Handbook of Targeted Cancer Therapy and Immunotherapy

101 predictor of disease recurrence despite adjuvant chemotherapy (18). In such patients, though there is a prognostic implication, there is currently no defined clinical role for the use of ctDNA to inform further cancer-directed therapy after completion of total neoadjuvant or adjuvant therapy, warranting its incorporation into future neoadjuvant and adjuvant therapy trials for clinical validation. Longitudinal monitoring of relative variant allele frequencies of specific genes is also being used to inform therapy. For instance, acquired RAS and EGFR mutations monitored serially in patients after progression on anti-epidermal growth factor receptor (EGFR) therapies have shown exponential decay in these mutations, which can lead to rechallenge strategies of anti-EGFR therapies (19). Pancreatic Cancer In pancreatic cancer, ctDNA has been shown to have diagnostic potential in differentiating pan creatic ductal adenocarcinoma (PDAC) from other pancreatic neoplasms and benign pancre atic conditions such as chronic pancreatitis (20,21). In a prospective study designed to evaluate the diagnostic accuracy of cfDNA in pancreaticobiliary patients using NGS of a 54-gene panel in both tumor and plasma-derived cfDNA, 13 of 26 (50%) patients were found to have 100% concordance between tissue and cfDNA, with an additional 12% showing partial concordance. Overall, 90.3% of mutations detected in tissue samples were also detected in cfDNA. Diagnostic accuracy of cfDNA was noted to be 97.7% with 92.3% sensitivity and 100% specificity for a panel of five genes (22). Subsequent studies have also demonstrated detection of ctDNA at diagnosis and postoperatively to be an indicator for worse overall survival. In patients who had undergone curative pancreatoduodenectomy, detection of KRAS mutations in ctDNA was associated with significantly worse median overall survival compared to those without detectable ctDNA (13.6 vs. 27.6 months, respectively). Multiple other studies have shown detection of postoperative ctDNA to be correlated with shorter DFS (21). In a study of 93 patients with resectable, borderline re sectable, and unresectable disease each having a median of three ctDNA assessments, ctDNA positivity occurred at a rate of 49.5%. RFS correlated strongly with postoperative ctDNA positiv ity (HR 8.0; p = 1.6e-6) (23). Adjuvant therapy trials with use of ctDNA to potentially escalate or

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