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Adjuvant Chemotherapy with Folfox for Primary Colorectal Cancer is associated with Increased Somatic Gene Mutations and Inferior Survival in Patients Undergoing Hepatectomy for Metachronous Liver Metastases
Jean-Nicolas Vauthey, Andreas Andreou*, Dipen M Maru*, Su Chen*, Eddie K Abdalla*, Steven A Curley, Christopher Garrett*, Michael Overman*, Thomas A Aloia*, Scott Kopetz*
MD Anderson Cancer Center, Houston, TX

OBJECTIVE: We hypothesized that metachronous colorectal liver metastases (CLM) have different biology after failure of oxaliplatin (FOLFOX) compared to 5-fluorouracil (5-FU) or no chemotherapy for adjuvant treatment of stage II/III colorectal cancer (CRC).
METHODS: We identified 371 patients who underwent hepatectomy for metachronous CLM (disease-free interval≥12m, 1993-2010). Mass-spectroscopy genotyping for KRAS, BRAF, NRAS, PIK3CA, CTNNB1, and PDGFRA in liver metastases was performed in a subset of 129 patients.
RESULTS: Adjuvant treatment for primary CRC was 5-FU in 169 patients, FOLFOX in 77 and no chemotherapy in 95. Node-positive primary was comparable between FOLFOX and 5-FU but lower in the no-chemotherapy group (P<0.0001). Median metastasis size was smaller in the adjuvant FOLFOX-group (2.5cm) compared to 5-FU (3.0cm) or no-chemotherapy (3.5cm), (P=0.008) although prehepatectomy chemotherapy utilization, metastases number, and carcinoembryonic antigen were similar. Disease-free survival (DFS) and overall survival (OS) after hepatectomy were worse with adjuvant FOLFOX (Figure; DFS at 3-years: 14% vs. 38%[5-FU] vs. 45%[no-chemo], OS at 3-years: 58% vs. 70%[5-FU] vs. 84%[no-chemo]). In multivariate analysis, adjuvant FOLFOX was associated with worse DFS (P<0.0001) and OS (P<0.0001). Mutation analysis revealed ≥1 mutations in 62% of patients (29/47) after FOLFOX, 39% (16/41) after 5-FU, and 37% (15/41) without chemotherapy (P=0.03).
CONCLUSION: Adjuvant FOLFOX chemotherapy for primary CRC is associated with a high rate of somatic mutations in liver metastases and inferior outcomes after hepatectomy for metachronous CLM.

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