Handbook of Targeted Cancer Therapy and Immunotherapy

97 p < 0.001) (9). In patients who received adjuvant chemotherapy, ctDNA positivity di rectly after completion was associated with worse recurrence-free survival (RFS) (HR 11; 95% CI 1.8–68; p = 0.001). Reinert et al. (10) used ultradeep multiplex polymerase chain reaction (PCR)-based NGS sequencing of ctDNA in their prospective multicenter cohort study of 130 patients with stage I–III CRC at selected time points, including before surgery, on post operative day 30, and once every 3 months for up to 3 years to evaluate its utility in detecting clinical recurrence and RFS. Using WES of tumor to identify 16 highly ranked somatic single-nucleotide variants and short indels, this group used a technology to construct personalized liquid biopsies for each patient. Preoperatively, 88.5% of patients had detectable ctDNA. Post-op ctDNA positivity was associated with seven times more likelihood of relapse (HR 7.2; 95% CI 2.7–19.0; p < 0.001), and ctDNA positivity after adjuvant chemotherapy was associated with 17 times more likelihood of relapse (HR 17.5; 95% CI 5.4–56.5; p < 0.001). Currently, although such assays are predictive of sur vival outcomes, prospective clinical trials are needed to determine if intervention with additional therapy based on ctDNA detection will improve these outcomes. Currently, the standard of care is to offer adjuvant chemotherapy after surgical resection for patients with stage III colon adenocarcinoma and high-risk stage II disease (T4, inadequate lymph node harvest [ ≤ 12], tumors complicated by obstruction or perforation, poorly differenti ated or vascular/perineural or lymphatic invasion) (11). There are no validated biomarkers in standard clinical practice for identification of MRD after surgical resection in colon cancer; how ever, ongoing prospective studies incorporating ctDNA analyses are underway to inform clini cal decision-making with regard to adjuvant therapy. In the prospective phase II/III COBRA trial (NCT04068103), patients with stage IIA disease without high-risk features after surgical resection who are deemed candidates for observation and no systemic chemotherapy will be randomized 1:1 to observation or prospective testing of ctDNA for both colon cancer–relevant genetic mutations and methylation profiling (12). Those in the ctDNA arm with detectable ctDNA will be treated for 6 months with adjuvant 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX)/capecitabine, oxaliplatin (CAPOX) chemotherapy. Primary endpoints of this study include the clearance of ctDNA with use of adjuvant systemic therapy and RFS in patients with detected ctDNA treated with or without sys temic therapy.

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