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PROSPECTIVE STUDY OF PERIOPERATIVE CIRCULATING TUMOR DNA DYNAMICS IN PATIENTS UNDERGOING HEPATECTOMY FOR COLORECTAL LIVER METASTASES
Timothy E. Newhook*, Michael J. Overman, Yun Shin Chun, Ching-Wei D. Tzeng, Hop Tran Cao, Yujiro Nishioka, Steven Wei, Scott Kopetz, Jean-Nicolas Vauthey
Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Prognostication is imprecise for patients undergoing hepatectomy for CLM, and ctDNA is a promising biomarker. However, clinical implications of perioperative ctDNA dynamics are not well established. We sought to evaluate the association of perioperative circulating tumor DNA (ctDNA) dynamics on outcomes following hepatectomy for colorectal liver metastases (CLM).
Methods: Patients who underwent curative-intent hepatectomy after preoperative chemotherapy for CLM during 2013-2017 and had paired prehepatectomy/postoperative ctDNA analyses via plasma-only assay were included. Tissue somatic mutational analyses were performed by next-generation sequencing panels on resection specimens. Positivity was determined using a proprietary variant classifier. Primary endpoint was recurrence-free survival (RFS). Median follow-up was 55.0 months.
Results: Forty-eight patients were included. ctDNA was detected before and after surgery (ctDNA+/+) in 14 (29%), before but not after surgery (ctDNA+/-) in 19 (40%), and not at all (ctDNA-/-) in 11 (23%). Three patients were found to have detectable ctDNA postoperatively following a preoperative negative ctDNA test (6.3% ctDNA-/+). Adverse somatic mutations in resected specimens were detected in TP53 (n=26; 54%), RAS (n=23; 48%), SMAD4 (n=5; 10%), FBXW7 (n=3; 6%), and BRAF (n=2; 4%). Bilateral CLM (OR 5.50, 95% CI 1.54-19.6) was associated with postoperative ctDNA detection, but individual adverse somatic mutations and prehepatectomy ctDNA detection were not. Prehepatectomy ctDNA detection alone was not associated with either RFS or OS. However, ctDNA+/+ was associated with worse RFS compared to patients without detectable perioperative ctDNA (ctDNA-/-) or those with ctDNA cleared by curative-intent hepatectomy (ctDNA+/-; median: ctDNA+/+, 6.0 months; ctDNA+/-, not reached; ctDNA-/-, 33.0 months; P=0.001; Fig 1). Compared to ctDNA+/+, ctDNA+/- was associated with improved RFS (hazard ratio [HR] 0.24 [95% CI 0.1-0.58]) and overall survival (HR 0.24 [95% CI 0.08-0.74]). Adverse somatic mutations in resected specimens were not associated with survival. After adjustment for prehepatectomy chemotherapy, synchronous disease, and ?2 CLM, ctDNA+/- and ctDNA-/- were independently associated with improved RFS compared to ctDNA+/+ (ctDNA+/-: HR 0.21, 95% CI 0.08-0.53; ctDNA-/-: HR 0.21, 95% CI 0.08-0.56).
Conclusions: Surgical clearance of ctDNA results is associated with significantly improved survival compared to those with detectable ctDNA following curative-intent hepatectomy for CLM. Perioperative ctDNA dynamics are associated with survival, identify patients with high recurrence risk following hepatectomy, and may be used to guide treatment decisions and surveillance in patients with CLM.



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