcinomatosis

“…Recently, tumor-informed ctDNA assay (Signatera TM ) has been favored to detect MRD and assess treatment response due to its higher sensitivity to detect tumor-specific gene mutations. 10 A recent report published by our group on tumor-informed ctDNA assays in GI cancers showed that ctDNA was detected in only 53% of patients with PC. 10 …”

“…The amount of ctDNA detected is influenced by disease burden, location of disease, treatment of disease, and tumor vascularization. 2 , 7 – 10 Peritoneal carcinomatosis (PC), an aggressive form of metastatic spread in GI cancers, with diffuse involvement of the peritoneal lining, represents a distinct form of metastatic disease as these tumors tend to be poorly vascularized, 11 and have less communication with systemic circulation due to the peritoneal-plasma barrier. 12 – 14 Despite the biologic differences of PC from other metastases, most ctDNA studies combine the metastatic sites.…”

Circulating Exosome Cargoes Contain Functionally Diverse Cancer Biomarkers: From Biogenesis and Function to Purification and Potential Translational Utility

“…[ 49 , 50 , 51 ]. Screening panels for ctDNA have already been commercialized (e.g., Signatera tumor-informed assay [ 52 ]) for molecular monitoring of residual disease, response to therapeutic treatment, and recurrence. Considering the value of ctDNA for the detection of cancer, high-throughput targeted next-generation sequencing panels have been developed for clinical screening of ctDNA from circulating genomic DNA (i.e., Illumina TruSight cancer panel) [ 53 , 54 ].…”

ASO Author Reflections: Challenges of Circulating Tumor DNA in the Management of Gastrointestinal Peritoneal Carcinomatosis

“…A recent study of a tumorinformed assay (Signatera TM , Natera, Austin, TX) published by our group showed that ctDNA was detected in only 53% of the patients with PC. 8 Although advances to improve the sensitivity of ctDNA detection such as DNA methylation markers may improve detection, the fundamental anatomic and pathologic differences in PC will continue to be a challenge. These challenges offer a rich opportunity to explore other liquid biopsy approaches, such as exosome-based liquid biopsy, that may be more reliable than ctDNA in PC.…”

“…A recent study of a tumor-informed assay (Signatera TM , Natera, Austin, TX) published by our group showed that ctDNA was detected in only 53% of the patients with PC. 8 …”