KRAS mutational status impacts pathologic response to pre-hepatectomy chemotherapy: a study from the International Genetic Consortium for Liver Metastases. HPB : the official journal of the International Hepato Pancreato Biliary Association Margonis, G. A., Amini, N., Andreatos, N., Sasaki, K., McVey, J., Mirza, M. B., Warner, S., Buettner, S., Barbon, C., Wang, J., Pulvirenti, A., Angelou, A., Kamphues, C., Antoniou, E., Pikoulis, E., Pawlik, T. M., Kaczirek, K., Poultsides, G., Wagner, D., Endo, I., Imai, K., Aucejo, F., Kreis, M. E., Wolfgang, C. L., Weiss, M. J. 2019


BACKGROUND: A major response to pre-hepatectomy chemotherapy has been associated with improved survival in patients who undergo resection of colorectal liver metastases (CRLM). However, the role of tumor biology, as exemplified by overall and codon-specific KRAS mutational status, in predicting response to chemotherapy is not well defined.METHODS: Pathologic response was characterized as minor or major depending on the percentage of remnant viable cells (>50% vs <50%, respectively). Multivariable logistic regression was used to identify factors associated with major response.RESULTS: 319 patients met inclusion criteria. 229 patients had a KRAS wild-type (wtKRAS) tumor and 90 harbored KRAS mutations (mutKRAS). A major pathologic response was more commonly noted in patients with wtKRAS compared to mutKRAS (48.5% vs 33.3%, P=0.01) and wtKRAS status remained independently associated with a major response (P=0.04). On a codon-specific level, major pathologic response occurred less frequently in those with codon 13 mutations (17.7%) compared to those with codon 12 (35.4%), and other KRAS mutations (33.3%). Importantly, codon 13 mutations were independently associated with minor pathologic response (P=0.023).CONCLUSIONS: Patients with wtKRAS tumors appear to have the highest likelihood of experiencing a major response after preoperative chemotherapy. Future studies in "all-comer" cohorts are needed to confirm these findings and further investigate the response of codon 13 mutations.

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