Patient specific circulating tumor DNA fingerprints to monitor treatment response across multiple tumors

Abstract

Background: Circulating tumor DNA (ctDNA) offers a convenient way to monitor tumor progression and treatment response. Because tumor mutational profiles are highly variable from person to person, a fixed content panel may be insufficient to track treatment response in all patients. Methods: We design ctDNA fingerprint panels specific to individual patients which are based on whole exome sequencing and target to high frequency clonal population clusters in patients. We test the fingerprint panels in 313 patients who together have eight tumor types (colorectal, hepatocellular, gastric, breast, pancreatic, and esophageal carcinomas and lung cancer and cholangiocarcinoma) and exposed to multiple treatment methods (surgery, chemotherapy, radiotherapy, targeted-drug therapy, immunotherapy, and combinations of them). We also monitor drugrelated mutations in the patients using a pre-designed panel with eight hotspot genes. Results: 291 (93.0%) designed fingerprint panels harbor less than ten previously known tumor genes. We detected 7475 ctDNA mutations in 238 (76%) patients and 6196 (96.0%) of the mutations are detected in only one test. Both the level of ctDNA content fraction (CCF) and fold change of CCF (between the definitive and proceeding tests) are highly correlated with clinical outcomes (p-values 1.36e-6 for level and 5.64e-10 for fold change, Kruskal-Wallis test). The CCFs of PD patients are an order of magnitude higher than the CCFs of SD and OR patients (median/mean 2.22%/8.96% for SD, 0.18/0.21% for PD, and 0.31/0.54% for OR; pairwise p-values 7.8e-6 for SD ~ PD, 2.7e-4 for OR ~ PD, and 7.0e-3 for SD ~ OR, Wilcoxon rank sum test). The fold change of CCF distinguishes the patient groups even better, which increases for PD, remains stable for SD, and decreases for OR patients (p-values 0.002, ~ 1, and 0.0001 respectively, Wilcoxon signed-rank test). Eleven drug-related mutations are identified from nine out of the 313 patients. Conclusions: The ctDNA fingerprint method improves both specificity and sensitivity of monitoring treatment response across several tumor types. It can identify tumor relapse/recurrence potentially earlier than imaging-based diagnosis. When augmented with tumor hotspot genes, it can track acquired drug-related mutations in patients.

Current Landscape and Future Directions of Biomarkers for Immunotherapy in Hepatocellular Carcinoma

“…A study with a large cohort of 313 patients with eight tumor types including HCC who received various treatments, including immunotherapy, showed that either the absolute value of ctDNA content fraction at the time of clinical imaging or the dynamic changes in ctDNA were highly correlated with clinical outcome. 41 Importantly, changes in ctDNA were found to be consistent with corresponding imaging-based evaluations of the same patients. 41 A recent prospective phase II clinical trial was conducted to assess the feasibility of using ctDNA in five different groups of patients with advanced solid tumors treated with pembrolizumab.…”

“… 41 Importantly, changes in ctDNA were found to be consistent with corresponding imaging-based evaluations of the same patients. 41 A recent prospective phase II clinical trial was conducted to assess the feasibility of using ctDNA in five different groups of patients with advanced solid tumors treated with pembrolizumab. 42 The study showed that both baseline and changes in ctDNA levels from baseline were correlated with OS and PFS.…”

Biliary Tract Cancers: Treatment Updates and Future Directions in the Era of Precision Medicine and Immuno-Oncology

“…A threshold of ≥5, in addition, had prognostic value in the IHC group and trended toward significance in non-metastatic CCAs. Li et al proposed the concept of ctDNA fingerprinting in eight tumor types, including CCA (74). The authors began with whole exosome sequencing (WES) in patients before the treatment (surgery or systemic therapy or locoregional therapy) appropriate to the disease.…”

“…Li et al. proposed the concept of ctDNA fingerprinting in eight tumor types, including CCA ( 74 ). The authors began with whole exosome sequencing (WES) in patients before the treatment (surgery or systemic therapy or locoregional therapy) appropriate to the disease.…”

Diagnostic and Prognostic Value of Circulating Cell-Free DNA for Cholangiocarcinoma

“…As such, tumor-representative ctDNA has been proposed as an adequate alternative to solid tumor biopsies, with the ability to provide diagnostic value, predict responsiveness to treatment and patient survival [17,18]. The concordance between the mutations detected in the ctDNA and their corresponding primary tumors has been shown in biliary tract cancers [18][19][20]. In the ctDNA of CCA patients, therapeutically relevant genomic alterations of the BRAF, ERBB2, FGFR2, and IDH1 genes were also reported [21].…”